MAIMUUTTUNUT US009901563B2 DIUTUMIA HIVI (12 ) United States Patent ( 10) Patent No. : US 9 ,901 , 563 B2 Brown (45 ) Date of Patent: Feb . 27, 2018

( 54 ) COMPOSITIONS TO IMPROVE THE 33 / 24 (2013 .01 ); A61K 38 / 19 (2013 . 01 ) ; A61K THERAPEUTIC BENEFIT OF 45/ 06 (2013 .01 ); CO7D 303 / 14 ( 2013 .01 ) ; SUBOPTIMALLY ADMINISTERED A61K 31 / 45 ( 2013 .01 ) CHEMICAL COMPOUNDS INCLUDING (58 ) Field of Classification Search SUBSTITUTED HEXITOLS SUCH AS CPC .. . A61K 31/ 047 ; A61K 31 / 045 ; A61K 31/ 165 DIANHYDROGALACTITOL AND USPC ...... 514 / 724 DIACETYLDIANHYDROGALACTITOL See application file for complete search history . (71 ) Applicant : DELMAR PHARMACEUTICALS , INC . , Vancouver (CA ) ( 56 ) References Cited ( 72 ) Inventor: Dennis M . Brown, Menlo Park , CA U . S . PATENT DOCUMENTS (US ) 6 , 180 , 824 B1 1/ 2001 Stamler et al . (73 ) Assignee: DELMAR PHARMACEUTICALS , INC ., Vancouver (CA ) FOREIGN PATENT DOCUMENTS GB 1490649 A 11 / 1977 ( * ) Notice : Subject to any disclaimer, the term of this WO WO 0191741 A2 * 12 /2001 ...... A61K 31/ 70 patent is extended or adjusted under 35 WO 2009053713 A2 4 / 2009 U .S . C . 154 (b ) by 0 days. WO WO 2012024367 A2 * 2 /2012 ...... A61K 31/ 44 (21 ) Appl. No. : 14 /753 , 911 OTHER PUBLICATIONS (22 ) Filed : Jun . 29 , 2015 Chinese Office Action for related Chinese Patent Application No . 201180050169. 2 dated Oct . 27 , 2015 , 9 Pages . (65 ) Prior Publication Data Zhao , “ New Drugs and Clinical Evaluation ” , Tianjin Science and Technology Publisher , Jun . 2013 , 4 Pages . US 2015 / 0297553 A1 Oct . 22, 2015 Xiao et al. , “ The Stability Research of DADAG ” , Journal of Medical Reviews, Dec . 2002, vol. 19 , Chapter 6 , 2 Pages. Yang et al. , “ Antitumor Effect of Diacetyldianhydrogalactitol and Related U . S . Application Data Its Mechanism ” , Chinese Journal of Cancer, 2000 , Issue 12 , pp . 1112 - 1115 . (63 ) Continuation - in -part of application No . 13 /817 , 096 , Sternson et al . , “ Chemical Derivatization as a Strategy to Enhance filed on Mar. 11 , 2013 , now Pat . No. 9 , 066 , 918 . Detectability of Agents Used in Cancer Management, ” Published in Journal of Pharmaceutical & Biomedical Analysis , vol . 6 , ( 1988 ) (51 ) Int. Ci. pp . 657 -668 . A61K 31/ 045 ( 2006 . 01 ) Järvinen et al. , “ Design and Pharmaceutical Applications of A61K 31 /336 ( 2006 . 01 ) Prodrugs” , published in Drug Discovery Handbook ( S .C . Gad , ed . , A61K 33/ 24 ( 2006 . 01 ) Wiley - Interscience , Hoboken , NJ, 2005 ) , ch . 17 , pp . 733 -796 . A61K 45 / 06 ( 2006 .01 ) Rowe et al . , “ Handbook of Pharmaceutical Excipients ” , published A61K 31/ 4741 ( 2006 . 01 ) in Pharmaceutical Press & American Pharmacists Association , 5th A61K 31 /353 ( 2006 .01 ) edition , 2006 , London , 3 pages. A61K 31 /513 ( 2006 . 01 ) Plenderleith , “ Treating the Treatment : Toxicity of Cancer Therapy ” , CO7D 303/ 14 ( 2006 . 01 ) published in Can Fam Physician vol. 36 : 1827 - 1830 , Oct. 1990 , pp . A61K 31 / 7088 ( 2006 .01 ) 1827 - 1830 , 4 pages. A61K 38 / 19 ( 2006 . 01 ) (Continued ) A61K 31/ 12 ( 2006 .01 ) A61K 31 / 155 ( 2006 .01 ) A61K 31/ 216 ( 2006 .01 ) Primary Examiner - Kevin E Weddington A61K 31/ 352 ( 2006 . 01 ) ( 74 ) Attorney, Agent, or Firm — Ditthavong & Steiner, A61K 314745 ( 2006 . 01 ) P . C . A61K 31/ 475 (2006 .01 ) A61K 31/ 713 ( 2006 . 01 ) A61K 9 /00 ( 2006 . 01 ) (57 ) ABSTRACT A61K 31 / 45 ( 2006 .01 ) The present invention describes methods and compositions (52 ) U . S . CI. for improving the therapeutic efficacy of therapeutic agents CPC ...... A61K 31336 ( 2013 .01 ) ; A61K 9 / 0019 previously limited by suboptimal therapeutic performance ( 2013 .01 ) ; A61K 31 / 12 ( 2013 .01 ) ; A61K by either improving efficacy as monotherapy or reducing 31 / 155 (2013 .01 ) ; A61K 31/ 216 ( 2013 . 01 ) ; side effects . Such methods and compositions are particularly A61K 31 /352 ( 2013 .01 ) ; A61K 31 /353 applicable to substituted hexitols such as dianhydrogalacti ( 2013 .01 ); A61K 31/ 475 ( 2013 .01 ) ; A61K tol and diacetyldianhydrogalactitol . 31/ 4741 (2013 .01 ) ; A61K 31 /4745 ( 2013 . 01 ) ; A61K 31 /513 ( 2013 .01 ) ; A61K 31 / 7088 (2013 .01 ) ; A61K 31/ 713 (2013 .01 ) ; A61K 10 Claims, No Drawings US 9, 901 ,563 B2 Page 2

( 56 ) References Cited OTHER PUBLICATIONS Han et al. , “ Targeted Prodrug Design to Optimize Drug Delivery” , published in AAPS PharmSciTech 2 (Article 6 ), Mar. 21, 2000 , pp . 1 - 11 . Brittain , “ Developing an Appropriate Salt Form for an Active Pharmaceutical Ingredient” , published in American Pharmaceutical Review , Dec . 1 , 2009 , retrieved on Dec . 19 , 2017 from http : / /www . americanpharmaceuticalreview . com / Featured - Articles /117788 - De veloping - an - Appropriate -Salt -Form - for- an - Active - Pharmaceutical Ingredient/ , 5 pages . * cited by examiner US 9 , 901, 563 B2 COMPOSITIONS TO IMPROVE THE including substituted hexitols such as dianhydrogalactitol THERAPEUTIC BENEFIT OF and diacetyldianhydrogalactitol, as well as other classes of SUBOPTIMALLY ADMINISTERED chemical agents . CHEMICAL COMPOUNDS INCLUDING SUBSTITUTED HEXITOLS SUCH AS BACKGROUND OF THE INVENTION DIANHYDROGALACTITOL AND DIACETYLDIANHYDROGALACTITOL The search for and identification of cures for many life - threatening diseases that plague humans still remains an CROSS - REFERENCES TO RELATED empirical and sometimes serendipitous process . While many 10 advances have been made from basic scientific research to APPLICATIONS improvements in practical patient management, there still remains tremendous frustration in the rational and successful This application is a continuation - in - part application and discovery of useful therapies particularly for life - threatening claims the benefit of U .S . patent application Ser. No. 13 /817 , diseases such as cancer , inflammatory conditions, infection , 096 by Dennis M . Brown , Ph . D . , filed Feb . 14 , 2013, and 15 and other conditions . entitled “ Compositions and Methods to Improve the Thera Since the “ War on Cancer” began in the early 1970 ' s by peutic Benefit of Suboptimally Administered Chemical the United States National Cancer Institute (NCI ) of the Compounds Including Substituted Hexitols Such as Dian - National Institutes of Health (NIH ) , a wide variety of hydrogalactitol and Diacetyldianhydrogalactitol, " which in strategies and programs have been created and implemented turn was a national stage and claimed the benefit of PCT 20 to prevent, diagnose , treat and cure cancer. One of the oldest Patent Application Ser .No . PCT/ US2011 /048031 by Dennis and arguably most successful programs has been the syn M . Brown , Ph .D ., filed Aug . 7 , 2011 , which in turn claimed thesis and screening of small chemical entities ( < 1500 MW ) the benefit of: ( 1) U . S . Provisional Application Ser. No. for biological activity against cancer . This program was 61/ 401 , 705 by Dennis M . Brown , Ph . D . , filed Aug . 18 , 2010 , organized to improve and streamline the progression of and entitled “ Compositions and Methods to Improve the 25 events from chemical synthesis and biological screening to Therapeutic Benefit of Suboptimally Administered Chemi- preclinical studies for the logical progression into human cal Compounds Including Substituted Hexitols Such as clinical trials with the hope of finding cures for the many Dianhydrogalactitol for the Treatment of Benign and Neo types of life - threatening malignant tumors . The synthesis plastic Hyperproliferative Disease Conditions” ; ( 2 ) U . S . and screening of hundreds of thousands of chemical com is M 30 pounds from academic and industrial sources , in addition to Provisional Application Ser. No. 61/ 401 , 706 by Dennis M . 30 the screening of natural products and extracts from prokary Brown, Ph . D ., filed Aug . 18 , 2010 , and entitled “ Composi otes, invertebrate animals , plant collections, and other tions and Methods to Improve the Therapeutic Benefit of sources from all over the world has been and continues to be Suboptimally Administered Chemical Compounds Includ a major approach for the identification of novel lead struc ing Substituted Hexitols Such as Diacetyldianhydrogalacti- 35 tures as potential new and useful medicines . This is in tol for the Treatment of Benign and Neoplastic Hyperpro addition to other programs including biotherapeutics liferative Disease Conditions” ; ( 3 ) U . S . Provisional designed to stimulate the human immune system with vac Application Ser . No. 61/ 401 , 707 by Dennis M . Brown , cines , therapeutic antibodies , cytokines, lymphokines, Ph . D . , filed Aug . 18 , 2010 , and entitled “ Compositions and inhibitors of tumor blood vessel development (angiogenesis ) Methods to Improve the Therapeutic Benefit of Subopti - 40 or gene and antisense therapies to alter the genetic make - up mally Administered Chemical Compounds Including Sub - of cancer cells , and other biological response modifiers . stituted Hexitols Such as Diacetyldianhydrogalactitol for the The work supported by the NCI, other governmental Condition of Benign and Neoplastic Hyperproliferative agencies both domestic and foreign in academic or industrial Conditions” ; (4 ) U .S . Provisional Application Ser . No . research and development laboratories has resulted in an 61 /401 , 709 by Dennis M . Brown, Ph . D ., filed Aug . 18 , 2010 , 45 extraordinary body of biological, chemical and clinical and entitled " Compositions and Methods to Improve the information . In addition , large chemical libraries have been Therapeutic Benefit of Suboptimally Administered Chemi created , as well as highly characterized in vitro and in vivo cal Compounds Including Substituted Hexitols Such as bibiological screening systems that have been successfully Diacetyldianhydrogalactitol for the Condition of Benign and used . However , from the tens of billions of dollars spent Neoplastic Hyperproliferative Conditions " . and ( 5 ) US, 50 over the past thirty years supporting these programs both preclinically and clinically , only a small number of com Provisional Application Ser. No. 61/ 401 ,712 by Dennis M . pounds have been identified or discovered that have resulted Brown, Ph . D . , filed Aug. 18 , 2010 , and entitled " Composi in the successful development of useful therapeutic prod tions and Methods to Improve the Therapeutic Benefit of ucts . Nevertheless , the biological systems both in vitro and Suboptimally Administered Chemical Compounds Includ 55 in vivo and the " decision trees ” used to warrant further ing Substituted Hexitols Such as Diacetyldianhydrogalacti animal studies leading to clinical studies have been vali tol for the Condition of Benign and Neoplastic Hyperpro dated . These programs, biological models , clinical trial liferative Conditions. " All the above -mentioned applications protocols , and other information developed by this work are incorporated herein in their entirety by this reference . remain critical for the discovery and development of any 60 new therapeutic agent. FIELD OF THE INVENTION Unfortunately, many of the compounds that have success fully met the preclinical testing and federal regulatory The present invention relates to the general field of requirements for clinical evaluation were either unsuccess hyperproliferative diseases including oncology with a focus ful or disappointing in human clinical trials . Many com on novel methods and compositions for the improved utility 65 pounds were found to have untoward or idiosyncratic side of chemical agents , compounds, and dosage forms previ- effects that were discovered during human clinical Phase I ously limited by suboptimal human therapeutic performance dose- escalation studies used to determine the maximum US 9 ,901 , 563 B2 tolerated dose (MTD ) and side - effect profile . In some cases , SUMMARY OF THE INVENTION these toxicities or the magnitude of their toxicity were not identified or predicted in preclinical toxicology studies. In This invention meets the needs described above for com other cases , chemical agents where in vitro and in vivo positions and methods that improve the therapeutic benefit studies suggested a potentially unique activity against a 5 of suboptimally administered chemical compounds and particular tumor type , molecular target or biological path therapeutic compositions. Specifically , this invention relates way were not successful in human Phase II clinical trials to novel compositions and methods to improve the utility of where specific examination of particular cancer indications / chemical agents with suboptimal performance in patients types were evaluated in government sanctioned ( e . g ., U . S . suffering with cancer. The invention describes novel FDA ), IRB approved clinical trials . In addition , there are 10 improvements, pharmaceutical ingredients, dosage forms, those cases where potential new agents were evaluated in excipients, solvents , diluents , drug delivery systems, preser randomized Phase III clinical trials where a significant vatives, more accurate drug administrations, improved dose clinical benefit could not be demonstrated ; such cases have determination and schedules , toxicity monitoring and ame also been the cause of great frustration and disappointment. liorization , techniques or agents to circumvent or reduce Finally , a number of compounds have reached commercial - 15 toxicity , techniques and tools to identify / predict those ization but their ultimate clinical utility has been limited by patients who might have a better outcome with a therapeutic poor efficacy as monotherapy ( < 25 % response rates ) and agent by the use of phenotype or genotype determination untoward dose - limiting side -effects (Grade III and IV ) ( e . g . , through the use of diagnostic kits or pharmacokinetic or myelosuppression , neurotoxicity , cardiotoxicity , gastrointes - metabolism monitoring approaches . The invention also tinal toxicities, or other significant side effects ) . 20 relates to the use of drug delivery systems, novel prodrugs , In many cases , after the great time and expense of polymer conjugates , novel routes of administration , other developing and moving an investigational compound into agents to potentiate the activity of the compounds or inhibit human clinical trials and where clinical failure has occurred , the repair of suboptimal cellular effects or sublethal damage the tendency has been to return to the laboratory to create a or to " push ” the cell into more destructive cellular phases better analog , look for agents with different structures but 25 such as apoptosis . In some case , the use of these suboptimal potentially related mechanisms of action , or try other modi- therapeutics in conjunction with radiation or other conven fications of the drug . In some cases , efforts have been made tional chemotherapeutic agents or biotherapeutic agents to try additional Phase I or II clinical trials in an attempt to such as antibodies , vaccines , cytokines, lymphokines , gene make some improvement with the side - effect profile or and antisense therapies, or other chemotherapeutic or bio therapeutic effect in selected patients or cancer indications . 30 therapeutic agents , would provide novel approaches and In many of those cases, the results did not realize a signifi - significant improvement. cant enough improvement to warrant further clinical devel In the inventive compositions and methods, the term opment toward product registration . Even for commercial - suboptimal therapy includes agents where Phase I toxicity ized products , their ultimate use is still limited by precluded further human clinical evaluation . It also includes suboptimal performance . 35 those agents from Phase II trials where limited ( < 25 % With so few therapeutics approved for cancer patients and response rates) or no significant tumor responses were the realization that cancer is a collection of diseases with a identified . Also , suboptimal therapy includes those agents , multitude of etiologies and that a patient ' s response and the subject of Phase III clinical trials the outcome of which survival from therapeutic intervention is complex with many was either medically or statistically not significant to war factors playing a role in the success or failure of treatment 40 rant regulatory submission or approval by government agen including disease indication , stage of invasion and meta - cies for commercialization or commercialized agents whose static spread , patient gender, age , health conditions , previous clinical performance ( i . e . response rates ) as a monotherapy therapies or other illnesses, genetic markers that can either are less than 25 % , or whose side - effects are severe enough promote or retard therapeutic efficacy , and other factors , the to limit wide utility . Agents with suboptimal clinical activity opportunity for cures in the near term remains elusive . 45 include but are not limited to the following : substituted Moreover, the incidence of cancer continues to rise with an hexitols such as dianhydrogalactitol and diacetyldianhy approximate 4 % increase predicted for 2003 in the United drogalactitol, Avastin (bevacizumab ) , Rituxan (rituximab ) , States by the American Cancer Society such that over 1 . 3 Nexavar ( sorafenib ) , dasatinib , nilotinib , Provenge ( sipuleu million new cancer cases are estimated . In addition , with cel- T ) , Tarceva ( erlotinib ), and Iressa (gefitinib ) . More spe advances in diagnosis such as mammography for breast 50 cifically , the inventive methods and compositions also focus cancer and PSA tests for prostate cancer , more patients are on improvements for substituted hexitols including dianhy being diagnosed at a younger age . For difficult to treat drogalactitol and diacetyldianhydrogalactitol. cancers, a patient' s treatment options are often exhausted One aspect of the invention is a method to improve the quickly resulting in a desperate need for additional treatment efficacy and / or reduce the side effects of suboptimally regimens . Even for the most limited of patient populations, 55 administered drug therapy comprising the steps of : any additional treatment opportunities would be of consid - ( i ) identifying at least one factor or parameter associated erable value . This invention focuses on inventive composi - with the efficacy and /or occurrence of side effects of the drug tions and methods for improving the therapeutic benefit of therapy ; and suboptimally administered chemical compounds including ( ii ) modifying the factor or parameter to improve the substituted hexitols such as dianhydrogalactitol. 60 efficacy and / or reduce the side effects of the drug therapy . Relevant literature includes Foye, W . O ., “ Cancer Che - In this method , the factor or parameter can be selected motherapeutic Agents , ” American Chemical Society , 1995 , from the group consisting of: and Dorr , R . T ., and Von Hoff , D . D . , “ Cancer Chemotherapy ( i ) dose modification ; Handbook ,” Appleton and Lange , 1994 . ( ii ) route of administration ; Therefore , there is a need for compositions and methods 65 ( iii ) schedule of administration ; that improve the therapeutic benefit of suboptimally admin - ( iv ) indications for use; istered chemical compounds and therapeutic compositions. ( v ) selection of disease stage ; US 9 , 901 ,563 B2 ( vi) other indications; (h ) administration of single and multiple doses escalating (vii ) patient selection ; from 5 mg/ m² / day via bolus; ( viii ) patient/ disease phenotype; ( i) oral dosages of below 30 mg/ m² ; and ( ix ) patient / disease genotype ; (j ) oral dosages of above 130 mg/ m² . ( x ) pre / post -treatment preparation 5 When the improvement is made by the route of admin ( xi ) toxicity management ; istration , the route of administration can be a route of (xii ) pharmacokinetic /pharmacodynamic monitoring ; administration selected from the group consisting of: ( a ) topical administration ; ( xiii ) drug combinations ; ( b ) intravesicular administration for bladder cancer ; (xiv ) chemosensitization ; 10 ( c ) oral administration ; ( xv ) chemopotentiation ; ( d ) slow release oral delivery ; ( xvi) post - treatment patientmanagement ; ( e ) intrathecal administration ; (xvii ) alternative medicine/ therapeutic support ; ( f ) intraarterial administration ; (xviii ) bulk drug product improvements ; ( g ) continuous infusion ; and ( xix ) diluent systems; 15 ( h ) intermittent infusion . ( xx ) solvent systems; When the improvement is made by the schedule of (xxi ) excipients ; administration , the schedule of administration can be a (xxii ) dosage forms; schedule of administration selected from the group consist ( xxiii ) dosage kits and packaging ; ing of: ( xxiv ) drug delivery systems; 20 (a ) daily administration ; (xxv ) drug conjugate forms; (b ) weekly administration ; ( xxvi) compound analogs ; ( c ) weekly administration for three weeks; (xxvii ) prodrugs ; ( d ) biweekly administration ; ( xxvii ) multiple drug systems ; ( e ) biweekly administration for three weeks with a 1 - 2 (xxviii ) biotherapeutic enhancement; 25 week rest period ; (xxix ) biotherapeutic resistance modulation ; ( f ) intermittent boost dose administration , and (xxx ) radiation therapy enhancement; ( g ) daily administration for one week for multiple weeks . ( xxxi) novel mechanisms of action ; and When the improvement is made by the indication for use , the indication for use can be an indication for use selected ( xxxii ) selective target cell population therapeutics . per 30 from the group consisting of: The drug therapy can be administered to treat a hyper - 30 ( a ) use for treatment of leukemias ; proliferative disease , such as cancer. ( b ) use for treatment of myelodysplastic syndrome; Typically , the suboptimally administered drug therapy ( c ) use for treatment of angiogenic diseases; comprises administration of a substituted hexitol. In one ( d ) use for treatment of benign prostatic hyperplasia ; alternative , preferably , the substituted hexitol is selected 35 ( e ) use for treatment of psoriasis ; from the group consisting of dianhydrogalactitol and a ( f) use for treatment of gout; derivative thereof. In this alternative , more preferably , the ( g ) use for treatment of transplantation rejections; substituted hexitol is dianhydrogalactitol. In another alter ( h ) use for prevention of restenosis in cardiovascular native , preferably , the substituted hexitol is selected from the disease ; group consisting of diacetyldianhydrogalactitol and a 40 (i ) use for treatment of mycosis fungoides ; derivative thereof. In this alternative , more preferably , the ( 1 ) use in bone marrow transplantation ; substituted hexitol is diacetyldianhydrogalactitol. ( k ) use as an anti - infective agent; In yet another alternative , the suboptimally administered ( 1) use for treatment of AIDS ; and drug therapy comprises administration of a therapeutic agent ( m ) use for treatment of lymphoma. selected from the group consisting of Avastin (bevaci - 45 When the improvement is made by selection of disease zumab ), Rituxan ( rituximab ) , Nexavar (sorafenib ) , dasat- stage , the selection of disease stage can be selected from the inib , nilotinib , Provenge ( sipuleucel- T ) , Tarceva ( erlotinib ) , group consisting of: and Iressa (gefitinib ) . ( a ) use for the treatment of localized polyp stage colon The following alternatives describe the use of dianhy cancer ; some cases 50 (b ) use for leukoplakia in the oral cavity ; drogalactitol, diacetyldianhydrogalactitol, or, in some cases 30 ( c ) use for angiogenesis inhibition to prevent or limit as set forth below , a derivative of either dianhydrogalactitol metastatic spread of a malignancy ; and or diacetyldianhydrogalactitol, together with a modification ( d ) use for treatment of HIV with a therapy selected from of a factor or parameter as described above to improve the the group consisting of azidothymidine (AZT ), dide efficacy and /or reduce the side effects of the drug therapy . 55 oxyadenosine (DDI ) , and reverse transcriptase inhibi When the improvement is made by dose modification , the tors . dose modification can be a modification selected from the When the improvement is made by other indications, the group consisting of: other indications can be selected from the group consisting ( a ) continuous i . v . infusion for hours to days; of: ( b ) biweekly administration ; 60 (a ) use as an anti- infective agent; ( c ) doses greater than 5 mg/m² / day ; ( b ) use as an antiviral agent; ( d ) progressive escalation of dosing from 1 mg/ m² /day ( c ) use as an antibacterial agent ; based on patient tolerance ; ( d ) use as an agent to treat pleural effusion ; ( e ) use of caffeine to modulate metabolism ; ( e ) use as an antifungal agent ; ( f ) use of isonazid to modulate metabolism ; 65 ( f ) use as an anti- parasitic agent ; ( g ) selected and intermittent boosting of dosage admin ( g ) use as an agent to treat eczema; istration ; (h ) use as an agent to treat herpes zoster (shingles ) ; US 9 , 901 ,563 B2 ( i ) use as an agent to treat condylomata ; ( e ) the use of a sustained -release form of nicotinamide ; ( 1 ) use as an agent to treat HPV ; and ( f ) the use of an inhibitor of poly - ADP ribose polymerase ; ( k ) use as an agent to treat HSV . ( g ) the use of caffeine ; When the improvement is made by patient selection , the ( h ) the use of leucovorin rescue ; patient selection can be carried out by a criterion selected 5 ( i) the use of sustained -release allopurinol; from the group consisting of: ( i) the non -oral use of allopurinol ; ( a ) selecting patients with a disease condition character ( k ) the use of bone marrow transplants ; ized by a high level of a metabolic enzyme selected ( 1) the use of a blood cell stimulant ; from the group consisting of histone deacetylase and ( m ) the use of blood or platelet infusions; ornithine decarboxylase ; 10 ( n ) the administration of an agent selected from the group ( b ) selecting patients with a low or high susceptibility to consisting of filgrastim (Neupogen® ) , G -CSF , and a condition selected from the group consisting of GM - CSF ; thrombocytopenia and neutropenia ; ( o ) the application of a pain management technique ; ( c ) selecting patients intolerant of GI toxicities ; and ( p ) the administration of an anti - inflammatory agent; ( d ) selecting patients characterized by over - or under - 15 ( 9 ) the administration of fluids ; expression of a gene selected from the group consisting ( r ) the administration of a corticosteroid ; of c - Jun , a GPCR , a signal transduction protein , VEGF, ( s ) the administration of an insulin control medication ; a prostate - specific gene , and a protein kinase . ( t ) the administration of an antipyretic ; Where the improvement is made by analysis of patient or ( u ) the administration of an anti -nausea treatment; disease phenotype, the analysis of patient or disease pheno - 20 ( v ) the administration of an anti - diarrheal treatment; type can be carried out by a method selected from the group ( w ) the administration of N -acetylcysteine ; and consisting of: ( x ) the administration of an antihistamine . (i ) use of a diagnostic tool, a diagnostic technique , a When the improvement is made by pharmacokinetic / diagnostic kit, or a diagnostic assay to confirm a pharmacodynamic monitoring, the pharmacokinetic / phar patient ' s particular phenotype ; 25 macodynamic monitoring can be performed by a method ( ii ) use of a method for measurement of a marker selected selected from the group consisting of: from the group consisting of histone deacetylase , orni- ( a ) multiple determinations of blood plasma levels; and thine decarboxylase, VEGF, a protein that is a gene (b ) multiple determinations of at least one metabolite in product of a prostate specific gene , a protein that is a blood or urine . gene product of jun , a protein kinase , quantity or 30 When the improvement is made by drug combination , the activity of MGMT, methylation of MGMT promoter, drug combination can be selected from the group consisting and mutant isocitrate dehydrogenase ( IDH ) ; of: ( iii ) surrogate compound dosing ; and ( a ) use with topoisomerase inhibitors ; ( iv ) low dose pre - testing for enzymatic status. ( b ) use with fraudulent nucleosides ; When the improvement is made by analysis of patient or 35 ( c ) use with fraudulent nucleotides; disease genotype, the analysis of patient or disease genotype ( d ) use with thymidylate synthetase inhibitors ; can be carried out by a method selected from the group ( e ) use with signal transduction inhibitors ; consisting of: ( f ) use with cisplatin or platinum analogs ; ( a ) use of a diagnostic tool, a diagnostic technique, a ( g ) use with alkylating agents ; diagnostic kit , or a diagnostic assay to confirm a 40 ( h ) use with anti - tubulin agents ; patient' s particular genotype ; ( i ) use with antimetabolites ; (b ) use of a gene chip ; (i ) use with berberine ; ( c ) use of gene expression analysis ; ( k ) use with apigenin ; ( d ) use of single nucleotide polymorphism (SNP ) analy ( 1) use with amonafide ; sis ; and 45 ( m ) use with vinca alkaloids; ( e ) measurement of the level of a metabolite or a meta (n ) use with 5 - fluorouracil ; bolic enzyme. ( o ) use with curcumin ; When the improvement is made by pre /post treatment ( p ) use with NF - kB inhibitors ; preparation , the pre/ post treatment preparation can be (q ) use with rosmarinic acid ; selected from the group consisting of: 50 ( r ) use with mitoguazone ; ( a ) the use of colchicine or an analog thereof; ( s ) use with tetrandrine ; ( b ) the use of a uricosuric ; ( t) use with an inhibitor of mutant isocitrate dehydroge ( c ) the use of uricase ; nase ( IDH ) ; (d ) the non -oral use of nicotinamide ; ( u ) use with a MGMT inhibitor ; and ( e ) the use of a sustained -release form of nicotinamide ; 55 ( v ) use with an agent that inhibits NF -KB - enhanced ( f) the use of an inhibitor of poly -ADP ribose polymerase; expression of MGMT. ( g ) the use of caffeine; When the improvement is made by chemosensitization , ( h ) the use of leucovorin rescue ; the chemosensitization can comprise the use of dianhy (i ) infection control; and drogalactitol as a chemosensitizer in combination with an (j ) the use of an anti -hypertensive agent . 60 agent selected from the group consisting of : When the improvement is made by toxicity management , (a ) topoisomerase inhibitors ; the toxicity management can be selected from the group ( b ) fraudulent nucleosides ; consisting of: ( c ) fraudulent nucleotides ; ( a ) the use of colchicine or an analog thereof; ( d ) thymidylate synthetase inhibitors ; ( b ) the use of a uricosuric ; 65 (e ) signal transduction inhibitors ; ( c ) the use of uricase ; ( f ) cisplatin or platinum analogs ; ( d ) the non -oral use of nicotinamide; ( g ) alkylating agents ; US 9 , 901 ,563 B2 10 ( h ) anti - tubulin agents ; ( d ) DMF ; ( i) antimetabolites; ( e ) ethanol; (j ) berberine ; ( f ) benzyl alcohol; ( k ) apigenin ; ( g ) dextrose - containing water for injection ; (1 ) amonafide; (h ) Cremophor; ( m ) vinca alkaloids; ( i ) cyclodextrin ; and ( n ) 5 - fluorouracil; (i ) PEG . (0 ) curcumin ; When the improvement is made by a solvent system , the ( p ) NF - KB inhibitors ; solvent system can be selected from the group consisting of: ( q ) rosmarinic acid ; 10 ( r ) mitoguazone ; and ( a ) an emulsion ; ( s ) tetrandrine . ( b ) dimethylsulfoxide ( DMSO ) ; When the improvement is made by chemopotentiation , ( c ) N - methylformamide (NMF ) the chemopotentiation can comprise the use of dianhydroga ( d ) DMF; lactitol as a chemopotentiator in combination with an agent 15 ( e ) ethanol; selected from the group consisting of: ( f) benzyl alcohol; ( a ) topoisomerase inhibitors ; ( g ) dextrose - containing water for injection ; ( b ) fraudulent nucleosides ; ( h ) Cremophor ; ( c ) fraudulent nucleotides ; ( i) cyclodextrin ; and ( d ) thymidylate synthetase inhibitors ; 20 (j ) PEG . (e ) signal transduction inhibitors ; When the improvement is made by use of an excipient, ( f ) cisplatin or platinum analogs ; the excipient can be selected from the group consisting of: ( g ) alkylating agents ; ( a ) mannitol; ( h ) anti -tubulin agents ; ( b ) albumin ; ( i ) antimetabolites ; 25 ( C ) EDTA ; ( i) berberine ; ( d ) sodium bisulfite ; ( k ) apigenin ; ( e ) benzyl alcohol; ( 1) amonafide ; ( f ) a carbonate buffer, and ( m ) vinca alkaloids; ( g ) a phosphate buffer . ( n ) 5 - fluorouracil; 30 ( o ) curcumin ; When the improvement is made by use of a dosage form , ( p ) NF -kB inhibitors; the dosage form can be selected from the group consisting ( q ) rosmarinic acid ; of: ( r) mitoguazone; and ( a ) tablets ; (s ) tetrandrine . 35 ( b ) capsules; When the improvement is made by post - treatment man ( c ) topical gels ; agement, the post- treatment management can be selected ( d ) topical creams; from the group consisting of: ( e ) patches; ( a ) a therapy associated with pain management; ( f ) suppositories ; and ( b ) administration of an anti -emetic ; 40 ( g ) lyophilized dosage fills . ( c ) an anti - nausea therapy ; When the improvement is made by use of dosage kits and ( d ) administration of an anti - inflammatory agent; packaging , the dosage kits and packaging can be selected ( e ) administration of an anti -pyretic agent; and from the group consisting of the use of amber vials to protect ( f ) administration of an immune stimulant. from light and the use of stoppers with specialized coatings When the improvement is made by alternative medicine / 45 to improve shelf - life stability . therapeutic support , the alternative medicine/ therapeutic When the improvement is made by use of a drug delivery support can be selected from the group consisting of: system , the drug delivery system can be selected from the ( a ) hypnosis ; group consisting of: ( b ) acupuncture; ( a ) nanocrystals ; ( c ) meditation ; 50 (b ) bioerodible polymers ; ( d ) a herbal medication created either synthetically or (c ) liposomes; through extraction ; and ( d ) slow release injectable gels ; and ( e ) applied kinesiology . ( e ) microspheres . When the improvement is made by a bulk drug product When the improvement is made by use of a drug conju improvement, the bulk drug product improvement can be 55 gate form , the drug conjugate form can be selected from the selected from the group consisting of: group consisting of: ( a ) salt formation ; ( a ) a polymer system ; ( b ) preparation as a homogeneous crystal structure ; ( b ) polylactides; ( c ) preparation as a pure isomer ; ( c) polyglycolides; ( d ) increased purity ; 60 ( d ) amino acids ; ( e ) preparation with lower residual solvent content; and ( e ) peptides ; and ( f) preparation with lower residual heavy metal content. ( f ) multivalent linkers . When the improvement is made by use of a diluent, the When the improvement is made by use of a compound diluent can be selected from the group consisting of : analog , the compound analog can be selected from the group (a ) an emulsion ; 65 consisting of: ( b ) dimethylsulfoxide (DMSO ) ; ( a ) alteration of side chains to increase or decrease lipo ( c ) N -methylformamide (NMF ) philicity ; US 9 ,901 , 563 B2 Jy 12 ( b ) addition of an additional chemical functionality to ( a ) inhibitors of poly - ADP ribose polymerase ; alter a property selected from the group consisting of (b ) agents that affect vasculature or vasodilation ; reactivity , electron affinity , and binding capacity ; and ( c ) oncogenic targeted agents ; ( d ) signal transduction inhibitors; ( c ) alteration of salt form . ( e ) EGFR inhibition ; When the improvement is made by use of a prodrug 5 ( f) protein kinase C inhibition ; system , the prodrug can be selected from the group consist ( g ) phospholipase C downregulation ; ing of : ( h ) Jun downregulation ; (a ) the use of enzyme sensitive esters ; ( i ) histone genes ; ( b ) the use of dimers ; ( 1) VEGF ; ( c ) the use of Schiff bases; 10 ( k ) ornithine decarboxylase ; ( d ) the use of pyridoxal complexes; and ( 1) ubiquitin C ; ( e ) the use of caffeine complexes . ( m ) jun D ; When the improvement is made by use of a multiple drug ( n ) v - jun ; ( 0 ) GPCRs; system , the multiple drug system can employ a mechanism 15 (p ) protein kinase A ; selected from the group consisting of : ( q ) protein kinases other than protein kinase A ; ( a ) use of multi- drug resistance inhibitors ; (r ) prostate specific genes ; ( b ) use of specific drug resistance inhibitors ; ( s ) telomerase ; and ( c ) use of specific inhibitors of selective enzymes ; ( t ) histone deacetylase . ( d ) use of signal transduction inhibitors ; 20 When the improvement is made by use of selective target ( e ) use of repair inhibition ; and cell population therapeutics , the use of selective target cell ( f ) use of topoisomerase inhibitors with non - overlapping population therapeutics can be a use selected from the group side effects . consisting of: When the improvement is made by use of biotherapeutic ( a ) use against radiation sensitive cells ; enhancement , the biotherapeutic enhancement can be per - 25 ( b ) use against radiation resistant cells ; formed by use in combination as sensitizers/ potentiators (c ) use against energy depleted cells ; and with a therapeutic agent or technique selected from the ( d ) use against endothelial cells . group consisting of: Another aspect of the present invention is a composition ( a ) cytokines ; to improve the efficacy and /or reduce the side effects of (b ) lymphokines ; 30 suboptimally administered drug therapy comprising an alter ( c ) therapeutic antibodies ; native selected from the group consisting of: ( d ) antisense therapies ; (i ) a therapeutically effective quantity of a modified ( e ) gene therapies; therapeutic agent or a derivative, analog , or prodrug of ( f ) ribozymes ; and a therapeutic agent or modified therapeutic agent, ( g ) RNA interference . 35 wherein the modified therapeutic agent or the deriva When the improvement is made by use of biotherapeutic tive , analog or prodrug of the therapeutic agent or resistance modulation , the biotherapeutic resistance modu modified therapeutic agent possesses increased thera lation can comprise use against tumors resistant to a thera peutic efficacy or reduced side effects as compared with peutic agent or technique selected from the group consisting an unmodified therapeutic agent; of: 40 ( ii ) a composition comprising : (a ) biological response modifiers; ( a ) a therapeutically effective quantity of a therapeutic ( b ) cytokines ; agent, a modified therapeutic agent or a derivative , ( c ) lymphokines ; analog , or prodrug of a therapeutic agent or modified ( d ) therapeutic antibodies; therapeutic agent; and ( e ) antisense therapies ; 4545 ( b ) at least one additional therapeutic agent, therapeutic ( f ) gene therapies ; agent subject to chemosensitization , therapeutic ( g ) ribozymes ; and agent subject to chemopotentiation , diluent, excipi ( h ) RNA interference . ent, solvent system , or drug delivery system , wherein When the improvement is made by use of radiation the composition possesses increased therapeutic effi therapy enhancement, the radiation therapy enhancement 50 cacy or reduced side effects as compared with an can be performed by use of an agent or technique selected unmodified therapeutic agent ; from the group consisting of: ( iii ) a therapeutically effective quantity of a therapeutic ( a ) hypoxic cell sensitizers ; agent , a modified therapeutic agent, or a derivative , ( b ) radiation sensitizers / protectors ; analog, or prodrug of a therapeutic agent or modified ( c ) photosensitizers ; 55 therapeutic agent that is incorporated into a dosage ( d ) radiation repair inhibitors ; form , wherein the therapeutic agent, themodified thera ( e ) thiol depleters ; peutic agent, or the derivative , analog , or prodrug of a ( f ) vaso - targeted agents ; therapeutic agent or modified therapeutic agent incor ( g ) DNA repair inhibitors ; porated into the dosage form possesses increased thera ( h ) radioactive seeds; 60 peutic efficacy or reduced side effects as compared with (i ) radionuclides ; an unmodified therapeutic agent; (i ) radiolabeled antibodies ; and ( iv ) a therapeutically effective quantity of a therapeutic ( k ) brachytherapy. agent, a modified therapeutic agent, or a derivative, When the improvement is made by use of novel mecha analog , or prodrug of a therapeutic agent or modified nisms of action , the novel mechanism of action can be a 65 therapeutic agent that is incorporated into a dosage kit therapeutic interaction with a target or mechanism selected and packaging, wherein the therapeutic agent, the from the group consisting of: modified therapeutic agent, or the derivative , analog , or US 9 ,901 , 563 B2 13 14 prodrug of a therapeutic agent or modified therapeutic (1 ) amonafide; agent incorporated into the dosage kit and packaging ( m ) vinca alkaloids ; possesses increased therapeutic efficacy or reduced side ( n ) 5 - fluorouracil ; effects as compared with an unmodified therapeutic ( o ) curcumin ; agent; and ( v ) a therapeutically effective quantity of a therapeutic ( p ) NF- kB inhibitors ; agent, a modified therapeutic agent, or a derivative, ( q ) rosmarinic acid ; analog, or prodrug of a therapeutic agent or modified ( r ) mitoguazone; therapeutic agent that is subjected to a bulk drug ( s ) tetrandrine ; product improvement, wherein the therapeutic agent, 10 (t ) an inhibitor of mutant isocitrate dehydrogenase the modified therapeutic agent, or the derivative , ana ( IDH ) ; log, or prodrug of a therapeutic agent or modified ( u ) a MGMT inhibitor; and therapeutic agent subject to the bulk drug product ( v ) an agent that inhibits NF -KB - enhanced expression improvement possesses increased therapeutic efficacy of MGMT. or reduced side effects as compared with an unmodified 15 In another alternative , the composition can comprise : therapeutic agent. ( i) dianhydrogalactitol; and Typically , the composition possesses increased efficacy or ( ii ) a therapeutic agent subject to chemosensitization reduced side effects for cancer therapy . Typically , the selected from the group consisting of : unmodified therapeutic agent is dianhydrogalactitol or ( a ) topoisomerase inhibitors ; diacetyldianhydrogalactitol. ( b ) fraudulent nucleosides ; In one alternative of a composition according to the ( c ) fraudulent nucleotides ; present invention , the composition can comprise a drug ( d ) thymidylate synthetase inhibitors ; combination comprising : ( e ) signal transduction inhibitors; ( i ) dianhydrogalactitol; and ( f ) cisplatin or platinum analogs ; ( ii ) an additional therapeutic agent selected from the 25 ( g ) alkylating agents ; group consisting of: ( h ) anti - tubulin agents ; ( a ) topoisomerase inhibitors ; (i ) antimetabolites; (b ) fraudulent nucleosides ; ( j) berberine ; ( c ) fraudulent nucleotides ; ( k ) apigenin ; ( d ) thymidylate synthetase inhibitors ; 30 ( 1 ) amonafide ; ( e ) signal transduction inhibitors ; ( m ) vinca alkaloids ; ( f ) cisplatin or platinum analogs ; ( n ) 5 - fluorouracil ; ( g ) alkylating agents ; (0 ) curcumin ; ( h ) anti- tubulin agents ; ( p ) NF -KB inhibitors ; ( i ) antimetabolites ; 35 ( q ) rosmarinic acid ; (j ) berberine; (r ) mitoguazone ; and ( k ) apigenin ; ( s ) tetrandrine ; (1 ) amonafide; wherein the dianhydrogalactitol acts as a chemosensitizer. ( m ) vinca alkaloids ; In yet another alternative, the composition can comprise : ( n ) 5 - fluorouracil ; 40 ( i ) diacetyldianhydrogalactitol; and ( o ) curcumin ; ( ii ) a therapeutic agent subject to chemosensitization ( p ) NF -KB inhibitors ; selected from the group consisting of: ( q ) rosmarinic acid ; ( a ) topoisomerase inhibitors ; (r ) mitoguazone ; ( b ) fraudulent nucleosides ; (s ) tetrandrine ; 45 ( c ) fraudulent nucleotides ; ( t ) an inhibitor of mutant isocitrate dehydrogenase ( d ) thymidylate synthetase inhibitors ; ( IDH ) ; ( e ) signal transduction inhibitors ; ( u ) a MGMT inhibitor; and ( f ) cisplatin or platinum analogs ; ( v ) an agent that inhibits NF- kB - enhanced expression ( g ) alkylating agents ; of MGMT. 50 (h ) anti- tubulin agents ; In another alternative of a composition according to the ( i ) antimetabolites ; present invention , the composition can comprise a drug ( j ) berberine ; combination comprising : ( k ) apigenin ; ( i ) diacetyldianhydrogalactitol; and (1 ) amonafide; (ii ) an additional therapeutic agent selected from the 55 ( m ) vinca alkaloids ; group consisting of: ( n ) 5 - fluorouracil ; ( a ) topoisomerase inhibitors ; ( o ) curcumin ; (b ) fraudulent nucleosides ; ( p ) NF -kB inhibitors ; ( c ) fraudulent nucleotides ; ( q ) rosmarinic acid ; ( d ) thymidylate synthetase inhibitors ; 60 ( r ) mitoguazone ; and ( e ) signal transduction inhibitors ; ( s ) tetrandrine ; ( f ) cisplatin or platinum analogs; wherein the diacetyldianhydrogalactitol acts as a chemosen (g ) alkylating agents ; sitizer . ( h ) anti- tubulin agents ; In yet another alternative , the composition comprises: ( i ) antimetabolites ; 65 ( i ) dianhydrogalactitol; and (i ) berberine ; ( ii ) a therapeutic agent subject to chemopotentiation (k ) apigenin ; selected from the group consisting of: US 9 , 901 ,563 B2 15 16 ( a ) topoisomerase inhibitors ; ( d ) DMF; (b ) fraudulent nucleosides ; ( e ) ethanol; ( c ) fraudulent nucleotides ; ( f ) benzyl alcohol; ( d ) thymidylate synthetase inhibitors ; ( g ) dextrose - containing water for injection ; ( e ) signal transduction inhibitors ; 3 (h ) Cremophor; ( f ) cisplatin or platinum analogs ; ( i ) cyclodextrin ; and ( g ) alkylating agents ; ( i ) PEG . ( h ) anti - tubulin agents ; In still another alternative of a composition according to (i ) antimetabolites; the present invention , the therapeutic agent is dianhydroga ( i ) berberine ; 10 (k ) apigenin ; lactitol or diacetyldianhydrogalactitol and the composition ( 1) amonafide ; comprises a solvent system , wherein the solvent system is (m ) vinca alkaloids; selected from the group consisting of: ( n ) 5 - fluorouracil ; ( a ) an emulsion ; ( o ) curcumin ; 15 ( b ) dimethylsulfoxide ( DMSO ) ; (p ) NF -kB inhibitors; ( c ) N -methylformamide ( NMF ); ( q ) rosmarinic acid ; ( d ) DMF; ( r ) mitoguazone ; ( e ) ethanol ; (s ) tetrandrine ; and ( f ) benzyl alcohol; (t ) biotherapeutics ; 20 ( g ) dextrose - containing water for injection ; wherein the dianhydrogalactitol acts as a chemopotentiator. ( h ) Cremophor ; In yet another alternative , the composition comprises: ( i ) cyclodextrin ; and ( i ) diacetyldianhydrogalactitol; and ( 1) PEG . ( ii ) a therapeutic agent subject to chemopotentiation In still another alternative of a composition according to selected from the group consisting of: 25 the present invention , the therapeutic agent is dianhydroga ( a ) topoisomerase inhibitors ; lactitol or diacetyldianhydrogalactitol and the composition (b ) fraudulent nucleosides ; comprises an excipient, wherein the excipient is selected ( c ) fraudulent nucleotides ; from the group consisting of: ( d ) thymidylate synthetase inhibitors ; ( a ) mannitol; ( e ) signal transduction inhibitors ; 30 ( b ) albumin ; ( f ) cisplatin or platinum analogs ; (c ) EDTA ; ( g ) alkylating agents ; ( d ) sodium bisulfite ; ( h ) anti - tubulin agents ; ( e ) benzyl alcohol; ( i) antimetabolites; ( f ) a carbonate buffer ; and (i ) berberine ; 35 ( g ) a phosphate buffer. ( k ) apigenin ; In still another alternative of a composition according to ( 1 ) amonafide; the present invention , the therapeutic agent is dianhydroga ( m ) vinca alkaloids ; lactitol or diacetyldianhydrogalactitol and the dianhydroga (n ) 5 - fluorouracil ; lactitol or diacetyldianhydrogalactitol is incorporated into a ( o ) curcumin ; 40 dosage form selected from the group consisting of: ( p ) NF -kB inhibitors ; ( a ) tablets ; ( q ) rosmarinic acid ; ( b ) capsules; ( r ) mitoguazone ; (c ) topical gels ; ( s ) tetrandrine ; and ( d ) topical creams; ( t ) biotherapeutics ; 45 ( e ) patches ; wherein the diacetyldianhydrogalactitol acts as a chemopo ( f) suppositories; and tentiator. ( g ) lyophilized dosage fills . In yet another alternative of a composition according to In still another alternative of a composition according to the present invention , the therapeutic agent is dianhydroga - the present invention , the therapeutic agent is dianhydroga lactitol or diacetyldianhydrogalactitol and the dianhydroga - 50 lactitol or diacetyldianhydrogalactitol and the dianhydroga lactitol or diacetyldianhydrogalactitol is subjected to a bulk lactitol or diacetyldianhydrogalactitol is incorporated into a drug product improvement, wherein the bulk drug product dosage kit and packaging selected from the group consisting improvement is selected from the group consisting of: of amber vials to protect from light and stoppers with ( a ) salt formation ; specialized coatings to improve shelf - life stability . ( b ) preparation as a homogeneous crystal structure ; 55 In still another alternative of a composition according to ( c ) preparation as a pure isomer; the present invention , the therapeutic agent is dianhydroga ( d ) increased purity ; lactitol or diacetyldianhydrogalactitol and the composition ( e ) preparation with lower residual solvent content; and comprises a drug delivery system selected from the group ( f) preparation with lower residual heavy metal content consisting of: In still another alternative of a composition according to 60 ( a ) nanocrystals ; the present invention , the therapeutic agent is dianhydroga (b ) bioerodible polymers ; lactitol or diacetyldianhydrogalactitol and the composition ( c ) liposomes ; comprises a diluent, wherein the diluent is selected from the ( d ) slow release injectable gels ; and group consisting of: ( e ) microspheres . ( a ) an emulsion ; 65 In still another alternative of a composition according to ( b ) dimethylsulfoxide ( DMSO ) ; the present invention , the therapeutic agent is dianhydroga ( c ) N -methylformamide (NMF ) lactitol or diacetyldianhydrogalactitol and the dianhydroga US 9 ,901 , 563 B2 17 18 lactitol or diacetyldianhydrogalactitol is present in the com tems, preservatives, more accurate drug administrations, position in a drug conjugate form selected from the group improved dose determination and schedules , toxicity moni consisting of: toring and ameliorization , techniques or agents to circum ( a ) a polymer system ; vent or reduce toxicity , techniques and tools to identify / ( b ) polylactides ; 5 predict those patients who might have a better outcome with ( c ) polyglycolides ; a therapeutic agent by the use of phenotype or genotype ( d ) amino acids; determination through the use of diagnostic kits or pharma ( e ) peptides ; and cokinetic or metabolism monitoring approaches, the use of (f ) multivalent linkers . drug delivery systems, novel prodrugs , polymer conjugates , In yet another alternative of a composition according to 10 novel routes of administration , other agents to potentiate the the present invention , the therapeutic agent is a modified activity of the compounds or inhibit the repair of suboptimal dianhydrogalactitol or a modified diacetyldianhydrogalactic cellular effects or sub - lethal damage or to “ push ” the cell tol and the modification is selected from the group consist into more destructive cellular phases such as apoptosis . In ing of: some cases , the inventive examples include the use of these (a ) alteration of side chains to increase or decrease lipo - 15 sub -optimal therapeutics in conjunction with radiation or philicity ; other conventional chemotherapeutic agents or biotherapeu (b ) addition of an additional chemical functionality to tic agents such as antibodies, vaccines, cytokines , lymphok alter a property selected from the group consisting of ines , gene and antisense therapies, or other chemotherapeu reactivity , electron affinity , and binding capacity ; and tic or biotherapeutic agents . ( c ) alteration of salt form . 20 By definition , the term " suboptimal therapy” includes In yet another alternative of a composition according to agents where Phase I toxicity precluded further human the present invention , the therapeutic agent is dianhydroga - clinical evaluation . It also includes those agents from Phase lactitol or diacetyldianhydrogalactitol and the dianhydroga - II trials where limited or no significant tumor responses were lactitol or diacetyldianhydrogalactitol is in the form of a identified . In addition , it also includes those agents , the prodrug system , wherein the prodrug system is selected 25 subject of Phase III clinical trials , whose outcome was either from the group consisting of: medically or statistically not significant to warrant submis ( a ) the use of enzyme sensitive esters ; sion or approval by regulatory agencies for commercializa ( b ) the use of dimers ; tion or commercialized agents whose response rates as a ( c ) the use of Schiff bases ; monotherapy are less than 25 % or whose side -effects are ( d ) the use of pyridoxal complexes ; and 30 severe enough to limit wider utility . Agents with suboptimal ( e ) the use of caffeine complexes. activity include but are not limited to the following: dian In still another alternative of a composition according to hydrogalactitol, diacetyldianhydrogalactitol, Avastin (beva the present invention , the therapeutic agent is dianhydroga - cizumab ), Rituxan (rituximab ) , Nexavar ( sorafenib ) , dasat lactitol or diacetyldianhydrogalactitol and the composition inib , nilotinib , Provenge ( sipuleucel- T ) , Tarceva (erlotinib ) , further comprises at least one additional therapeutic agent to 35 and Iressa ( gefitinib ) . More specifically , the inventive meth form a multiple drug system , wherein the at least one ods and compositions also focus on improvements for additional therapeutic agent is selected from the group substituted hexitols including dianhydrogalactitol and consisting of: diacetyldianhydrogalactitol. ( a ) an inhibitor of multi -drug resistance; ( I) Suboptimal Therapeutics ( b ) a specific drug resistance inhibitor ; 40 In general , examples of compounds with suboptimal (c ) a specific inhibitor of a selective enzyme; therapeutic activity include , but are not limited to , com ( d ) a signal transduction inhibitor; pounds of the following classes: DNA / nucleic acid binding ( e ) an inhibitor of a repair enzyme; and reactive agents , topoisomerase inhibitors, anti -tubulin (f ) a topoisomerase inhibitor with non -overlapping side agents , signal transduction inhibitors, protein synthesis effects . 45 inhibitors, inhibitors of DNA transcribing enzymes , DNA / Analogous methods of use , compositions , and improve - RNA intercalating agents , DNA minor groove binders , drugs ments also apply to other suboptimally administered thera that block steroid hormone action , photochemically active peutic agents including, but not limited to , Avastin (beva agents , immune modifying agents , hypoxia selective cyto cizumab ) , Rituxan (rituximab ) , Nexavar ( sorafenib ) , toxins, chemical radiation sensitizers and protectors , anti dasatinib , nilotinib , Provenge (sipuleucel - T ) , Tarceva ( erlo - 50 sense nucleic acids, oligonucleotides and polynucleotides tinib ), and Iressa ( gefitinib ) . therapeutic agents , immune modifying agents , antitumor antibiotics, biotherapeutics, biologic agents such as cancer DETAILED DESCRIPTION OF THE vaccines , antibody therapies , cytokines, lyphokines , gene INVENTION therapies, nucleic acid therapies, and cellular therapies . In 55 some cases , a compound may fall within more than one of This invention relates to novel compositions and methods these classes , such compounds are also within the scope of to improve the utility of chemical agents including substi - the invention . tuted hexitols such as dianhydrogalactitol or diacetyldian - In some cases , compounds or compositions may be in hydrogalactitol with suboptimal performance for patients current clinical use for one or more indications , but yet be with cancer, as well as additional therapeutic agents or 60 considered suboptimal for another indication , such as a agents capable of therapeutic application including , but not different type of malignancy , either in terms of the cell type limited to , Avastin (bevacizumab ) , Rituxan (rituximab ), involved in the malignancy or in terms of the stage of the Nexavar ( sorafenib ) , dasatinib , nilotinib , Provenge ( sipuleu - malignancy . Such compounds or compositions are within cel - T ) , Tarceva ( erlotinib ) , Iressa ( gefitinib ) , curcumin , ber - the scope of the invention . berine, and tetrandrine . The invention describes the novel 65 Specific examples include : fluoropyrimidines; thiopu development of improved pharmaceutical ingredients , dos rines ; inhibitors of nucleoside diphosphate reductase ; 2 ' - de age forms, excipients , solvents , diluents , drug delivery sys - oxyribonucleoside analogs ; nucleosides ; folic acid analogs ; US 9 ,901 , 563 B2 19 20 methotrexate ; 6 -diazo -5 -oxo -norleucine ; L - asparaginase ; doxorubicin ; lomustine; lonidamine; maytansine ; N - (phosphoacetyl ) - L - aspartic acid ; nitrogen mustard ; mechloethamine hydrochloride; menogaril ; 6 -mercaptopu mechlorethamine ; chlorambucil ; melphalan ; cyclophosph - rine ; mesna ; N -methylformamide ; mifepristone ; mitogua amide ; estramustine ; platinum complexes; nitrosoureas; zone ; mitomycin C ; mitotane ; mitoxantrone hydrochloride ; BCNU : BCNU wafer (Gliadel ) ; CCNU ; streptozotocin ; 5 nabilone ; nafoxidine ; neocarzinostatin ; octreotide acetate ; alkyl sulfonates ; busulfan ; clomesone ; triazenylimidazoles ormaplatin ; oxaliplatin ; paclitaxe ; pala ; pentostatin ; pipera and related triazenes ; mitozolomide; temozolomide ( Temo zinedione ; pipobroman ; pirarubicin ; piritrexim ; piroxan dar ) ; aziridines; tris ( 1 - aziridinyl) phosphine sulfide ; aziridi nylphosphines ; 3 , 6 - diaziridinyl- 2 , 5 -bis (carboethoxyamino ) trone hydrochloride; plicamycin ; porfimer sodium ; predi 1 , 4 -benzoquinone (Diaziquone ) ( AZQ ) ; AZQ analogs ; 10 mustine ; procarbazine; progestins; pyrazofurin ; razoxane ; bendamustine ( Treanada ) ; procarbazine ; hexamethylamine ; sargramostim ; semustine ; spirogermanium ; streptonigrin ; topoisomerase I inhibitors, including camptothecin and streptozocin ; sulofenur; suramin sodium ; tamoxifen ; taxo camptothecin analogs; topoisomerase II inhibitors , includ tere ; tegafur; teniposide; terephthalamidine ; teroxirone ; ing anthracyclines , doxorubicin , epirubicin , etoposide ; DNA thioguanine ; thiotepa ; thymidine ; tiazofurin ; topotecan ; intercalatingintercalating agents :; amsacrine ;: CIC1- 921021 (1o2methoxy ( 9 - [ [ 2 -methoxy - 4 -. 1515 tormifene ; tretinoin ; trifluoroperazine hydrochloride; triflu [ (methylsulfonyl )amino ] phenyl] amino ] - N ,5 - dimethyl- 4 ridine; trimetrexate ; uracil mustard ; vinblastine sulfate ; vin acridinecarboxamide 2 - hydroxyethanesulfonate ( 1 : 1 ) ) , cristine sulfate ; vindesine ; vinorelbine; vinzolidine ; Yoshi l ' - carbamate analogs of amsacrine ; 9 - aminoacridine - 4 - car 864 ; zorubicin ; 2 -chloro - 2 'deoxyadenosine ; 3 -deazauridine ; boxamides ; acridine carboxamide ; tricyclic carboxamides ; 4 - nitroestrone; 6 -methylmercaptopurine riboside ; 9 -amin 1 -nitroacridine ; acridine derivatives; diacridines ; triacri - 20 ocamptothecin ; nitrocamptothecin ; acodazole HCl; ADR dines ; podophyllotoxins; ellipticine; merbarone ; benzisoqui - 529 ; ICRF -187 ; amasacrine; aminothiadiazole ; ADTA ; nolinediones; etoposide; teniposide ; aminoanthraquinones ; amonafide ; antibiotic FR901228 ; aphidicolin glycinate ; inhibitors of DNA - transcribing enzymes ; transcription AZT; bizelesin ; brefeldins ; wortmannins ; cantharidins; bro inhibitors ; replication inhibitors ; RNA replication inhibitors ; modeoxyuridines ; bryostatin ; BSO ; CAI; caracemide; chlo DNA or RNA polymerase inhibitors ; rifamycins ; actinomy - 25 rosulfaquinoxaline sulfonamide ; cyclocytidine HCl; cins; DNA minor groove binding compounds; bisbenzimide cyclodisone ; cyclopentenylcytosine ; deoxyspergualin ; (Hoechst 33258 ) ; mitomycins ; CC - 1065; mithramycins ; DHAC ; didemnin B ; dideoxy -B - fluorouracil ; dideoxyade chloromycins ; olivomycins ; phthalanilides; anthramycins ; nosine ; dideoxyinosine ; dihydrotriazine benzene sulfonyl antimitotic agents ; vinca alkaloids, including vinblastine and analogs and vincristine and analogs ; navelbine ; colchicine 30 fluoride; dolastatin 10 ; ecteinascidin 743 ; etanidazole ; ethio and analogs ; bleomycin and analogs; estramustine; aro fos (WR - 2721) ; fazarabine; flavopiridol; fludarabine phos matase inhibitors ; tamoxifen ; LHRH antagonists and ana phate ; fostriecin ; genistein ; genistin ; 6 " - O -malonylgenistin , logs porfimer ; hematoporphyrins , electron - affinic oxygen 6 " - O - acetylgenistin ; daidzein ; daidzin ; 6 " - O -malonyldaid mimetics ; nitroaromatics ; nitroheterocyclics ; nitroimida zin ; 6 " - O -acetylgenistin ; glycitein ; glycitin ; 6 " -O -malonyl zoles : tirapazamine, mitomycins : menadione and analogs : 35 glycitin ; 6 - O -acetylglycitin ; hepsulfam ; HMBA ; 1odode naphthoquinones ; aziridoquinones; amine oxides; N -oxides ; oxyuridine ; ipomeanol ; KNI- 272; leucovorin calcium ; metal complexes ; bioreductive agents ; bioreductive alkylat levamisole ; menogaril ; merbarone ; misonidazole ; mitogua ing agents; radiation sensitizers ; radiation protectors ; anti zone ; mitoxantrone HCl; mitozolomide ; 06 -benzylguanine ; sense agents ; antigene agents ; transcription factor inhibitors ; PALA ; pancratistatin ; penclomedine ; pentamethylmelamine ODN complexes ; ribozymes; double - stranded RNA; antitu - 40 HCl; pentamidine isethionate ; pentostatin ; perillyl alcohol; mor antibiotics ; acivicin ; aclararubicin ; acodazole ; acrony - phyllanthoside ; pibenzimole HCI; piroxantrone ; pyrazine cine ; adozelesin ; alanosine ; allopurinol ; altretamine ; amino - diazohydroxide; pyrazoloacridine ; quinocarmycins, rebec glutethimide ; amonafide ; amsacrine ; androgens ; anguidine; camycins; rhizoxin ; semustine ; (methyl CCNU ) , suramin aphidicolin glycinate ; asaley ; 5 - azacytidine ; 5 -aza - 2' - deoxy - sodium ; Nexavar ; Gleevec; dasatinib (Sprycell ) ; decitabine ; cytidine ; azathioprine ; Baker ' s Antifol; B - 2' -deoxythio - 45 5 -azacytidine (Vidaza ) ; Homoharringtonine (HHT , omac guanosine ; bisantrene HCl; bleomycin sulfate ; busulfan ; etaxine ); Taxol; temozolomide ( Temodar ) ; terephthalami buthionine sulfoximine ( BSO ) ; BWA 773U82; BW 502U83 dine ; teroxirone ; thioguanine ; thymidine; tiazofurin ; HCl; BW 7U85 mesylate ; caracemide; carbetimer; carbo TMCA ; topotecan ; 5 - fluorouracil; ras inhibitors ; farnesy platin ; carmustine ; chlorambucil ; chloroquinoxaline sulfo namide ; chlorozotocin ; chromomycin A3 ; cisplatin ; cladrib - 50 lation inhibitors ; bromodeoxyuridine , tetracycline com ine; carboplatin ; oxaliplatin ; rhodamine compounds; pounds ; arsenic trioxide ; combretastatins; 2 -methoxyestra corticosteroids; irinotecan (CPT - 11 ) ; cristanol; cyclocyti diol; thalidomide and analogs ; cephalotaxine derivatives; dine ; cyclophosphamide ; cytarabine ; cytembena ; dabis stributyrin ; triciribine phosphate ; trimetrexate ; UCN -01 ; maleate ; dacarbazine ; dactinomycin ; daunorubicin HCl; 7 -hydroxystaurosporine ; uridine ; lycurium ; ritrosulfan ; deazauridine; dexrazoxane ; diacetyldianhydrogalactitol 55 artemisinin ; artesunate ; lonidamine; bromomannitol; pipo (DADAG ) , dianhydrogalactitol (DAG ) ; didemnin B ; dieth broman ; phenesterin ; pyrazine diazohydroxide ; terephthal yldithiocarbamate ; diglycoaldehyde ; dihydro - 5 - azacytidine ; amidine; bufalin ; FMDC ; colchicine; thiocolchicine; colchi doxorubicin ; echinomycin ; edatrexate ; edelfosine ; eflorni cine analogs ; LHRH analogs; curcumin ; berberine ; thine ; elsamitrucin ; epirubicin ; esorubicin ; estramustine tetrandrine ; paclitaxel ; MGBG ; Nexavar ( sorafenib ) ; nilo phosphate , estrogens ; etanidazole ; ethiofos ; fadrazole ; 60 tinib ; Provenge (sipuleucel - T ) ; Tarceva (erlotinib ); Iressa fazarabine ; fenretinide ; finasteride ; flavone acetic acid ; (gefitinib ) ; and antibody therapies such as Avastin , Hercep floxuridine ; fludarabine phosphate ; 5 - fluorouracil; fluta - tin , Rituxan , and Erbitux . mide ; gallium nitrate; gemcitabine; goserelin acetate ; hep In particular, the invention is directed to galactitols , sulfam ; hexamethylene bisacetamide; hydrazine sulfate ; substituted galactitols , and derivatives thereof, including 4 - hydroxyandrostenedione ; hydroxyurea ; idarubicin HCl; 65 dianhydrogalactitol and diacetyldianhydrogalactitol. ifosfamide ; 4 - ipomeanol; iproplatin ; isotretinoin ; leuprolide The structure of dianhydrogalactitol is shown in Formula acetate ; levamisole ; liposomal daunorubicin ; liposomal (I ), below . US 9 , 901 ,563 B2 22 mune anemias such as autoimmune hemolytic anemia , pure ( 1) red cell aplasia , idiopathic thrombocytopenic purpura , Evans syndrome, vasculitis such as Wegener ’ s granuloma tosis , pemphigus, pemphigoid , Type 1 diabetes mellitus, 0 Sjögren ' s syndrome, Devic ' s disease , and thyroid - associ OH ated opththalmopathy . Nexavar (sorafenib ) has the chemical structure 4 - [4 - [[ 4 chloro -3 -( trifluoromethyl) phenyl] carbamoylamino ]phe noxyl- N -methyl - pyridine - 2 - carboxamide and is an inhibitor 10 of several tyrosine protein kinases (VEGFR and PDGFR ) Also within the scope of the invention are derivatives of and Raf . Sorafenib targets the MAP kinase pathway ( Raf/ dianhydrogalactitol that, for example, have the hydrogen of Mek / Erk pathway ) . It is used or suggested for use in the hydroxyl groups replaced with lower alkyl, have the advanced renal cancer, hepatocellular carcinoma, non - re hydrogen attached to the epoxide ring replaced with lower sponsive thyroid cancer , and recurrent glioblastoma. alkyl. or have the methyl groups attached to the same 15 Dasatinib is an oral multi -BRCIABL and Src family tyrosine kinase inhibitor that has the chemical structure carbons that bear the hydroxyl groups replaced with lower N - ( 2 -chloro - 6 -methylphenyl ) - 2 - [ [6 - [ 4 - ( 2 -hydroxyethyl ) - 1 alkyl or substituted with , for example , halo groups. piperazinyl ] - 2 -methyl - 4 -pyrimidinyl ] amino ] - 5 - thiazolecar The structure of diacetyldianhydrogalactitol is shown in boxamide monohydrate . It is currently used to treat chronic Formula ( II ) , below . 20 myelogenous leukemia and Philadelphia - chromosome- posi tive acute lymphoblastic leukemia , and is being evaluated for treatment of numerous other cancers . ( II) Nilotinib is a tyrosine kinase inhibitor that inhibits BCR ABL , KIT , LCK , EPHA3, EPHA8 , DDR1, DDR2, PDG 25 FRB , MAPK11 and ZAK kinases and has the chemical structure 4 -methyl - N - [ 3 - ( 4 -methyl - 1H - imidazol- 1 - yl) - 5 ( trifluoromethyl) phenyl] - 3 - [ ( 4 -pyridin - 3 - ylpyrimidin - 2 -yl ) amino ]benzamide hydrochloride salt. It is currently used to treat drug - resistant chronic myelogenous leukemia . 30 Provenge ( sipuleucel - T ) is a therapeutic cancer vaccine that is a protein subunit . It is currently being tried for metastatic , asymptomatic , hormone - refractory prostate can Also within the scope of the invention are derivatives of cer . diacetyldianhydrogalactitol that, for example , have the Tarceva ( erlotinib ) is an EGFR inhibitor that has the methyl groups that are part of the acetyl moieties replaced 35 chemical structure N - ( 3 -ethynylphenyl ) - 6 , 7 - bis ( 2 -methoxy with lower alkyl, have the hydrogen attached to the epoxide ethoxy ) quinazolin - 4 -amine and is used to treat non - small ring replaced with lower alkyl, or have the methyl groups cell lung cancer , pancreatic cancer, and other types of attached to the same carbons that bear the acetyl groups cancer. replaced with lower alkyl or substituted with , for example , Iressa (gefitinib ) is also an EGFR inhibitor that has the halo groups. 40 chemical structure N - ( 3 - chloro - 4 - fluoro -phenyl ) - 7 In another alternative , the invention is directed to an agent methoxy - 6 - ( 3 -morpholin - 4 - ylpropoxy ) quinazolin - 4 - amine . with suboptimal activity selected from the group consisting Iressa also is effective in patients that have an EGFR of: Avastin (bevacizumab ) , Rituxan ( rituximab ) , Nexavar mutation . Iressa is considered particularly effective in treat ( sorafenib ), dasatinib , nilotinib , Provenge ( sipuleucel- T ) , ing some types of non - small -cell lung cancer, including Tarceva ( erlotinib ) , and Iressa ( gefitinib ) . 45 adenocarcinoma . Avastin (bevacizumab ) is a humanized ( from mouse ) ( II ) Dose Modification monoclonal antibody that binds VEGF - A and is an angio Improvements for suboptimal chemotherapeutics includ genesis inhibitor. It has been approved or suggested for use ing substituted hexitols such as dianhydrogalactitol or in combination with standard chemotherapy for metastatic diacetyldianhydrogalactitol are made by alterations to the colon cancer and non - small - cell lung cancer. There have 50 time that the compound is administered , the use of dose been suggestions that it might be useful in metastatic breast modifying agents that control the rate ofmetabolism of the cancer , although approval by the FDA for this specific compound , normal tissue protective agents , and other altera indication was revoked . Bevacizumab has also been tried in tions . General examples include : variations of infusion macular degeneration , and clinical studies are also underway schedules ( e . g ., bolus i. v . versus continuous infusion ) , the for bevacizumab in non -metastatic breast cancer , renal cell 55 use of lymphokines ( e . g . , G - CSF, GM - CSF , EPO ) to carcinoma, glioblastoma multiforme, ovarian cancer, hor increase leukocyte count for improved immune response or mone- refractory prostate cancer , non -metastatic unresect for preventing anemia caused by myelosuppressive agents , able liver cancer , and metastatic or unresectable locally or the use of rescue agents such as leucovorin for 5 - FU or advanced pancreatic cancer. thiosulfate for cisplatin treatment. Specific inventive Rituxan ( rituximab ) is a chimeric mouse /human mono - 60 examples for substituted hexitols such as dianhydrogalacti clonal antibody that binds CD20 , which is a marker primar - tol or diacetyldianhydrogalactitol include: continuous i. v . ily found on the surface of B cells . Rituximab is used in the infusion for hours to days ; biweekly administration ; doses treatment ofmany leukemias and lymphomas ; it is also used greater than 5 mg/ m2 / day ; progressive escalation of dosing to treat transplant rejection and autoimmune disorders . It is from 1 mg/ m² / day based on patient tolerance ; doses less being used in rheumatoid arthritis, particularly in combina - 65 than 1 mg/ m - for greater than 14 days ; use of caffeine to tion with methotrexate , and is being used to some extent in modulate metabolism ; use of isoniazid to modulate metabo multiple sclerosis , systemic lupus erythematosus , autoim - lism ; selected and intermittent boost dose administrations ; US 9 ,901 , 563 B2 23 24 bolus single and multiple doses escalating from 5 mg/ m² ; or diacetyldianhydrogalactitol are made by using the com oral doses below 30 or above 130 mg /m2 . pound for non -malignant diseases and conditions. General ( III) Route of Administration examples include : premalignant conditions, benign hyper Improvements for suboptimal chemotherapeutics includ proliferative conditions, treatment of infections, parasites, ing substituted hexitols such as dianhydrogalactitol or 5 usage to relieve pain , control of pleural effusions . Specific diacetyldianhydrogalactitol are made by alterations in the inventive examples for substituted hexitols such as dianhy route by which the compound is administered . General drogalactitol or diacetyldianhydrogalactitol include: use as examples include : changing route from oral to intravenous anti- infectives ; use as antivirals ; use as antibacterials ; use administration and vice versa ; or the use of specialized for pleural effusions ; use as antifungals ; use as antiparasit routes such as subcutaneous , intramuscular , intraarterial, 10 ics ; use for eczema ; use for shingles ; use for condylomata ; intraperitoneal , intralesional, intralymphatic, intratumoral, use as an anti- HPV agent; use as an anti -HSV agent. intrathecal, intravesicular, intracranial. Specific inventive ( VIII ) Patient Selection examples for substituted hexitols such as dianhydrogalacti - Improvements for suboptimal chemotherapeutics includ tol or diacetyldianhydrogalactitol include : topical ; intrave - ing substituted hexitols such as dianhydrogalactitol or sicular for bladder cancer ; oral administration ; slow release 15 diacetyldianhydrogalactitol are made by alterations to the oral delivery ; intrathecal; intraarterial; continuous infusion ; type of patient that would best tolerate or benefit from the or intermittent infusion . use of the compound . General examples include : use of (IV ) Schedule of Administration pediatric doses for elderly patients , altered doses for obese Improvements for suboptimal chemotherapeutics includ - patients, exploitation of co -morbid disease conditions such ing substituted hexitols such as dianhydrogalactitol or 20 as diabetes, cirrhosis , or other conditions that may uniquely diacetyldianhydrogalactitol are made by alterations to the exploit a feature of the compound . Specific inventive time that the compound is administered . General examples examples for substituted hexitols such as dianhydrogalacti include: changing from a monthly administration to a tol or diacetyldianhydrogalactitol include : patients with dis weekly or daily dosing or variations of the schedule . Specific ease conditions with high levels of metabolic enzymes , inventive examples for substituted hexitols such as dianhy - 25 histone deacetylase , protein kinases, or ornithine decarboxy drogalactitol or diacetyldianhydrogalactitol include : daily ; lase ; patients with disease conditions with low levels of weekly for three weeks , weekly for two weeks, biweekly ; metabolic enzymes, histone deacetylase, protein kinases , or biweekly for three weeks with a 1 - 2 week rest period ; ornithine decarboxylase; patients with low or high suscep intermittent boost dose administration ; or daily for one week tibility to thrombocytopenia or neutropenia ; patients intol then once per week for multiple weeks. 30 erant of GI toxicities ; or over - or under - expression of jun , ( V ) Indications for Use GPCR ' s and signal transduction proteins , VEGF, prostate Improvements for suboptimal chemotherapeutics includ - specific genes, protein kinases , or telomerase . ing substituted hexitols such as dianhydrogalactitol or ( IX ) Patient/ Disease Phenotype diacetyldianhydrogalactitol are made by alterations in the Improvements for suboptimal chemotherapeutics includ types of disease , clinical stage of disease that the compound 35 ing substituted hexitols such as dianhydrogalactitol or is administered . General examples include : the use of solid diacetyldianhydrogalactitol are made by more precise iden tumor agents for leukemias and vice versa , the use of tification of a patient' s ability to tolerate , metabolize and antitumor agents for the treatment of benign hyperprolifera - exploit the use of the compound . General examples include : tive disease such as psoriasis or benign prostate hypertrophy. use of diagnostic tools and kits to better characterize a Specific inventive examples for substituted hexitols such as 40 patient ' s ability to process /metabolize a chemotherapeutic dianhydrogalactitol or diacetyldianhydrogalactitol include : agent or their susceptibility to toxicity caused by potential use for the treatment of leukemias ( acute and chronic , ALL specialized cellular , metabolic , organ system phenotypes : CLL , CML CLL ) ; myelodysplastic syndrome (MDS ) ; Specific inventive examples for substituted hexitols such as angiogenic diseases ; benign prostate hypertrophy ; psoriasis ; dianhydrogalactitol or diacetyldianhydrogalactitol include: gout ; autoimmune conditions ; prevention of transplantation 45 diagnostic tools , techniques , kits and assays to confirm a rejection ; restenosis prevention in cardiovascular disease ; patient ' s particular phenotype and for the measurement of mycosis fungoides ; use in bone marrow transplantation ; as metabolism enzymes and metabolites , histone deacetylase , an anti -infective agent ; treatment for AIDS ; or treatment for protein kinases , ornithine decarboxylase , VEGF, prostate lymphoma. specific genes , protein kinases , telomerase , jun GPCR ' s , (VI ) Disease Stages 50 quantity or activity of MGMT, methylation of MGMT Improvements for suboptimal chemotherapeutics includ - promoter , and mutant isocitrate dehydrogenase ( IDH ) ; or ing substituted hexitols such as dianhydrogalactitol or surrogate compound dosing or low dose drug pre- testing for diacetyldianhydrogalactitol are made by alterations in the enzymatic status. stage of disease at diagnosis /progression that the compound (X ) Patient/ Disease Genotype is administered . General examples include: the use of che - 55 Improvements for suboptimal chemotherapeutics includ motherapy for non -resectable local disease , prophylactic use ing substituted hexitols such as dianhydrogalactitol or to preventmetastatic spread or inhibit disease progression or diacetyldianhydrogalactitol are made by testing and analyz conversion to more malignant stages . Specific inventive ing a patient' s genotype for unique features that may be of examples for substituted hexitols such as dianhydrogalacti - value to predict efficacy , toxicity , metabolism , or other tol or diacetyldianhydrogalactitol include: use for the treat - 60 factors affecting the therapeutic efficacy of the drug. General ment of localized polyp stage colon cancer; leukoplakia in examples include: biopsy samples of tumors or normal the oral cavity ; angiogenesis inhibition to prevent or limit tissues ( e . g ., white blood cells ) that may also be taken and metastatic spread ; or against HIV with AZT, DDI, or reverse analyzed to specifically tailor or monitor the use of a transcriptase inhibitors. particular drug against a gene target ; studies of unique tumor (VII ) Other Indications 65 gene expression patterns ; or analysis of SNP ' s ( single Improvements for suboptimal chemotherapeutics includ - nucleotide polymorphisms) , to enhance efficacy or to avoid ing substituted hexitols such as dianhydrogalactitol or particular drug -sensitive normal tissue toxicities. Specific US 9 ,901 , 563 B2 25 26 inventive examples for substituted hexitols such as dianhy - synergistic improvement in efficacy or side- effect manage drogalactitol or diacetyldianhydrogalactitol include : diag ment . General examples include : alkylating agents with nostic tools , techniques, kits and assays to confirm a anti- metabolites , topoisomerase inhibitors with antitubulin patient' s particular genotype; gene/ protein expression chips agents . Specific inventive examples for substituted hexitols and analysis ; Single Nucleotide Polymorphisms (SNP ' s ) 5 such as dianhydrogalactitol or diacetyldianhydrogalactitol assessment; SNP ' s for histone deacetylase , ornithine decar include: in combination with topoisomerase inhibitors ; use boxylase , GPCR ' s , protein kinases , telomerase , or jun ; or in combination with fraudulent nucleosides; use in combi identification and the measurement of metabolism enzymes nation with fraudulent nucleotides ; use in combination with and metabolites . thymidylate synthetase inhibitors ; use in combination with (XI ) Pre/ Post - Treatment Preparation 10 signal transduction inhibitors ; use in combination with cis Improvements for suboptimal chemotherapeutics includ - platin or platinum analogs ; use in combination with alky ing substituted hexitols such as dianhydrogalactitol or lating agents such as the nitrosoureas (BCNU , Gliadel diacetyldianhydrogalactitol are made by specialized prepa - wafers , CCNU ) bendamustine ( Treanda ) ; use in combina ration of a patient prior to or after the use of a chemothera - tion with anti -tubulin agents; use in combination with anti peutic agent. General examples include : induction or inhi - 15 metabolites ; use in combination with berberine ; use in bition of metabolizing enzymes, specific protection of combination with apigenin ; use in combination with amona sensitive normal tissues or organ systems. Specific inventive fide ; use in combination with colchicine and analogs; use in examples for substituted hexitols such as dianhydrogalacti- combination with genistein ; use in combination with etopo tol or diacetyldianhydrogalactitol include : the use of colchi- side ; use in combination with cytarabine ; use in combination cine or analogs; use of diuretics such as probenecid ; use of 20 with camptothecins; use in combination with vinca alka uricase ; non - oral use of nicotinamide ; sustained release loids ; use in combination with topoisomerase inhibitors ; use forms of nicotinamide ; use of inhibitors of polyADP ribose in combination with 5 - fluorouracil ; use in combination with polymerase ; use of caffeine ; use of leucovorin rescue ; use of curcumin ; use in combination with NF -KB inhibitors ; use in infection control ; or use of antihypertensives . combination with rosmarinic acid ; use in combination with (XII ) Toxicity Management 25 mitoguazone; use in combination with tetrandrine ; use in Improvements for suboptimal chemotherapeutics includ - combination with an inhibitor of mutant isocitrate dehydro ing substituted hexitols such as dianhydrogalactitol or genase ( IDH ) ; use in combination with a MGMT inhibitor ; diacetyldianhydrogalactitol are made by use of additional use in combination with an agent that inhibits NF - KB drugs or procedures to prevent or reduce potential side - enhanced expression of MGMT; or use in combination with effects or toxicities . General examples include: the use of 30 biological therapies such as antibodies such as Avastin , anti - emetics , anti -nausea , hematological support agents to Rituxan , Herceptin , Erbitux . limit or prevent neutropenia , anemia , thrombocytopenia , (XV ) Chemosensitization vitamins , antidepressants , treatments for sexual dysfunction , Improvements for suboptimal chemotherapeutics includ and other supportive techniques. Specific inventive ing substituted hexitols such as dianhydrogalactitol or examples for substituted hexitols such as dianhydrogalacti- 35 diacetyldianhydrogalactitol are made by exploiting them as tol or diacetyldianhydrogalactitol include : the use of colchi- chemosensitizers where no measurable activity is observed cine or analogs; use of diuretics such as probenecid ; use of when used alone but in combination with other therapeutics uricase ; non -oral use of nicotinamide; use of sustained a more than additive or synergistic improvement in efficacy release forms of nicotinamide ; use of inhibitors of poly is observed . General examples include : misonidazole with ADP -ribose polymerase ; use of caffeine ; use of leucovorin 40 alkylating agents , or tirapazamine with cisplatin . Specific rescue ; use of sustained release allopurinol; non - oral use of inventive examples for substituted hexitols such as dianhy allopurinol; use of bone marrow transplant stimulants , drogalactitol or diacetyldianhydrogalactitol include : as a blood , platelet infusions, Neupogen , G - CSF, or GM - CSF ; chemosensitizer in combination with topoisomerase inhibi pain management; use of anti- inflammatories ; fluids ; corti tors ; as a chemosensitizer in combination with fraudulent costeroids , insulin control medications ; anti- pyretics ; anti- 45 nucleosides ; as a chemosensitizer in combination with nausea treatments ; anti- diarrhea treatment; N - acetyl cyste - fraudulent nucleotides ; as a chemosensitizer in combination ine ; or antihistamines . with thymidylate synthetase inhibitors; as a chemosensitizer (XIII ) Pharmacokinetic / Pharmacodynamic Monitoring in combination with signal transduction inhibitors ; as a Improvements for suboptimal chemotherapeutics includ - chemosensitizer in combination with cisplatin or platinum ing substituted hexitols such as dianhydrogalactitol or 50 analogs , as a chemosensitizer in combination with alkylating diacetyldianhydrogalactitol are made by the use of monitor - agents such as BCNU Gliadel wafers , CCNU , bendamustine ing drug levels after dosing in an effort to maximize a ( Treanda ) , temozolomide ( Temodar ) ; as a chemosensitizer patient' s drug plasma level, to monitor the generation of in combination with anti - tubulin agents ; as a chemosensi toxic metabolites , monitoring of ancillary medicines that tizer in combination with antimetabolites ; as a chemosensi could be beneficial or harmful in terms of drug - drug inter - 55 tizer in combination with berberine; as a chemosensitizer in actions. General examples include: the monitoring of drug combination with apigenin ; as a chemosensitizer in combi plasma protein binding , and monitoring of other pharma- nation with amonafide ; as a chemosensitizer in combination cokinetic or pharmacodynamic variables . Specific inventive with colchicine and analogs ; as a chemosensitizer in com examples for substituted hexitols such as dianhydrogalacti- bination with genistein ; as a chemosensitizer in combination tol or diacetyldianhydrogalactitol include : multiple determi- 60 with etoposide ; as a chemosensitizer in combination with nations of drug plasma levels ; or multiple determinations of cytarabine ; as a chemosensitizer in combination with camp metabolites in the blood or urine . tothecins; as a chemosensitizer in combination with vinca (XIV ) Drug Combinations alkaloids, as a chemosensitizer in combination with topoi Improvements for suboptimal chemotherapeutics includ - somerase inhibitors ; as a chemosensitizer in combination ing substituted hexitols such as dianhydrogalactitol or 65 with 5 - fluorouracil ; as a chemosensitizer in combination diacetyldianhydrogalactitol are made by exploiting unique with curcumin ; as a chemosensitizer in combination with drug combinations that may provide a more than additive or NF -KB inhibitors ; as a chemosensitizer in combination with US 9 , 901, 563 B2 27 28 rosmarinic acid ; as a chemosensitizer in combination with NF -KB inhibitors (such as parthenolide, curcumin , or ros mitoguazone; or as a chemosensitizer in combination with marinic acid ) ; natural anti- inflammatories ( including rhein tetrandrine . or parthenolide ) ; immunostimulants ( such as those found in (XVI ) Chemopotentiation Echinacea ) ; antimicrobials ( such as berberine ) ; flavonoids , Improvements for suboptimal chemotherapeutics includ - 5 isoflavones , and flavones ( such as apigenenin , genistein , ing substituted hexitols such as dianhydrogalactitol or genistin , 6 " - O -malonylgenistin , 6 " - O - acetylgenistin , daid diacetyldianhydrogalactitol are made by exploiting them as zein , daidzin , 6 " - O -malonyldaidzin , 6 " - O -acetylgenistin , chemopotentiators where minimal therapeutic activity is glycitein , glycitin , 6 " - O -malonylglycitin , and 6 - O -acetyl observed alone but in combination with other therapeutics glycitin ); or applied kinesiology . unique drug a more than additive or synergistic improve - 10 (XIX ) Bulk Drug Product Improvements ment in efficacy is observed . General examples include : Improvements for suboptimal chemotherapeutics includ amonafide with cisplatin or 5 - FU . Specific inventive ing substituted hexitols such as dianhydrogalactitol or examples for substituted hexitols such as dianhydrogalacti diacetyldianhydrogalactitol are made by alterations in the tol or diacetyldianhydrogalactitol include: as a chemopoten pharmaceutical bulk substance . General examples include : tiator in combination with topoisomerase inhibitors ; as a 15 salt formation , homogeneous crystalline structure , pure iso chemopotentiator in combination with fraudulent nucleo - mers . Specific inventive examples for substituted hexitols sides ; as a chemopotentiator in combination with thymidy - such as dianhydrogalactitol or diacetyldianhydrogalactitol late synthetase inhibitors ; as a chemopotentiator in combi- include : salt formation ; homogeneous crystalline structure ; nation with signal transduction inhibitors; as a pure isomers ; increased purity ; or lower residual solvents chemopotentiator in combination with cisplatin or platinum 20 and heavy metals . analogs; as a chemopotentiator in combination with alky - (XX ) Diluent Systems lating agents such as BCNU , BCNU wafers , Gliadel, or Improvements for suboptimal chemotherapeutics includ bendamustine ( Treanda ) ; as a chemopotentiator in combi- ing substituted hexitols such as dianhydrogalactitol or nation with anti - tubulin agents; as a chemopotentiator in diacetyldianhydrogalactitol are made by alterations in the combination with antimetabolites ; as a chemopotentiator in 25 diluents used to solubilize and deliver / present the compound combination with berberine ; as a chemopotentiator in com - for administration . General examples include : Cremophor bination with apigenin ; as a chemopotentiator in combina - EL , cyclodextrins for poorly water soluble compounds . tion with amonafide ; as a chemopotentiator in combination Specific inventive examples for substituted hexitols such as with colchicine and analogs; as a chemopotentiator in com dianhydrogalactitol or diacetyldianhydrogalactitol include : bination with genistein ; as a chemopotentiator in combina - 30 use of emulsions ; dimethyl sulfoxide (DMSO ) ; N -methyl tion with etoposide ; as a chemopotentiator in combination formamide (NMF ) ; dimethylformamide (DMF ) ; dimethyl with cytarabine; as a chemopotentiator in combination with acetamide (DMA ) ; ethanol; benzyl alcohol ; dextrose con camptothecins ; as a chemopotentiator in combination with taining water for injection ; Cremophor ; cyclodextrins; or vinca alkaloids; as a chemopotentiator in combination with PEG . topoisomerase inhibitors ; as a chemopotentiator in combi- 35 (XXI ) Solvent Systems nation with 5 - fluorouracil ; as a chemopotentiator in combi - Improvements for suboptimal chemotherapeutics includ nation with curcumin ; as a chemopotentiator in combination ing substituted hexitols such as dianhydrogalactitol or with NF -kB inhibitors ; as a chemopotentiator in combina - diacetyldianhydrogalactitol are made by alterations in the tion with rosmarinic acid ; as a chemopotentiator in combi- solvents used or required to solubilize a compound for nation with mitoguazone; as a chemopotentiator in combi - 40 administration or for further dilution . General examples nation with or tetrandrine . include : ethanol, dimethylacetamide (DMA ) . Specific (XVII ) Post- Treatment Patient Management inventive examples for substituted hexitols such as dianhy Improvements for suboptimal chemotherapeutics includ drogalactitol or diacetyldianhydrogalactitol include: the use ing substituted hexitols such as dianhydrogalactitol or of emulsions; DMSO ; NMF; DMF ; DMA ; ethanol, benzyl diacetyldianhydrogalactitol are made by drugs , treatments 45 alcohol; dextrose containing water for injection ; Cremo and diagnostics to allow for the maximum benefit to patients phor ; or PEG . treated with a compound . General examples include : pain (XXII ) Excipients management, nutritional support, anti - emetics , anti -nausea Improvements for suboptimal chemotherapeutics includ therapies , anti - anemia therapy , anti - inflammatories . Specific ing substituted hexitols such as dianhydrogalactitol or inventive examples for substituted hexitols such as dianhy - 50 diacetyldianhydrogalactitol are made by alterations in the drogalactitol or diacetyldianhydrogalactitol include : use materials/ excipients, buffering agents , or preservatives with therapies associated with pain management; nutritional required to stabilize and present a chemical compound for support; anti - emetics ; anti- nausea therapies ; anti -anemia proper administration . General examples include : mannitol, therapy ; anti - inflammatories : antipyretics ; or immune stimu albumin , EDTA , sodium bisulfite , benzyl alcohol. Specific lants . 55 inventive examples for substituted hexitols such as dianhy (XVIII ) Alternative Medicine/ Therapeutic Support drogalactitol or diacetyldianhydrogalactitol include : the use Improvements for suboptimal chemotherapeutics includ - ofmannitol ; albumin ; EDTA ; sodium bisulfite ; benzyl alco ing substituted hexitols such as dianhydrogalactitol or hol; carbonate buffers ; or phosphate buffers . diacetyldianhydrogalactitol are made by the use of unap - (XXII ) Dosage Forms proved / non - conventional therapeutics or methods to 60 Improvements for suboptimal chemotherapeutics includ enhance effectiveness or reduce side effects . General ing substituted hexitols such as dianhydrogalactitol or examples include: hypnosis , acupuncture ,meditation , herbal diacetyldianhydrogalactitol are made by alterations in the medications and extracts, applied kinesiology , prayer. Spe potential dosage forms of the compound dependent on the cific inventive examples for substituted hexitols such as route of administration , duration of effect, plasma levels dianhydrogalactitol or diacetyldianhydrogalactitol include : 65 required , exposure to side - effect normal tissues and metabo hypnosis ; acupuncture ; meditation ; herbal medications cre - lizing enzymes . General examples include : tablets , capsules , ated either synthetically or through extraction including topical gels, creams, patches, suppositories . Specific inven US 9 ,901 , 563 B2 29 30 tive examples for substituted hexitols such as dianhydroga - examples include: enzyme sensitive esters, dimers, Schiff lactitol or diacetyldianhydrogalactitol include : the use of bases. Specific inventive examples for substituted hexitols tablets ; capsules; topical gels ; topical creams; patches ; sup such as dianhydrogalactitol or diacetyldianhydrogalactitol positories ; or lyophilized dosage fills. include: the use of enzyme sensitive esters ; dimers; Schiff (XXIV ) Dosage Kits and Packaging 5 bases ; pyridoxal complexes ; or caffeine complexes . Improvements for suboptimal chemotherapeutics includ - (XXIX ) Multiple Drug Systems ing substituted hexitols such as dianhydrogalactitol or Improvements for suboptimal chemotherapeutics includ diacetyldianhydrogalactitol are made by alterations in the ing substituted hexitols such as dianhydrogalactitol or dosage forms, container / closure systems, accuracy of mix - diacetyldianhydrogalactitol are made by the use of addi ing and dosage preparation and presentation . General 10 tional compounds , biological agents that when administered examples include : amber vials to protect from light, stoppers in the proper fashion , a unique and beneficial effect can be with specialized coatings . Specific inventive examples for realized . General examples include : inhibitors of multi - drug substituted hexitols such as dianhydrogalactitol or diacetyl- resistance , specific drug resistance inhibitors , specific dianhydrogalactitol include: the use of amber vials to protect inhibitors of selective enzymes, signal transduction inhibi from light or stoppers with specialized coatings to improve 15 tors , repair inhibition . Specific inventive examples for sub shelf - life stability . stituted hexitols such as dianhydrogalactitol or diacetyldian (XXV ) Drug Delivery Systems hydrogalactitol include : the use of inhibitors of multi -drug Improvements for suboptimal chemotherapeutics includ - resistance ; specific drug resistance inhibitors; specific ing substituted hexitols such as dianhydrogalactitol or inhibitors of selective enzymes ; signal transduction inhibi diacetyldianhydrogalactitol are made by the use of delivery 20 tors ; repair inhibition ; or topoisomerase inhibitors with systems to improve the potential attributes of a pharmaceu - non - overlapping side effects . tical product such as convenience , duration of effect, reduc (XXX ) Biotherapeutic Enhancement tion of toxicities . General examples include : nanocrystals , Improvements for suboptimal chemotherapeutics includ bioerodible polymers , liposomes, slow release injectable ing substituted hexitols such as dianhydrogalactitol or gels, microspheres . Specific inventive examples for substi - 25 diacetyldianhydrogalactitol are made by their use in com tuted hexitols such as dianhydrogalactitol or diacetyldian - bination as sensitizers / potentiators with biological response hydrogalactitol include : the use of nanocrystals ; bioerodible modifiers . General examples include : use in combination as polymers; liposomes ; slow release injectable gels ; or micro sensitizers /poteniators with biological response modifiers , spheres . cytokines , lymphokines , therapeutic antibodies , antisense (XXVI ) Drug Conjugate Forms 30 therapies , gene therapies . Specific inventive examples for Improvements for suboptimal chemotherapeutics includ - substituted hexitols such as dianhydrogalactitol or diacetyl ing substituted hexitols such as dianhydrogalactitol or dianhydrogalactitol include : use in combination as sensitiz diacetyldianhydrogalactitol are made by alterations to the ers/ potentiators with biological response modifiers; cytok parent molecule with covalent, ionic , or hydrogen bonded ines; lymphokines; therapeutic antibodies; antisense moieties to alter the efficacy , toxicity , pharmacokinetics , 35 therapies ; therapies such as Avastin , Herceptin , Rituxan , and metabolism , or route of administration . General examples Erbitux ; gene therapies ; ribozymes ; or RNA interference . include : polymer systems such as polyethylene glycols , (XXXI ) Biotherapeutic Resistance Modulation polylactides , polyglycolides, amino acids, peptides , or mul Improvements for suboptimal chemotherapeutics includ tivalent linkers . Specific inventive examples for substituted ing substituted hexitols such as dianhydrogalactitol or hexitols such as dianhydrogalactitol or diacetyldianhydroga - 40 diacetyldianhydrogalactitol are made by exploiting their lactitol include : the use of polymer systems such as poly - selective use to overcome developing or complete resistance ethylene glycols ; polylactides; polyglycolides; amino acids; to the efficient use of biotherapeutics. General examples peptides; or multivalent linkers . include : tumors resistant to the effects of biological response (XXVII ) Compound Analogs modifiers , cytokines, lymphokines, therapeutic antibodies , Improvements for suboptimal chemotherapeutics includ - 45 antisense therapies , gene therapies. Specific inventive ing substituted hexitols such as dianhydrogalactitol or examples for substituted hexitols such as dianhydrogalacti diacetyldianhydrogalactitol are made by alterations to the tol or diacetyldianhydrogalactitol include: the use against parent structure of a molecule with additional chemical tumors resistant to the effects of biological response modi functionalities that may alter efficacy , or reduce toxicity , fiers ; cytokines ; lymphokines ; therapeutic antibodies ; anti pharmacological performance , route of administration , or 50 sense therapies ; therapies such as Avastin , Rituxan , Hercep another relevant factor for therapeutic efficacy. General tin , and Erbitux ; gene therapies ; ribozymes ; or RNA examples include: alteration of side chains to increase or interference . decrease lipophilicity , additional chemical functionalities to (XXXII ) Radiation Therapy Enhancement alter reactivity , electron affinity , binding capacity , salt forms. Improvements for suboptimal chemotherapeutics includ Specific inventive examples for substituted hexitols such as 55 ing substituted hexitols such as dianhydrogalactitol or dianhydrogalactitol or diacetyldianhydrogalactitol include: diacetyldianhydrogalactitol are made by exploiting their use alteration of side chains to increase or decrease lipophilicity ; in combination with ionizing radiation , phototherapies , heat additional chemical functionalities to alter reactivity ; elec therapies , or radio - frequency generated therapies . General tron affinity ; binding capacity ; or salt forms. examples include: hypoxic cell sensitizers , radiation sensi (XXVIII ) Prodrugs 60 tizers /protectors , photosensitizers , radiation repair inhibi Improvements for suboptimal chemotherapeutics includ - tors . Specific inventive examples for substituted hexitols ing substituted hexitols such as dianhydrogalactitol or such as dianhydrogalactitol or diacetyldianhydrogalactitol diacetyldianhydrogalactitol are made by alterations to the include : the use with hypoxic cell sensitizers ; radiation molecule such that improved pharmaceutical performance is sensitizers/ protectors ; photosensitizers ; radiation repair gained with a variant of the active molecule in that after 65 inhibitors ; thiol depletion ; vaso - targeted agents ; use with introduction into the body a portion of the molecule is radioactive seeds, radionuclides , radiolabeled antibodies; or cleaved to reveal the preferred active molecule . General brachytherapy . US 9 ,901 , 563 B2 31 32 (XXXIII ) Novel Mechanisms of Action (25 ) drug conjugate forms; Improvements for suboptimal chemotherapeutics includ ( 26 ) compound analogs; ing substituted hexitols such as dianhydrogalactitol or ( 27 ) prodrugs ; diacetyldianhydrogalactitol are made by optimizing their ( 28 ) multiple drug systems; utility by determining the various mechanisms of action , 5 ( 29 ) biotherapeutic enhancement; biological targets of a compound for greater understanding ( 30 ) biotherapeutic resistance modulation ; and precision to better exploit the utility of the molecule . ( 31) radiation therapy enhancement; General examples include: Gleevec for chronic myelocytic (32 ) novel mechanisms of action ; and leukemia (CML ) , arsenic trioxide for acute promyelocytic ( 33 ) selective target cell population therapeutics . leukemia ( APL ) , retinoic acid for APL . Specific inventive 10 Typically , the hyperproliferative disease is cancer. Meth examples for substituted hexitols such as dianhydrogalacti - ods according to the present invention are applicable to tol or diacetyldianhydrogalactitol include : the use with many forms of cancer , including, but not limited to : ( A ) inhibitors of poly - ADP ribose polymerase ; agents that effect breast cancer, including : ( 1 ) ductal carcinoma , including vasculature ; vasodilation ; oncogenic targeted agents ; signal ductal carcinoma in situ (DCIS ) ( comedocarcinoma , cribri transduction inhibitors ; EGFR inhibition ; Protein Kinase C 15 form , papillary , micropapillary ) , infiltrating ductal carci inhibition ; Phospholipase C down - regulation ; jun down - noma ( IDC ) , tubular carcinoma, mucinous ( colloid ) carci regulation ; histone genes ; VEGF ; ornithine decarboxylase ; noma, papillary carcinoma, metaplastic carcinoma, and jun D ; v - jun ; GPCRs ; protein kinase A ; telomerase , prostate inflammatory carcinoma ; ( 2 ) lobular carcinoma , including specific genes ; protein kinases ; or histone deacetylase . lobular carcinoma in situ (LCIS ) and invasive lobular car (XXXIV ) Selective Target Cell Population Therapeutics 20 cinoma; and ( 3 ) Paget ' s disease of the nipple ; ( B ) cancers of Improvements for suboptimal chemotherapeutics includ - the female reproductive system , including : ( 1 ) cancers of the ing substituted hexitols such as dianhydrogalactitol or cervix uteri, including cervical intraepithelial neoplasia diacetyldianhydrogalactitol are made by more precise iden - (Grade I) , cervical intraepithelial neoplasia (Grade II) , cer tification and exposure of the compound to those select cell vical intraepithelial neoplasia (Grade III ) (squamous cell populations where the compound ' s effect can be maximally 25 carcinoma in situ ) , keratinizing squamous cell carcinoma, exploited . General examples include : tirapazamine and nonkeratinizing squamous cell carcinoma, verrucous carci mitomycin C for hypoxic cells , vinca alkaloids for cells noma, adenocarcinoma in situ , adenocarcinoma in situ , entering mitosis . Specific inventive examples for substituted endocervical type , endometrioid adenocarcinoma, clear cell hexitols such as dianhydrogalactitol or diacetyldianhydroga adenocarcinoma, adenosquamous carcinoma, adenoid cystic lactitol include : use against radiation sensitive cells ; radia - 30 carcinoma, small cell carcinoma, and undifferentiated car tion resistant cells ; energy depleted cells ; or endothelial cinoma; ( 2 ) cancers of the corpus uteri , including endometri cells . oid carcinoma, adenocarcinoma, adenocanthoma ( adenocar Accordingly , one aspect of the present invention is a cinoma with squamous metaplasia ) , adenosquamous method to improve the efficacy and /or reduce the side effects carcinoma (mixed adenocarcinoma and squamous cell car of suboptimally administered drug therapy comprising the 35 cinoma, mucinous adenocarcinoma, serous adenocarci steps of: noma, clear cell adenocarcinoma , squamous cell adenocar ( 1 ) identifying at least one factor or parameter associated cinoma, and undifferentiated adenocarcinoma; ( 3 ) cancers of with the efficacy and / or occurrence of side effects of the drug the ovary , including serous cystadenoma . serous cystadeno therapy ; and carcinoma, mucinous cystadenoma, mucinous cystadenocar ( 2 ) modifying the factor or parameter to improve the 40 cinoma, endometrioid tumor, endometrioid adenocarci efficacy and/ or reduce the side effects of the drug therapy . noma , clear cell tumor , clear cell cystadenocarcinoma, and Typically , the factor or parameter is selected from the unclassified tumor; ( 4 ) cancers of the vagina , including group consisting of: squamous cell carcinoma and adenocarcinoma; and (5 ) ( 1 ) dose modification ; cancers of the vulva , including vulvar intraepithelial neo ( 2 ) route of administration ; 45 plasia (Grade I ) , vulvar intraepithelial neoplasia (Grade II ) , (3 ) schedule of administration ; vulvar intraepithelial neoplasia (Grade III ) ( squamous cell ( 4 ) indications for use; carcinoma in situ ) ; squamous cell carcinoma, verrucous ( 5 ) selection of disease stage ; carcinoma, Paget ' s disease of the vulva , adenocarcinoma (6 ) other indications ; (NOS ) , basal cell carcinoma (NOS ) , and Bartholin ' s gland ( 7 ) patient selection ; 50 carcinoma ; ( C ) cancers of the male reproductive system , ( 8 ) patient/ disease phenotype; including: ( 1 ) cancers of the penis , including squamous cell (9 ) patient/ disease genotype ; carcinoma; ( 2 ) cancers of the prostate , including adenocar ( 10 ) pre /post - treatment preparation cinoma , sarcoma, and transitional cell carcinoma of the (11 ) toxicity management; prostate; ( 3 ) cancers of the testis , including seminomatous (12 ) pharmacokinetic /pharmacodynamic monitoring ; 55 tumor, nonseminomatous tumor, teratoma, embryonal car ( 13 ) drug combinations ; cinoma, yolk sac tumor , and Choriocarcinoma; ( D ) cancers ( 14 ) chemosensitization ; of the cardiac system , including sarcoma ( angiosarcoma, ( 15 ) chemopotentiation ; fibrosarcoma, rhabdomyosarcoma , liposarcoma ) , myxoma , ( 16 ) post - treatment patient management; rhabdomyoma, fibroma, lipoma and teratoma; ( E ) cancers of ( 17 ) alternative medicine /therapeutic support; 60 the respiratory system , including squamous cell carcinoma ( 18 ) bulk drug product improvements ; of the larynx , primary pleural mesothelioma , and squamous (19 ) diluent systems; cell carcinoma of the pharynx ; ( F ) cancers of the lung, ( 20 ) solvent systems; including squamous cell carcinoma ( epidermoid carci (21 ) excipients ; noma ) , variants of squamous cell carcinoma, spindle cell (22 ) dosage forms; 65 carcinoma , small cell carcinoma, carcinoma of other cells , ( 23 ) dosage kits and packaging ; carcinoma of intermediate cell type , combined oat cell (24 ) drug delivery systems; carcinoma, adenocarcinoma , acinar adenocarcinoma, papil US 9 , 901, 563 B2 33 34 lary adenocarcinoma, bronchiolo - alveolar carcinoma, solid in situ , transitional urothelial cell carcinoma, papillary tran carcinoma with mucus formation , large cell carcinoma, giant sitional cell carcinoma , squamous cell carcinoma, adenocar cell carcinoma, clear cell carcinoma , and sarcoma ; ( G ) cinoma , undifferentiated ; ( I ) cancers of muscle , bone , and cancers of the gastrointestinal tract, including: ( 1 ) cancers of soft tissue , including : ( 1 ) cancers of bone, including : ( a ) the ampulla of Vater , including primary adenocarcinoma , 5 bone - forming : osteosarcoma; ( b ) cartilage - forming : chon carcinoid tumor , and lymphoma ; ( 2 ) cancers of the anal drosarcoma and mesenchymal chondrosarcoma; ( c ) diant canal, including adenocarcinoma, squamous cell carcinoma, cell tumor , malignant ; ( d ) Ewing ' s sarcoma ; ( e ) vascular and melanoma; ( 3 ) cancers of the extrahepatic bile ducts , tumors : hemangioendothelioma, hemangiopericytoma, and including carcinoma in situ , adenocarcinoma , papillary angiosarcoma ; ( f ) connective tissue tumors: fibrosarcoma , adenocarcinoma, adenocarcinoma , intestinal type , mucinous 10 liposarcoma , malignant mesenchymoma, and undifferenti adenocarcinoma , clear cell adenocarcinom , segnet -ring cell ated sarcoma ; and ( g ) other tumors : chordoma and adaman carcinoma, adenosquamous carcinoma, squamous cell car tinoma of long bones; ( 2 ) cancers of soft tissues, including : cinoma, small cell ( cat) carcinoma, undifferentiated carci alveolar soft -part sarcoma, angiosarcoma, epithelioid sar noma, carcinoma (NOS ) , sarcoma , and carcinoid tumor; ( 4 ) coma, extraskeletal chondrosarcoma , fibrosarcoma , leio cancers of the colon and rectum , including adenocarcinoma 15 myosarcoma , liposarcoma, malignant fibrous histiocytoma , in situ , adenocarcinoma, mucinous adenocarcinoma ( colloid malignant hemangiopericytoma , malignant mesenchy type ; greater than 50 % mucinous carcinoma ) , signet ring moma, malignant schwannoma, rhabdomyosarcoma, syn cell carcinoma ( greater than 50 % signet ring cell ) , squamous ovial sarcoma, and sarcoma (NOS ) ; ( 3 ) cancers of the cell (epidermoid ) carcinoma, adenosquamous carcinoma, nervous system , including cancers of the skull (osteoma , small cell ( oat cell) carcinoma, undifferentiated carcinoma , 20 hemangioma, granuloma , xanthoma, osteitis deformans ) , carcinoma (NOS ), sarcoma, lymphoma, and carcinoid cancers of the meninges (meningioma , meningiosarcoma, tumor ; ( 5 ) cancers of the esophagus , including squamous gliomatosis ) , cancers of the brain ( astrocytoma, medullo cell carcinoma , adenocarcinoma, leiomyosarcoma, and lym - blastoma , glioma, ependymoma , germinoma ( pilealoma ) , phoma; (6 ) cancers of the gallbladder , including adenocar glioblastoma multiform , oligodendroglioma, schwannoma, cinoma, adenocarcinoma , intestinal type, adenosquamous 25 retinoblastoma , congenital tumors ) , and cancers of the spinal carcinoma , carcinoma in situ , carcinoma (NOS ), clear cell cord neurofibroma, meningioma, glioma, sarcoma ) ; ( 4 ) adenocarcinoma , mucinous adenocarcinoma, papillary hematologic cancers , including myeloid leukemia ( acute and adenocarcinoma, signet - ring cell carcinoma, small cell ( oat chronic ), acute lymphloblastic leukemia , chronic lympho cell ) carcinoma, squamous cell carcinoma, and undifferen - cytic leukemia , myeloproliferative diseases, multiple tiated carcinoma ; ( 7 ) cancers of the lip and oral cavity , 30 myeloma; myelodysplastic syndrome) , Hodgkin ' s disease , including squamous cell carcinoma; ( 8 ) cancers of the liver , and non -Hodgkin ' s lymphoma (malignant lymphoma ) ; ( 5 ) including hepatoma ( hepatocellular carcinoma) , cholangio - cancers of the endocrine system , including : ( a ) cancers of carcinoma, hepatoblastoma, angiosarcoma , hepatocellular the thyroid gland , including papillary carcinoma ( including adenoma, and hemangioma; (9 ) cancers of the exocrine those with follicular foci) , follicular carcinoma, medullary pancreas , including duct cell carcinoma , pleomorphic giant 35 carcinoma, and undifferentiated (anaplastic ) carcinoma; and cell carcinoma, giant cell carcinoma, osteoclastoid type , ( b ) neuroblastomas , including sympathicoblastoma , sym adenocarcinoma, adenosquamous carcinoma, mucinous pathicogonioma, malignant ganglioneuroma, gangliosym ( colloid ) carcinoma, cystadenocarcinoma, acinar cell carci- pathicoblastoma , and ganglioneuroma; ( 6 ) cancers of the noma, papillary carcinoma, small cell (oat cell) carcinoma, skin , including squamous cell carcinoma, spindle cell vari mixed cell typed , carcinoma (NOS ) , undifferentiated carci- 40 ant of squamous cell carcinoma, basal cell carcinoma, noma , endocrine cell tumors arising in the islets of langer - adenocarcinoma developing from sweat or sebaceous gland , hans , and carcinoid ; ( 10 ) cancers of the salivary glands, and malignant melanoma ; ( 7 ) cancers of the eye , including : including acinic (acinar ) cell carcinoma , adenoid cystic ( a ) cancers of the conjunctiva , including carcinoma of the carcinoma (cylindroma ) , adenocarcinoma, squamous cell conjunctiva ; ( b ) cancers of the eyelid , including basal cell carcinoma , carcinoma in pleomorphic adenoma (malignant 45 carcinoma , squamous cell carcinoma , melanoma of the mixed tumor ) , mucoepidermoid carcinoma (well differenti - eyelid , and sebaceous cell carcinoma; ( c ) cancers of the ated or low grade ), and mucoepidermoid carcinoma ( poorly lacrimal gland , including adenocarcinoma, adenoid cystic differentiated or high grade ) ; ( 11 ) cancers of the stomach , carcinoma, carcinoma in pleomorphic adenoma , mucoepi including adenocarcinoma, papillary adenocarcinoma, tubu - dermoid carcinoma, and squamous cell carcinoma ; ( d ) can lar adenocarcinoma , mucinous adenocarcinoma, signet ring 50 cers of the uvea , including spindle cell melanoma, mixed cell carcinoma, adenosquamous carcinoma, squamous cell cellmelanoma , and epithelioid cellmelanoma ; (e ) cancers of carcinoma, small cell carcinoma, undifferentiated carci- the orbit , including sarcoma of the orbit, soft tissue tumor, noma, lymphoma, sarcoma, and carcinoid tumor ; and ( 12 ) and sarcoma of bone ; and ( f ) retinoblastoma. In particular, cancers of the small intestine , including adenocarcinoma, methods according to the present invention and composi lymphoma, carcinoid tumors , Kaposi ' s sarcoma, leio - 55 tions suitable for use according to those methods are appli myoma, hemangioma, lipoma, neurofibroma , and fibroma; cable to lower grade astrocytomas and other primary central ( H ) cancers of the urinary system , including : ( 1 ) cancers of nervous system tumors besides glioblastoma multiforme the kidney , including renal cell carcinoma, carcinoma of (GBM ), as well as to central nervous system metastases of Bellini' s collecting ducts , adenocarcinoma, papillary carci other tumors including solid tumors and hematologic tumors noma , tubular carcinoma , granular cell carcinoma, clear cell 60 ( e . g . , breast , lung , bladder , and bowel tumors , leukemias , carcinoma (hypernephroma ) , sarcoma of the kidney , and and lymphomas ) , in addition to squamous cell non - small nephroblastoma; ( 2 ) cancers of the renal pelvis and ureter , cell lung cancer. In addition , methods according to the including transitional cell carcinoma , papillary transitional present invention and compositions suitable for use accord cell carcinoma , squamous cell carcinoma, and adenocarci- ing to those methods are applicable to melanoma, breast noma; ( 3 ) cancers of the urethra, including transitional cell 65 lymphoma ( both Hodgkins and non -Hodgkins ) , colorectal carcinoma, squamous cell carcinoma, and adenocarcinoma; cancer, acute lymphoblastic leukemia , and for lowering the and (4 ) cancers of the urinary bladder, including carcinoma incidence of central nervous system leukemia , non -small US 9 , 901, 563 B2 35 36 cell lung cancer , cervical carcinoma, bladder carcinoma, and ( h ) use for prevention of restenosis in cardiovascular metastatic hemangiopericytoma. disease ; In one alternative , preferably , the substituted hexitol is ( i) use for treatment ofmycosis fungoides ; selected from the group consisting of dianhydrogalactitol (j ) use in bone marrow transplantation ; and a derivative thereof . In this alternative , more preferably , 5 ( k ) use as an anti - infective agent; the substituted hexitol is dianhydrogalactitol. In another ( 1) use for treatment of AIDS; and alternative , preferably , the substituted hexitol is selected (m ) use for treatment of lymphoma. from the group consisting of diacetyldianhydrogalactitol and When the improvement is made by selection of disease a derivative thereof. In this alternative , more preferably , the stage , the selection of disease stage can be , but is not limited substituted hexitol is diacetyldianhydrogalactitol. Deriva - 10 to , at least one selection of disease stage selected from the tives of dianhydrogalactitol and of diacetyldianhydrogalac - group consisting of: titol are described above . (a ) use for the treatment of localized polyp stage colon The following improvements all apply either to dianhy cancer ; drogalactitol, diacetyldianhydrogalactitol , or derivatives of ( b ) use for leukoplakia in the oral cavity ; either dianhydrogalactitol or diacetyldianhydrogalactitol , as 15 ( c ) use for angiogenesis inhibition to prevent or limit indicated with respect to the specific improvement described metastatic spread of a malignancy ; and below . ( d ) use for treatment of HIV with a therapy selected from When the improvement is dose modification , the dose the group consisting of azidothymidine (AZT ) , dide modification can be , but is not limited to , at least one dose oxyadenosine (DDI ) , and reverse transcriptase inhibi modification selected from the group consisting of: 20 tors . ( a ) continuous i. v . infusion for hours to days; When the improvement is made by other indications , the ( b ) biweekly administration ; other indications can be , but are not limited , to at least one (c ) doses greater than 5 mg/ m² / day ; other indication selected from the group consisting of: ( d ) progressive escalation of dosing from 1 mg/ m² /day ( a ) use as an anti - infective agent; based on patient tolerance ; 25 ( b ) use as an antiviral agent; ( e ) use of caffeine to modulate metabolism ; (c ) use as an antibacterial agent ; ( f ) use of isonazid to modulate metabolism ; ( d ) use as an agent to treat pleural effusion ; ( g ) selected and intermittent boosting of dosage admin ( e ) use as an antifungal agent; istration ; ( f ) use as an anti -parasitic agent; ( h ) administration of single and multiple doses escalating 30 ( g ) use as an agent to treat eczema; from 5 mg/ m - / day via bolus ; ( h ) use as an agent to treat herpes zoster ( shingles ) ; ( i) oral dosages of below 30 mg/ m² ; and ( i ) use as an agent to treat condylomata ; ( i ) oral dosages of above 130 mg/m² . ( i ) use as an agent to treat human papilloma virus (HPV ) ; When the improvement is made by route of administra and tion , the route of administration can be , but is not limited to , 35 ( k ) use as an agent to treat herpes simplex virus (HSV ) . at least one route of administration selected from the group When the improvement is made by patient selection , the consisting of: patient selection can be , but is not limited to , a patient ( a ) topical administration ; selection carried out by a criterion selected from the group ( b ) intravesicular administration for bladder cancer; consisting of: ( c ) oral administration ; 40 ( a ) selecting patients with a disease condition character (d ) slow release oral delivery ; ized by a high level of a metabolic enzyme selected ( e ) intrathecal administration ; from the group consisting of histone deacetylase and ( f ) intraarterial administration ; ornithine decarboxylase ; ( g ) continuous infusion ; and ( b ) selecting patients with a low or high susceptibility to ( h ) intermittent infusion . 45 a condition selected from the group consisting of When the improvement is made by schedule of adminis thrombocytopenia and neutropenia ; tration , the schedule of administration can be, but is not ( c ) selecting patients intolerant ofGI toxicities, and limited to , at least one schedule of administration selected ( d ) selecting patients characterized by over - or under from the group consisting of : expression of a gene selected from the group consisting ( a ) daily administration ; 50 of c -Jun , a GPCR , a signal transduction protein , VEGF, ( b ) weekly administration ; a prostate - specific gene, and a protein kinase . ( c ) weekly administration for three weeks ; The cellular proto - oncogene c - Jun encodes a protein that, ( d ) biweekly administration ; in combination with c -Fos , forms the AP - 1 early response ( e ) biweekly administration for three weeks with a 1 - 2 transcription factor. This proto -oncogene plays a key role in week rest period ; 55 transcription and interacts with a large number of proteins ( f) intermittent boost dose administration ; and affecting transcription and gene expression . It is also ( g ) daily administration for one week for multiple weeks. involved in proliferation and apoptosis of cells that form part When the improvement is made by indication for use , the of a number of tissues , including cells of the endometrium indication for use can be , but is not limited to , at least one and glandular epithelial cells . G - protein coupled receptors indication for use selected from the group consisting of: 60 (GPCRs ) are important signal transducing receptors. The ( a ) use for treatment of leukemias ; superfamily of G protein coupled receptors includes a large ( b ) use for treatment of myelodysplastic syndrome ; number of receptors . These receptors are integralmembrane ( c ) use for treatment of angiogenic diseases ; proteins characterized by amino acid sequences that contain ( d ) use for treatment of benign prostatic hyperplasia ; seven hydrophobic domains, predicted to represent the ( e ) use for treatment of psoriasis ; 65 transmembrane spanning regions of the proteins. They are ( f ) use for treatment of gout ; found in a wide range of organisms and are involved in the ( g ) use for treatment of transplantation rejections; transmission of signals to the interior of cells as a result of US 9 ,901 , 563 B2 37 38 their interaction with heterotrimeric G proteins. They such damage is directly related to the number of MGMT respond to a diverse range of agents including lipid ana - molecules that it contains and to the rate of de novo logues , amino acid derivatives , small molecules such as synthesis of MGMT in the cell . epinephrine and dopamine , and various sensory stimuli. The Although MGMT can act at different rates on a wide properties of many known GPCR are summarized in S . 5 variety of O -alkyl groups ( and even in a minor degree on Watson & S . Arkinstall , “ The G - Protein Linked Receptor 04- methylthymine which is an alkylation product of the Facts Book ” ( Academic Press , London , 1994 ), incorporated pyrimidine thymine) , the majority of studies have focused herein by this reference . GPCR receptors include , but are not limited to , acetylcholine receptors , B -adrenergic receptors, on the endogenous substrate Oº- methylguanine . Ofthe more Bz- adrenergic receptors , serotonin ( 5 -hydroxytryptamine ) 10 than 12 different types of nitrogen and oxygen adducts of receptors , dopamine receptors , adenosine receptors , angio purine and pyrimidine bases produced by alkylating agents , tensin Type II receptors , bradykinin receptors , calcitonin OO -methylguanine is , in fact , one of the least abundant , but receptors, calcitonin gene -related receptors , cannabinoid of great importance in cancer biology. Oº- methylguanine receptors , cholecystokinin receptors, chemokine receptors , affects cytosine methylation , the binding of transcription cytokine receptors , gastrin receptors , endothelin receptors , 15 factors , recombinogenic capacity , and may inhibit DNA y -aminobutyric acid (GABA ) receptors, galanin receptors , replication or cleavage if located at a replication origin or at glucagon receptors, glutamate receptors , luteinizing hor - a topoisomerase 1 site . mone receptors , choriogonadotrophin receptors , follicle Amounts of MGMT protein in cells vary according to stimulating hormone receptors , thyroid - stimulating hor- cellular type . In healthy cells , the level and activity of mone receptors , gonadotrophin -releasing hormone 20 MGMT are regulated by protein phosphorylation status, receptors , leukotriene receptors , Neuropeptide Y receptors , binding ofthe E6 papillomavirus oncoprotein , and the action opioid receptors, parathyroid hormone receptors, platelet of the tumor suppressor p53 , glucocorticoid hormone , and activating factor receptors , prostanoid (prostaglandin ) other transcription factors over its 5 ' - CpG island , which receptors , somatostatin receptors, thyrotropin -releasing hor- includes a classical promoter without TATA and CAAT mone receptors , vasopressin and oxytocin receptors . 25 boxes and a 59 by enhancer element located at the first When the improvement is made by analysis of patient or exon - intron boundary . Mutations in the MGMT gene , disease phenotype, the analysis of patient or disease pheno including point mutations , have been described in associa type can be , but is not limited to , a method of analysis of tion withwith esophageal cancer in Chinese patients (L . Wang et patient or disease phenotype carried out by a method al ., “ Mutations of O? -Methylguanine - DNA Methyltrans selected from the group consisting of : ( a ) use of a diagnostic tool, a diagnostic technique , a 30 ferase Gene in Esophageal Cancer Tissues from Northern diagnostic kit , or a diagnostic assay to confirm a China, ” Int . J . Cancer 71 : 719 - 723 (1997 ) , incorporated patient 's particular phenotype ; herein by this reference ), but the significance of these (b ) use of a method for measurement of a marker selected mutations is not established . from the group consisting of histone deacetylase , orni - 35 The MGMT protein is decreased in some tumors with thine decarboxylase , VEGF, a protein that is a gene respect to their normal tissue counterpart ; a subset of tumor product of a prostate specific gene, a protein that is a cell lines, termed Mer- , completely lack MGMT activity . gene product of jun , a protein kinase , quantity or However, in most cases, loss of expression is not commonly activity of MGMT, methylation of MGMT promoter, due to deletion , mutation or rearrangement of the MGMT and mutant isocitrate dehydrogenase ( IDH ) ; 40 gene or instability of mRNA transcribed from the MGMT ( c ) surrogate compound dosing ; and gene , so it is believed that other causes for loss of MGMT ( d ) low dose pre -testing for enzymatic status . activity are involved in the majority of cases where it occurs . The role of O®- methylguanine DNA methyltransferase Methylation of cytosine in CpG dinucleotides is the main (MGMT ) in human cancer has been described in M . Esteller epigenetic modification of DNA in normal mammalian cells . & J . G . Herman , “ Generating Mutations but Providing 45 The human MGMT gene possesses a CpG island in the 5 Chemosensitivity : The Role of O?-Methylguanine DNA portion of the gene . Hypermethylation of normally unmeth Methyltransferase in Human Cancer, " Oncology 23 : 1 - 8 ylated CpG islands in the promoter regions of many genes , ( 2004 ) , incorporated herein by this reference. MGMT is a including p161NK4a, p144RF , VHL , BRCA1, hMLH1 and DNA repair protein that removes mutagenic and cytotoxic E -cadherin , correlates with loss of transcription of the genes adducts from Oº- guanine in DNA . Alkylation of DNA at the 50 involved . Hypermethylation of the MGMT CpG island as O position of guanine is an important step in the formation the cause of MGMT transcriptional silencing in cell lines of mutations associated with malignancies, primarily due to defective in O ' -methylguanine repair has been demon the tendency of the Oº- methylguanine to pair with thymine strated . As for other genes inactivated by CPG island meth during replication , resulting in the conversion of guanine ylation , hypermethylation of the promoter region is accom cytosine to adenine - thymine pairs ( i. e ., transversion muta - 55 panied by histone hypoacetylation and methylation , binding tions ) in DNA . Furthermore , the Oº- alkylguanine - DNA of specific methyl- binding proteins, and loss of normal adduct ( especially the Oº- chloroethylguanine ) may cross - nucleosomepositioning . All of these alterations can result in link with the opposite cytosine residues, blocking DNA a " closed " chromatin state that prevents gene transcription . replication , which requires separation of the two nucleotide It has also been shown that in vitro treatment of cancer cells strands of the double helix . MGMT protects cells against 60 with demethylation - inducing drugs restores MGMT expres these lesions , transferring the alkyl group from the OC - gua - sion . nine in DNA to an active cysteine within its own sequence Typically , in cancer, the loss of MGMT function is in a reaction that inactivates one MGMTmolecule for each associated with hypermethylation of the promoter region in lesion repaired . The alkylated MGMT protein then becomes a wide spectrum of human tumors; these tumors include detached from DNA and is targeted for degradation by 65 gliomas, lymphomas, colon , head and neck and non - small ubiquitination , which marks the ubiquitinated protein for cell lung carcinomas . This aberrant MGMT promoter meth degradation . Accordingly, the ability of a cell to withstand ylation has been correlated with loss of MGMT protein , lack US 9 ,901 , 563 B2 39 40 of mRNA expression , and loss of enzymatic activity . The occurrence is strongly associated with hypermethylation of promoter hypermethylation is considered to be an early the MGMT promoter ; these mutations have been found in event in carcinogenesis . colon cancer, gliomas , and non - small - cell lung carcinomas . The causes of mutations in oncogenes and tumor sup . However, a reduction in functional MGMTactivity is also pressor genes are multifactorial. Exogenous and endogenous 5 associated with increased sensitivity to alkylating agents , a compounds are known to cause damage in DNA , including number of which result in the generation of alkylation at the deletions, insertions and base substitutions, either transver - O position of guanine . Thus, hypermethylation of the sions (change of purine to pyrimidine or vice versa ) or MGMT promoter can be associated with enhanced sensitiv transitions , change or purine to another purine or pyrimidine ity of tumors with such hypermethylation to alkylating to another pyrimidine . A number of well -known reactions 10 agents . However, there is no associated enhanced sensitivity have been shown to generate point mutations . These reac - for cisplatin , but there is for cyclophosphamide . tions include : deamination of cytosine and 5 -methylcytosine It is important to note that MGMT hypermethylation to uracil and thymine , respectively ; depurination ; DNA alone , without treatment with an alkylating agent, is not a polymerase infidelity ; and oxidative damage from endog - good prognostic factor. In fact , it is a poor prognostic factor, enously produced free radicals . Other sources for mutations 15 probably due to the finding that patients with epigenetic include abnormalities in DNA repair or replication . Several silencing of MGMT accumulate more mutations in genes mechanisms can be invoked to contribute to the infidelity of such as p53 and K -ras . This is an example of the difference DNA synthesis , including imbalances in deoxynucleotide between predictive and prognostic markers . Prognostic triphosphate pools , mutations in DNA polymerase - a and markers suggest a difference in outcome that is independent slippage of DNA polymerase at nucleotide repeats . 20 of the treatment received , including the possibility of no In particular , one mutator pathway has been defined in treatment. Predictive markers , on the other hand , predict a human cancer. Germline mutations in the two DNA mis - response , and thereby often survival differences, related to a match repair (MMR ) genes hMLH1 and hMSH2 are the specific form of therapy . Thus , while both types of markers genetic abnormalities responsible for the vast majority of can predict differences in survival , predictive markers poten hereditary nonpolyposis colorectal carcinoma cases ; in these 25 tially provide information leading to treatment decisions. cancers , the presence of deletions and insertions in micro - MGMT methylation is definitively a negative prognostic satellite sequences is a common hallmark . However, in the marker , but a positive predictive marker. Therefore, an nonfamilial cases , the presence of microsatellite instability analysis of the existence or lack of hypermethylation of the is attributable to methylation -associated silencing of MGMT promoter can be used in determination of chemo hMLH1 as indicated by the extremely tight association 30 therapeutic strategies. It is also possible to promote sensi between both phenomena , the restoration of MMR activity tivity of tumors to alkylating agents by administration of the using demethylating agents , and the early ( premalignant) MGMT inhibitor Oº- benzylguanine. appearance of hMLH1 hypermethylation . The resulting epi - U .S . Pat. No. 9, 050 ,280 to Vlassenbroeck et al. , incorpo genetic silencing ofhMLH1 then leads to mutations in target rated herein by this reference, discloses a method of detect genes such as BAX or TGFRBII . 35 ing the presence and / or amount of a methylated or unmeth Methylation -mediated silencing of MGMT causes ylated gene of interest in a DNA - containing sample that another strong and important mutator pathway in human comprises the steps of: (i ) contacting the DNA -containing cancer ; this mutator pathway is considered to be more sample with a reagent which selectively modifies unmeth prevalent than microsatellite instability . The persistence of ylated cytosine residues in the DNA to produce detectable O®- methylguanine adducts , resulting from alkylating agents , 40 modified residues but which does not modify methylated may cause DNA polymerase to misread base pairing accord cytosine residues ; ( ii ) amplifying at least a portion of the ing to the normal Watson - Crick scheme because of the methylated or unmethylated gene of interest using at least altered hydrogen -bonding properties of a base that contains one primer pair , at least one primer of which is designed to an additional methyl or ethyl group . Thus, O®- methylgua - bind only to the sequence of methylated or unmethylated nine is read as an adenine and mispairs with thymine . 45 DNA following treatment with the reagent, wherein at least Supporting these data , the most common mutations caused one primer in the primer pair produces a detectable fluores by alkylating agents are G : C to A : T transitions exemplified cence signal during amplification which is detected in real in the frequent generation of G to A transitions in the time; and ( iii ) quantifying the results of the real - time detec oncogene K - ras when the carcinogen N -methylnitrosourea , tion against a standard curve for the methylated or a mutagen that forms Oº- methylguanine adducts, is used in 50 unmethylated gene of interest to produce an output of gene experimentally induced tumor systems. The mutagenic copy number . Preferred reagents that selectively modify effect is avoided if functional MGMTactivity is present, and unmethylated cytosine residues in the DNA to produce MGMT expression has been shown to protect mammalian detectable modified residues but which do not modify meth cell lines from spontaneous G : C to A : T transitions in the aprt y lated cytosine residues include bisulfites, such as sodium gene. MGMT inactivation is also strongly associated with 55 bisulfite . The method can employ fluorescence resonance K - ras mutations in human tumors. K -ras mutation is rare in energy transfer ( FRET) for detection . This method can be human primary breast carcinomas, but occurs in approxi used for determination of the methylation status of the mately half of colorectal carcinomas. This mutation distri - MGMT promoter. bution strongly resembles the pattern of MGMT promoter United States Patent Application Publication No. 2007 / hypermethylation described ; while MGMT aberrant meth - 60 0264672 by Dasmahapatra et al ., incorporated herein by this ylation is not present in breast carcinomas where K - ras reference , discloses methods for assaying MGMT activity , mutations are extremely rare, it occurs in approximately including an immunoassay method , a method employing 40 % of cases of colorectal carcinomas associated with loss labeled O -benzylguanine , and a fluorescence polarization of MGMT expression , and is also frequent in non - small - cell method . lung carcinoma. Mutations that could be reversed by the 65 Isocitrate dehydrogenase ( IDH ) is an enzyme that nor activity of MGMT are also frequently found in the p53 gene ; mally catalyzes the oxidative decarboxylation of isocitrate , typically , these are again G :C to A : T transitions, and their producing a -ketoglutarate and CO2. This is a two - step US 9 ,901 , 563 B2 41 process , which involves oxidation of isocitrate ( a secondary alcohol) to oxalosuccinate ( a ketone ), followed by the decar ( S - II) boxylation of the carboxyl group ß to the ketone, forming a -ketoglutarate . In humans, IDH exists in three isoforms: Ra IDH3 catalyzes the third step of the citric acid cycle while 5 o Mn O- RO converting NAD + to NADH in the mitochondria . The iso forms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP + as a cofactor instead of NAD +. They localize to the cytosol as wherein : (i ) each R " and R is independently hydrogen , a well as the mitochondrion and peroxisome. In the context of 10 metal ion , or a negative charge ; ( ii ) R° is a hydrogen bond cancer therapy, the significant isoforms are IDH1 and IDH2, donor or acceptor, and can be bound to the carbon chain by especially IDH1. Specific mutations in the isocitrate dehy a single or double bond , as indicated by the dashed line; and drogenase gene IDH1 have been found in several brain ( iii ) n is 0 , 1 , or 2 . Alternatively , an inhibitor of the tumors including astrocytoma, oligodendroglioma, and glio - 15 neoactivity can be administered . blastoma multiforme, with mutations found in nearly all U . S . Pat. No . 8 , 685, 660 to Vogelstein et al. , incorporated cases of secondary glioblastomas which develop from herein by this reference , discloses clinically significant lower - grade gliomas , but rarely in primary high - grade glio - mutations in IDH1 and IDH2, including: R132H in IDHI, blastoma multiforme ( F . E . Bleeker et al. , “ Recent Advancesces R132S in IDH1, R132C in IDH1, R132L in IDH1 , R132G in the Molecular Understanding of Glioblastoma " J . New 2 in IDH1, R172M in IDH2, R172K in IDH2, and R172G in rooncol. 108: 11 - 27 ( 2012 ) , incorporated herein by this IDH2 . reference ). Patients whose tumor had an IDH1 mutation had When the improvement is made by analysis of patient or longer survival . Furthermore , mutations of IDH2 and IDH1 disease genotype , the analysis of patient or disease genotype were found in up to 20 % of cytogenetically normal acute can be , but is not limited to , a method of analysis of patient myeloid leukemia ( AML ) ( P . S . Ward et al. , “ The Common 25 or disease genotype carried out by a method selected from Feature of Leukemia -Associated IDH1 and IDH2 Mutations the group consisting of: is a Neomorphic Enzyme Activity Converting a - ketoglut ( a ) use of a diagnostic tool , a diagnostic technique , a diagnostic kit , or a diagnostic assay to confirm a arate to 2 -Hydroxyglutarate , ” Cancer Cell 17 : 225 - 234 patient' s particular genotype ; (2010 ), incorporated herein by this reference ). These muta ( b ) use of a gene chip ; tions are known to produce (D )- 2- hydroxyglutarate , an ( c ) use of gene expression analysis ; abnormal product , from a -ketoglutarate . ( D ) - 2 -hydroxyglu ( d ) use of single nucleotide polymorphism (SNP ) analy tarate can then accumulate to very high concentrations, sis ; and which inhibits the function of enzymes that are dependenton (e ) measurement of the level of a metabolite or a meta a - ketoglutarate . This leads to a hypermethylated state of 25 bolic enzyme. DNA and histones, which results in different gene expres The use of gene chips is described in A . J. Lee & S. sion that can activate oncogenes and inactivate tumor - Ramaswamy. “ DNA Microarrays in Biological Discovery suppressor genes. Ultimately , this may lead to the types of and Patient Care ” in Essentials of Genomic and Personal cancer described above ( R . J . Molenaar et al . , “ The Driver ized Medicine (G . S . Ginsburg & H . F . Willard , eds. , and Passenger Effects of Isocitrate Dehydrogenase 1 and 2 40 Academic Press , Amsterdam , 2010 ) , ch . 7 , pp . 73 - 88 , incor Mutations in Oncogenesis and Survival Prolongation ,” Bio - porated herein by this reference . chim . Biophys. Acta 1846 : 326 -341 ( 2014 ) , incorporated When the method is the use of single nucleotide poly herein by this reference ) . morphism (SNP ) analysis , the SNP analysis can be carried U . S . Pat. No. 8, 883, 438 to Cantley et al. , incorporated out on a gene selected from the group consisting of histone herein by this reference , discloses methods of diagnosing a 45 deacetylase , ornithine decarboxylase , VEGF, a prostate spe subject having a cell proliferation - related disorder or sus cific gene , c - Jun , and a protein kinase . The use of SNP pected of having a cell proliferation -related disorder char - analysis is described in S . Levy and Y .- H . Rogers , “ DNA acterized by : (i ) the presence, distribution , or level of an Sequencing for the Detection ofHuman Genome Variation ” isocitrate dehydrogenase 1 enzyme having a mutation at in Essentials of Genomic and Personalized Medicine ( G . S . residue 97 wherein the glycine residue has been replaced 50 Ginsburg & H . F . Willard , eds. , Academic Press, Amster with an aspartic acid residue ( IDH1-G97D ) , which has dam , 2010 ) , ch . 3 , pp . 27 - 37 , incorporated herein by this 2 -hydroxyglutarate (2HG ) neoactivity , wherein 2HG neoac - reference . tivity is the ability to convert a -ketoglutarate to 2 -hydroxy - Still other genomic techniques such as copy number glutarate , or ( ii ) elevated levels of 2HG due to the presence variation analysis and analysis of DNA methylation can be of IDH1- G97D mutant enzyme having 2HG neoactivity , 55 employed . Copy number variation analysis is described in C . wherein the method comprises analyzing the presence , dis - Lee et al. , “ Copy Number Variation and Human Health ” in tribution , or level of 2HG in a tissue , product, or bodily fluid Essentials of Genomic and Personalized Medicine ( G . S . of said subject by a chromatographic method , wherein an Ginsburg & H . F . Willard , eds ., Academic Press, Amster increased presence , distribution , or level of 2HG indicates dam , 2010 ), ch . 5 , pp . 46 -59 , incorporated herein by this the presence of the cell proliferation - related disorder, 60 reference . DNA methylation analysis is described in S . thereby diagnosing the subject for the cell proliferation Cottrell et al. , “ DNA Methylation Analysis : Providing New related disorder. The chromatographic method can be LC - Insight into Human Disease ” in Essentials of Genomic and MS or GC -MS . Alternatively , a mutation can be an IDH2 Personalized Medicine (G . S . Ginsburg & H . F . Willard , 137 mutation . A method for treating a malignancy eds . , Academic Press , Amsterdam , 2010 ) , ch . 6 , pp . 60 - 72 , characterized by a mutation in IDH can include administra - 65 incorporated herein by this reference . tion of a cellular structural analog of an a -hydroxy neoac When the improvement is made by pre / post- treatment tivity product of Formula ( S -II ): preparation , the pre /post -treatment preparation can be , but is US 9 ,901 , 563 B2 43 44 not limited to , a method of pre /post treatment preparation be used in a similar manner. GM - CSF is granulocyte mac selected from the group consisting of: rophage colony - stimulating factor and stimulates stem cells ( a ) the use of colchicine or an analog thereof; to produce granulocytes ( eosinophils , neutrophils , and baso ( b ) the use of a uricosuric ; phils ) and monocytes ; its administration is useful to prevent ( c ) the use of uricase ; 5 or treat infection . (d ) the non -oral use of nicotinamide ; Anti - inflammatory agents are well known in the art and ( e ) the use of a sustained -release form of nicotinamide ; include corticosteroids and non -steroidal anti- inflammatory (f ) the use of an inhibitor of poly - ADP ribose polymerase ; agents (NSAIDs ) . Corticosteroids with anti -inflammatory ( g ) the use of caffeine ; activity include , but are not limited to , hydrocortisone , ( h ) the use of leucovorin rescue ; ( i ) infection control ; and cortisone, beclomethasone dipropionate , betamethasone , (j ) the use of an anti - hypertensive agent. dexamethasone , prednisone , methylprednisolone , triamci Uricosurics include , but are not limited to , probenecid , nolone , fluocinolone acetonide , and fludrocortisone . Non benzbromarone , and sulfinpyrazone. A particularly preferred steroidal anti- inflammatory agents include , but are not lim uricosuric is probenecid . Uricosurics, including probenecid , 15 ited to , acetylsalicylic acid (aspirin ), sodium salicylate , may also have diuretic activity . choline magnesium trisalicylate , salsalate , diflunisal, sul Poly -ADP ribose polymerase inhibitors are described in fasalazine , olsalazine, acetaminophen , indomethacin , sulin G . J. Southan & C . Szabó , “ Poly (ADP - Ribose ) Inhibitors, ” dac , tolmetin , diclofenac, ketorolac , ibuprofen , naproxen , Curr. Med . Chem . 10 : 321- 240 ( 2003 ) , incorporated herein flurbiprofen , ketoprofen , fenoprofin , oxaprozin , mefenamic by this reference , and include nicotinamide, 3 - aminobenz - 20 acid , meclofenamic acid , piroxicam , meloxicam , nabume amide, substituted 3, 4 -dihydroisoquinolin - 1 (2H ) -ones and tone , rofecoxib , celecoxib , etodolac , nimesulide , ace isoquinolin - 1 (2H ) -ones , benzimidazoles , indoles , clofenac , alclofenac , alminoprofen , amfenac , ampiroxicam , phthalazin - 1 ( 2H ) -ones , quinazolinones , isoindolinones , apazone , araprofen , azapropazone , bendazac , benoxaprofen , phenanthridinones, and other compounds. benzydamine, bermoprofen , benzpiperylon , bromfenac , Leucovorin rescue comprises administration of folinic 25 bucloxic acid , bumadizone , butibufen , carprofen , cimicoxib , acid ( leucovorin ) to patients in which methotrexate has been cinmetacin , cinnoxicam , clidanac, clofezone, clonixin , administered . Leucovorin is a reduced form of folic acid that clopirac , darbufelone , deracoxib , droxicam , eltenac , enfe bypasses dihydrofolate reductase and restores hematopoietic namic acid , epirizole , esflurbiprofen , ethenzamide , etofena function . Leucovorin can be administered either intrave - mate , etoricoxib , felbinac , fenbufen , fenclofenac , fenclozic nously or orally . 30 acid , fenclozine , fendosal, fentiazac , feprazone , filenadol, In one alternative , wherein the pre / post treatment is the flobufen , florifenine , flosulide , flubichin methanesulfonate , use of a uricosuric , the uricosuric is probenecid or an analog flufenamic acid , flufenisal, flunixin , flunoxaprofen , flupro thereof. fen , fluproquazone, furofenac , ibufenac , imrecoxib , indo When the improvement is made by toxicity management, profen , isofezolac , isoxepac , isoxicam , licofelone , lobupro the toxicity management can be , but is not limited to , a 35 fen , lomoxicam , lonazolac , loxaprofen , lumaricoxib , method of toxicity management selected from the group mabuprofen , miroprofen , mofebutazone , mofezolac , mora consisting of: zone , nepafanac , niflumic acid , nitrofenac , nitroflurbiprofen , ( a ) the use of colchicine or an analog thereof; nitronaproxen , orpanoxin , oxaceprol, oxindanac , oxpinac , ( b ) the use of a uricosuric ; oxyphenbutazone , pamicogrel, parcetasal , parecoxib , ( c ) the use of uricase ; 40 parsalmide , pelubiprofen , pemedolac , phenylbutazone, pira ( d ) the non -oral use of nicotinamide; zolac , pirprofen , pranoprofen , salicin , salicylamide , salicyl ( e ) the use of a sustained - release form of nicotinamide ; salicylic acid , satigrel , sudoxicam , suprofen , talmetacin , (f ) the use of an inhibitor of poly - ADP ribose polymerase ; talniflumate , tazofelone, tebufelone , tenidap , tenoxicam , ( g ) the use of caffeine; tepoxalin , tiaprofenic acid , tiaramide , tilmacoxib , tinoridine , ( h ) the use of leucovorin rescue ; 45 tiopinac , tioxaprofen , tolfenamic acid , triflusal, tropesin , ( i ) the use of sustained - release allopurinol; ursolic acid , valdecoxib , ximoprofen , zaltoprofen , zidometa ( i) the non -oral use of allopurinol; cin , and zomepirac, and the salts , solvates, analogues, con ( k ) the use of bone marrow transplants ; geners , bioisosteres, hydrolysis products , metabolites, pre ( 1 ) the use of a blood cell stimulant ; cursors , and prodrugs thereof. ( m ) the use of blood or platelet infusions ; 50 The clinical use of corticosteroids is described in B . P . ( n ) the administration of an agent selected from the group Schimmer & K . L . Parker , " Adrenocorticotropic Hormone ; consisting of filgrastim (Neupogen® ) , G - CSF , and Adrenocortical Steroids and Their Synthetic Analogs ; GM - CSF ; Inhibitors of the Synthesis and Actions of Adrenocortical ( c ) the application of a pain management technique; Hormones ” in Goodman & Gilman ' s The Pharmacological ( p ) the administration of an anti- inflammatory agent; 55 Basis of Therapeutics ( L . L . Brunton , ed . , 11th ed ., McGraw (q ) the administration of fluids; Hill, New York , 2006 ), ch . 59, pp . 1587 - 1612 , incorporated (r ) the administration of a corticosteroid ; herein by this reference. ( s ) the administration of an insulin control medication ; Anti -nausea treatments include , but are not limited to , (t ) the administration of an antipyretic ; ondansetron , metoclopramide , promethazine , cyclizine , ( u ) the administration of an anti - nausea treatment ; 60 hyoscine , dronabinol, dimenhydrinate , diphenhydramine , ( v ) the administration of an anti -diarrheal treatment; hydroxyzine, medizine, dolasetron , granisetron , palonose ( w ) the administration of N -acetylcysteine ; and tron , ramosetron , domperidone , haloperidol, chlorpromaz ( x ) the administration of an antihistamine . ine , fluphenazine , perphenazine, prochlorperazine, betame Filgrastim is a granulocytic colony - stimulating factor thasone, dexamethasone , lorazepam , and thiethylperazine . (G -CSF ) analog produced by recombinant DNA technology 65 Anti- diarrheal treatments include , but are not limited to , that is used to stimulate the proliferation and differentiation diphenoxylate , difenoxin , loperamide , codeine , racecadotril , of granulocytes and is used to treat neutropenia ; G - CSF can octreoside , and berberine . US 9 , 901, 563 B2 45 46 N -acetylcysteine is an antioxidant and mucolytic that also platin , cyclophosphamide, American Cyanamid CL - 286558 , provides biologically accessible sulfur. Sanofi CY- 233 , cyplatate , Degussa D - 19- 384, Sumimoto When the improvement is made by pharmacokinetic DACHP (Myr )2 , diphenylspiromustine , diplatinum cyto pharmacodynamic monitoring , the pharmacokinetic / phar static , Erba distamycin derivatives, Chugai DWA -2114R , macodynamic monitoring can be, but is not limited to a 5 ITI E09 , elmustine , Erbamont FCE - 24517 , estramustine method selected from the group consisting of: phosphate sodium , fotemustine , Unimed G - 6 - M , Chinoin ( a ) multiple determinations of blood plasma levels ; and GYKI- 17230 , hepsul- fam , ifosfamide , iproplatin , lomustine , ( b ) multiple determinations of at least one metabolite in mafosfamide , melphalan , mitolactol, Nippon Kayaku blood or urine. NK - 121 , NCI NSC - 264395 , NCI NSC - 342215 , oxaliplatin , Typically , determination of blood plasma levels or deter- 10 Upjohn PCNU , prednimustine, Proter PTT - 119 , rani mination of at least one metabolite in blood or urine is mustine , semustine , SmithKline SK & F - 101772 , Yakult carried out by immunoassays . Methods for performing Honsha SN -22 , spiromustine , Tanabe Seiyaku TA - 077 , tau immunoassays are well known in the art , and include romustine, temozolomide , teroxirone, tetraplatin and radioimmunoassay, ELISA (enzyme - linked immunosorbent trimelamol, as described in U . S . Pat . No. 7 ,446 , 122 by Chao assay ) , competitive immunoassay, immunoassay employing 15 et al. , incorporated herein by this reference . lateral flow test strips , and other assay methods. Anti - tubulin agents include , but are not limited to , vinca When the improvement is made by drug combination , the alkaloids, taxanes, podophyllotoxin , halichondrin B , and drug combination can be , but is not limited to , a drug homohalichondrin B . combination selected from the group consisting of: Antimetabolites include , but are not limited to : metho ( a ) use with topoisomerase inhibitors ; 20 trexate , pemetrexed , 5 - fluorouracil , capecitabine , cytara ( b ) use with fraudulent nucleosides ; bine , gemcitabine, 6 -mercaptopurine , and pentostatin , ( c ) use with fraudulent nucleotides ; alanosine, AG2037 ( Pfizer ) , 5 - FU - fibrinogen , acanthifolic ( d ) use with thymidylate synthetase inhibitors ; acid , aminothiadiazole , brequinar sodium , carmofur , Ciba ( e ) use with signal transduction inhibitors ; Geigy CGP - 30694 , cyclopentyl cytosine, cytarabine phos ( f ) use with cisplatin or platinum analogs ; 25 phate stearate , cytarabine conjugates , Lilly DATHF, Merrill (g ) use with alkylating agents ; Dow DDFC , deazaguanine, dideoxycytidine , ( h ) use with anti- tubulin agents ; dideoxyguanosine , didox , YoshitomiDMDC , doxifluridine , ( i ) use with antimetabolites ; Wellcome EHNA , Merck & Co . EX -015 , fazarabine , floxu ( i) use with berberine ; ridine , fludarabine phosphate , N - ( 2 ' -furanidyl ) - 5 - fluoroura ( k ) use with apigenin ; 30 cil , Daiichi Seiyaku FO - 152 , isopropyl pyrrolizine , Lilly ( 1 ) use with amonafide; LY- 188011, Lilly LY - 264618 , methobenzaprim , methotrex ( m ) use with vinca alkaloids; ate , Wellcome MZPES , norspermidine , NCI NSC - 127716 , ( n ) use with 5 - fluorouracil ; NCI NSC -264880 , NCI NSC - 39661, NCI NSC -612567 , ( 0 ) use with curcumin ; Warner- Lambert PALA , piritrexim , plicamycin , Asahi (p ) use with NF -kB inhibitors; Chemical PL - AC , Takeda TAC - 788 , thioguanine, tiazofurin , ( q ) use with rosmarinic acid ; Erbamont TIF, trimetrexate , tyrosine kinase inhibitors, tyro ( r ) use with mitoguazone ; sine protein kinase inhibitors , Taiho UFT and uricytin . ( s ) use with tetrandrine ; Berberine has antibiotic activity and prevents and sup ( t) use with an inhibitor of mutant isocitrate dehydroge presses the expression of pro - inflammatory cytokines and nase (IDH ) ; 40 E - selectin , as well as increasing adiponectin expression . ( u ) use with a MGMT inhibitor, and Apigenin is a flavone that can reverse the adverse effects ( v ) use with an agent that inhibits NF -KB -enhanced of cyclosporine and has chemoprotective activity , either expression of MGMT. alone or derivatized with a sugar. Topoisomerase inhibitors include , but are not limited to , Amonafide is a topoisomerase inhibitor and DNA inter irinotecan , topotecan , camptothecin , lamellarin D , amsa - 45 calator that has anti - neoplastic activity . crine , etoposide , etoposide phosphate, teniposide, doxoru - Curcumin is believed to have anti -neoplastic , anti - inflam bicin , and ICRF - 193 . matory , antioxidant, anti - ischemic , anti - arthritic , and anti Fraudulent nucleosides include , but are not limited to , amyloid properties and also has hepatoprotective activity . cytosine arabinoside , gemcitabine , and fludarabine ; other NF -kB inhibitors include , but are not limited to , bort fraudulent nucleosides are known in the art . 50 ez Fraudulent nucleotides include , but are not limited to , Rosmarinic acid is a naturally - occurring phenolic anti tenofovir disoproxil fumarate and adefovir dipivoxil ; other oxidant that also has anti - inflammatory activity . fraudulent nucleotides are known in the art . Mitoguazone is an inhibitor of polyamine biosynthesis Thymidylate synthetase inhibitors include , but are not through competitive inhibition of S - adenosylmethionine limited to , raltitrexed , pemetrexed , nolatrexed , ZD9331, 55 decarboxylase . GS7094L , fluorouracil, and BGC 945 . Tetrandrine has the chemical structure 6 , 6 ', 7 ,12 - tetram Signal transduction inhibitors are described in A . V . Lee ethoxy - 2 , 2 - dimethyl- 1 B -berbaman and is a calcium chan et al. , “ New Mechanisms of Signal Transduction Inhibitor nel blocker that has anti - inflammatory , immunologic , and Action : Receptor Tyrosine Kinase Down -Regulation and antiallergenic effects , as well as an anti - arrhythmic effect Blockade of Signal Transactivation , " Clin . Cancer Res . 9 : 60 similar to that of quinidine . It has been isolated from 516s (2003 ), incorporated herein in its entirety by this Stephania tetranda and other Asian herbs. reference . In one alternative , when the drug combination is use with Alkylating agents include, but are not limited to , Shionogi an alkylating agent, the alkylating agent can be selected 254 - S , aldo - phosphamide analogues , altretamine , anax - from the group consisting of BCNU , BCNU wafers (Glia irone , Boehringer Mannheim BBR - 2207 , bendamustine , 65 del ) , and CCNU . bestrabucil , budotitane , Wakunaga CA - 102 , carboplatin , Inhibitors of mutant isocitrate dehydrogenase ( IDH ) are carmustine, Chinoin - 139, Chinoin - 153 , chlorambucil, cis - known in the art . US 9 ,901 , 563 B2 47 48 U .S . Pat . No. 8 ,957 , 068 to Caferro et al ., incorporated ( ix ) wherein said aryl, heteroaryl, heterocyclic and C3 -C10 herein by this reference , discloses 3 - pyrimidin - 4 -yl - oxazo cycloalkyl are optionally substituted with one to three lidin -2 -ones as inhibitors of mutant IDH , including com substituents each independently selected from the pounds of Formula (S -1 ) : group consisting of: halo ; hydroxyl ; cyano ; nitro ; CZ -C4 alkoxy; C , -Cz haloalkyl ; C ,- Cz haloalkoxy; C1- C6 alkyl; Cz- Co cycloalkyl optionally substituted ( S - I) with one to three substituents each independently selected from the group consisting of: hydroxyl, cyano , C - Cz alkyl, C , - Cz alkoxy, and C , - Cz haloalkyl; phenyl 10 optionally substituted with one to three substituents each independently selected from the group consisting HN N of: halo , hydroxyl, cyano , nitro , C -Cz alkoxy , C , -CZ R5a haloalkyl, C -Cz haloalkoxy, C1 -C6 alkyl, Cz -Co D? cycloalkyl, 5 -6 membered heteroaryl, 5 - 6 membered R6 R56 R46 R heterocyclic , phenoxy, COOR , SOR ", - NHC R46 R32 (O ) R " , and — NRÞRÓ ; 5 -6 membered heteroaryl option ally substituted with one to three substituents each wherein : independently selected from the group consisting of: ( i) RP and R2 are each independently hydrogen , deute - 30 halo , hydroxyl, cyano , C -Cz alkyl, C -Cz alkoxy ; 5 -6 rium , halo , hydroxyl, NH2, aryl, heteroaryl, or option membered heterocyclyl optionally substituted with one ally substituted C ,- C4 alkyl, wherein C , - C4 alkyl is to three substituents each independently selected from optionally substituted with one to three substituents the group consisting of: halo , hydroxyl , oxo , NH2, and each independently selected from the group consisting C2- Cz alkyl ; _ CH _ R " ; - OR " ; - C (O )R " ; - NR “ R " ; of: halo , hydroxyl, and NH?; 25 _ COOR “ ; — SO R "; SO , R "; NHC (O )R "; — NHC ( ii ) R3a is hydrogen , deuterium , C7 -C . alkyl, phenyl, or ( O ) R " ; - C ( O )NR " R " ; C ( O )NHR " ; and benzyl; - SO?NR " R " ; or (iii ) R36 is hydrogen , deuterium , C . - C . alkyl; or R3a and ( x ) R $ 6 and R? are joined together forming an optionally R36 are joined together forming an optionally substi substituted C3- C , cycloalkyl group or an optionally tuted 3 -7 membered cycloalkyl ring or an optionally 30 substituted group of Formula ( S - I ( a ) ) : substituted 4 - 7 membered heterocyclic ring , wherein said cycloalkyl and heterocyclic rings are each option ally substituted with one or two substituents each ( S - I ( a )) independently selected from the group consisting of : halo , hydroxyl, oxo, NH2, and C , - Cz alkyl; (iv ) R4a is hydrogen , C . - C . alkyl, optionally substituted phenyl , optionally substituted benzyl , optionally sub stituted heteroaryl, or methylene -dibenzene , wherein said phenyl, benzyl, and heteroaryl rings are optionally 10 substituted with one to three substituents each indepen dently selected from the group consisting of: halo , wherein n is 1 , 2 , or 3 ; and hydroxyl , cyano , nitro , C , -C4 alkoxy, C . -Cz haloalkyl, ( xii) said C3- C , cycloalkyl and group of formula (a ) are C , - Cz haloalkoxy, C , - Co alkyl, Cz- Co cycloalkyl, phe optionally substituted with one to three substituents nyl, 5 -6 membered heteroaryl, 5 - 6 membered hetero - 45 each independently selected from the group consisting cyclic , phenoxy, COOR ", SOR" , NHC (O )R ", of: halo , hydroxyl, cyano , nitro , C1- C2 alkoxy, C7 -C3 and — NR ” R ; haloalkyl, C1- Cz haloalkoxy, C . - C . alkyl, Cz -Co ( v ) R4b is hydrogen , deuterium , or C , -Cz alkyl, or R4a and cycloalkyl , 5 - 6 membered heteroaryl, 5 -6 membered R h are joined together forming an optionally substi heterocyclyl, benzyloxy, COOR " , - SO , R " , - NHC tuted 3 - 7 membered cycloalkyl ring or an optionally 50 ( O ) R ' , and — NROR " ; substituted 4 - 7 membered heterocyclic ring , wherein (xiii ) each R is independently optionally substituted said cycloalkyl and heterocyclic rings are optionally phenyl, optionally substituted heteroaryl, optionally substituted with one or two substituents each indepen substituted heterocyclic , or optionally substituted dently selected from the group consisting of: halo , C3 - C , cycloalkyl, hydroxyl, oxo , NH2, and C , -Cz alkyl, provided that 55 (xiv ) wherein said phenyl and heteroaryl are optionally only one of R3a and R36 and R4a and R45 are joined substituted with one to three substituents each indepen together forming a ring ; dently selected from the group consisting of halo , ( vi) R $ a is hydrogen or deuterium ; hydroxyl, cyano , nitro , C , -Cz alkoxy , C7 -Cz haloalkyl, (vii ) RS6 is hydrogen , deuterium ,methyl , ethyl, CD3, CF3, C1- Cz haloalkoxy , and C1- C2 alkyl, CH F , or CHF2 and 60 ( XV ) wherein said heterocyclic is optionally substituted (viii ) R is optionally substituted C . - C . alkyl , optionally with one to three substituents each independently substituted aryl , optionally substituted heteroaryl, selected from the group consisting of halo , hydroxyl, optionally substituted heterocyclyl, or optionally sub oxo , C , -Cz alkoxy, C . - Cz haloalkyl, C . - Cz haloalkoxy , stituted C3 -C10 cycloalkyl; C , -C4 alkyl, Cz- C , cycloalkyl, - C ( O )R ", and ( viii ) wherein said C , - Co alkyl is optionally substituted 65 NR ' R ; and with one substituent selected from the group consisting ( xvi) wherein said C3- C , cycloalkyl is optionally substi of hydroxyl, C , -Cz alkoxy and - OR " ; tuted with one to three substituents each independently US 9 ,901 , 563 B2 49 50 selected from the group consisting of halo , hydroxyl, ( iv ) X , is - S 0 - , - S ( O ) 2 - - C (R20 ) (R21 ) — or oxo , C , - Cz alkoxy , C1- C2 haloalkyl, C . - Cz haloalkoxy, - N (RB ) — , wherein Ro is independently hydrogen , and C . -Cz alkyl; and aliphatic , substituted aliphatic , heteroaryl, substituted (xvii ) each R is independently hydrogen or C , - C . alkyl. heteroaryl, aryl or substituted aryl; U .S . Pat . No . 8 ,883 ,438 to Cantley et al ., incorporated 5 ( v ) each R , and R , is independently hydrogen , halogen , herein by this reference , discloses methods of diagnosing a aliphatic , substituted aliphatic , aryl or substituted aryl ; subject having a cell proliferation - related disorder or sus (vi ) Rz is hydrogen , halogen , aliphatic , substituted ali pected of having a cell proliferation -related disorder char phatic , aryl or substituted aryl; acterized by : (i ) the presence , distribution , or level of an ( vii ) each R10 , and R2g is independently absent, hydrogen , isocitrate dehydrogenase 1 enzyme having a mutation at halogen , OR20 , SR203 - NR20 R21 , CF3, CN , residue 97 wherein the glycine residue has been replaced - NO2, N3, C (O )OR20 , C ( O )R20 ; C ( O ) NR20R21 , acyl , alkoxy , substituted alkoxy , alkylamino , with an aspartic acid residue ( IDH1 -G97D ), which has substituted alkylamino , dialkylamino , substituted 2 - hydroxyglutarate ( 2HG ) neoactivity , wherein 2HG neoac dialkylamino , substituted or unsubstituted alkylthio , tivity is the ability to convert a -ketoglutarate to 2 -hydroxy - 15 . substituted or unsubstituted alkylsulfonyl, aliphatic , glutarate , or ( ii ) elevated levels of 2HG due to the presence substituted aliphatic , aryl or substituted aryl, or alter of IDH1- G97D mutant enzyme having 2HG neoactivity , natively two of R10 groups together with the atoms to wherein the method comprises analyzing the presence , dis which they are attached and any intervening atoms may tribution , or level of 2HG in a tissue, product, or bodily fluid form an additional optionally substituted , 3 , 4 , 5 , 6 or of said subject by a chromatographic method , wherein an 20 7 membered ring, wherein each R20 and R21 is inde increased presence , distribution , or level of 2HG indicates pendently hydrogen , halogen , aliphatic , substituted ali the presence of the cell proliferation - related disorder , phatic , aryl or substituted aryl; thereby diagnosing the subject for the cell proliferation ( viii ) each Run is independently absent, hydrogen , halo related disorder. The chromatographic method can be LC gen , OR203 — SR20 — NR20 R21 , CF3, CN , MS or GC -MS . Alternatively , a mutation can be an IDH2 - , - NO2, N3, - C ( O )R20 , - C ( O ) OR20 , C (O ) 137 mutation . A method for treating a malignancy NR20 R21 , acyl, alkoxy, substituted alkoxy, alkylamino , characterized by a mutation in IDH can include administra substituted alkylamino , dialkylamino , substituted tion of a cellular structural analog of an a -hydroxy neoac dialkylamino , substituted or unsubstituted alkylthio , tivity product of Formula ( S -II ): substituted or unsubstituted alkylsulfonyl, aliphatic , 30 substituted aliphatic , aryl or substituted aryl, or alter natively two of R , groups together with the atoms to (S - II) which they are attached and any intervening atoms may form an additional optionally substituted , 3 , 4 , 5 , 6 or Po 7 membered ring ; and - 35 ( ix ) Cyl is an optionally substituted aryl or optionally substituted heteroaryl. United States Patent Application Publication No. 2014 / 0094503 by Ma et al. , incorporated herein by this reference , wherein : (i ) each Ra and R is independently hydrogen , a discloses RNA - interference -mediated interference with metal ion , or a negative charge ; ( ii ) R is a hydrogen bond 4040 expression of IDH1, including interference mediated by donor or acceptor, and can be bound to the carbon chain by small nucleic acid molecules such as short interfering a single or double bond , as indicated by the dashed line ; and nucleic acid ( siNA ), short interfering RNA ( SRNA ) , double ( iii ) n is 0 , 1, or 2 . Alternatively, an inhibitor of the stranded RNA ( dsRNA ) , micro -RNA (miRNA ) , and short neoactivity can be administered . hairpin RNA ( shRNA ) molecules. United States Patent Application Publication No . 2014 / 45 United States Patent Application Publication No . 2013 / 0100223 by Hussain et al. , incorporated herein by this 0109643 by Riggins et al. , incorporated herein by this reference , discloses compounds and methods for the treat reference , discloses methods for treating various forms of ment of isocitrate - dehydrogenase - related diseases , including cancer, including a malignant low - grade glioma, a second compounds?? of Formula ( S - III) : ary glioblastoma, a transforming myeloproliferative disor 50 der ( MPD ) , and an acute myelogenous leukemia (AML ), with glutaminase inhibitors , including , but not limited to : ( S - III ) ( A ) glutaminase inhibitors of Formula ( S - IV ) :

(R1 ) Cyl 55 ( 1) ( 10 )P , RI ( S - IV ) N N N 60 HNHN NH wherein : ( i ) each n and m is independently 0 , 1 , 2 or 3 ; ( ii ) each p and q is independently 0 , 1 , 2 , 3 , 4 , 5, 6 or 7 ; Ri ( iii ) X , is — C ( O ) N (RA ) or — C ( S ) N (R2 ) — , wherein RA is independently hydrogen , aliphatic , substituted 65 wherein X is sulfur or oxygen ; R , and R2 are independently aliphatic , heteroaryl, substituted heteroaryl, aryl or selected from the group consisting of lower alkyl, lower substituted aryl; alkoxyl, aryl, thiophenyl and (CH2 ) n - aryl; wherein n is 0 US 9 ,901 , 563 B2 51 52 or 1 , and aryl is a monocyclic aromatic or heteroaromatic (i ) antimetabolites ; group , having ring atoms selected from the group consisting (j ) berberine; of carbon , nitrogen , oxygen , and sulfur, and having at most ( k ) apigenin ; three non -carbon ring atoms, which group may be unsub (1 ) amonafide ; stituted or substituted with one or more substituents selected 5 from the group consisting of halogen , lower alkyl, lower ( m ) vinca alkaloids; alkoxyl, amino , lower alkyl amino , amino ( lower alkyl) , or ( n ) 5 - fluorouracil; halo (lower alkyl) ; and ( 0 ) curcumin ; ( B ) a compound selected from the group consisting of ( p ) NF -KB inhibitors ; 6 - diazo - 5 - oxo - L -norleucine , acivicin , N - ethylmaleim - 10 ( q ) rosmarinic acid ; ide , p - chloromercuriphenylsulfonate, L - 2 -amino - 4 ( r ) mitoguazone ; and oxo - 5 - chloropentoic acid , azaserine , and 5 - ( 3 - bromo ( S ) tetrandrine . 4 - (dimethylamino )phenyl ) -2 ,2 -dimethyl - 2 ,3 ,5 ,6 When the improvement is made by chemopotentiation , tetrahydrobenzo [ a ]phenanthridin - 4 ( 1H )- one; and the chemopotentiation can comprise, but is not limited to , pharmaceutically acceptable salts thereof; a particucu - 1515 the use of dianhydrogalactitol or diacetyldianhydrogalactitol larly preferred compound is bis -2 - (5 -phenylacetamido as a chemopotentiator in combination with an agent selected 1 , 2 , 4 - thiadiazol- 2 -yl ) ethyl sulfide . from the group consisting of: MGMT inhibitors are known in the art. ( a ) topoisomerase inhibitors ; U .S . Pat. No. 8 ,791 ,081 to Liu et al. , incorporated herein ( b ) fraudulent nucleosides ; by this reference, disclosesjoses thethe use of MGMT inhibitors forfor 2020 ( c ) fraudulent nucleotides ; the treatment of neoplastic disorders . The MGMT inhibitors ( d ) thymidylate synthetase inhibitors ; can include , but are not limited to , Oº- substituted guanine ( e ) signal transduction inhibitors; derivatives or glucose conjugates thereof. Suitable MGMT ( f ) cisplatin or platinum analogs ; inhibitors include Oº- benzylguanine , O? -2 - fluoropyridinyl ( g ) alkylating agents ; methyl guanine , Oº - 3 - iodobenzyl guanine , Oº - 4 -bromophe - 25 ( h ) anti - tubulin agents ; nylguanine, Oº -5 - iodothenylguanine , Oº -benzyl - 8 -oxogua ( i ) antimetabolites ; nine , O?- ( p - chlorobenzyl) guanine, O?- ( p -methylbenzyl ) ( 1) berberine ; guanine , 0 - ( p - bromobenzyl ) guanine, O?- ( p ( k ) apigenin ; isopropylbenzyl) guanine , Oº - ( 3 , 5 -dimethylbenzyl ) guanine , ( 1 ) amonafide ; 0°- ( p - n -butylbenzyl ) guanine, O?- ( p -hydroxymethybenzyl ) 30 ( m ) vinca alkaloids; guanine, O® -benzylhypoxanthine , N² -acetyl -0 -benzylgua ( n ) 5 - fluorouracil; nine, NP -acetyl -O® - benzyl - 8 -oxo - guanine , 2 - amino - 6 - (p ( o ) curcumin ; methyl- benzyl - thio )purine , 2- amino -6 -( benzyloxy )- 9 ( p ) NF -KB inhibitors ; [ (ethoxycarbonyl )methyl ] purine , 2 -amino - 6 -( benzyloxy ) -9 ( q ) rosmarinic acid ; ( pivaloyloxymethyl )purine , 2 - amino - 6 - (benzyl - thio )purine , 35 ( r ) mitoguazone ; and Oº- benzyl - 7 , 8 - dihydro - 8 - oxoguanine , 2 , 4 , 5 - triamino -6 ( s ) tetrandrine . benzyloxyprimidine, O®- benzyl - 9 - [( 3 -oxo -5a -androstan In one alternative , when the chemopotentiation involves 17B -yloxycarbonyl ) methyllguanine , O?- benzyl - 9 -[ (3 -oxo - chemopotentiation of an alkylating agent by the activity of 4 - androsten - 17ß - yloxycarbonyl) methylguanine ], and dianhydrogalactitol or diacetyldianhydrogalactitol . the alky 8 -amino -o? -benzylguanine , as well as C8 - linker - glucose - 40 lating agent can be selected from the group consisting of conjugates thereof. BCNU , BCNU wafers (Gliadel ) , CCNU , bendamustine Inhibitors of NF -kB - enhanced expression of MGMT are ( Treanda ) , and temozolimide ( Temodar ) . known in the art . When the improvement is made by post - treatment man U . S . Pat. No . 8 ,299 , 237 to Lavon , incorporated herein by agement, the post- treatment management can be , but is not this reference , discloses nucleic acid sequences and modi- 45 limited to , a method selected from the group consisting of: fied nucleotides comprising NF -KB binding sites within the ( a ) a therapy associated with pain management; MGMT promoter region that are useful as decoy molecules ( b ) administration of an anti -emetic ; for inhibiting NF - KB - enhanced expression of MGMT. ( c ) an anti -nausea therapy ; Modified nucleotides can include , for example , bicyclic ( d ) administration of an anti - inflammatory agent ; nucleotide analogs , nucleotide analogs that are intercalator 50 ( e ) administration of an anti - pyretic agent; and pseudonucleotide molecules, and peptide analogs of nucleo ( f ) administration of an immune stimulant. tides with repeating N -( 2 -aminoethyl ) - glycine units linked When the improvement is made by alternative medicine by peptide bonds in place of deoxyribose or ribose sugar post - treatment support , the alternative medicine /post - treat backbones . ment support can be, but is not limited to , a method selected When the improvement is made by chemosensitization , 55 from the group consisting of: the chemosensitization can comprise, but is not limited to , ( a ) hypnosis ; the use of dianhydrogalactitol or diacetyldianhydrogalactitol (b ) acupuncture ; as a chemosensitizer in combination with an agent selected ( c ) meditation ; from the group consisting of: ( d ) a herbal medication created either synthetically or ( a ) topoisomerase inhibitors; 60 through extraction ; and ( b ) fraudulent nucleosides ; ( e ) applied kinesiology. ( c ) fraudulent nucleotides; In one alternative, when themethod is a herbal medication ( d ) thymidylate synthetase inhibitors ; created either synthetically or through extraction , the herbal ( e ) signal transduction inhibitors ; medication created either synthetically or through extraction (f ) cisplatin or platinum analogs ; 65 can be selected from the group consisting of: ( g ) alkylating agents ; ( a ) a NF - KB inhibitor ; ( h ) anti - tubulin agents ; ( b ) a natural anti - inflammatory ; US 9 , 901 ,563 B2 53 54 ( c ) an immunostimulant; ( f ) a carbonate buffer ; and ( d ) an antimicrobial; and ( g ) a phosphate buffer . ( v ) a flavonoid , isoflavone, or flavone . When the improvement is made by use of a dosage form , When the herbal medication created either synthetically the dosage form can be, but is not limited to , a dosage form or through extraction is a NF -KB inhibitor, the NF -KB 5 selected from the group consisting of: inhibitor can be selected from the group consisting of ( a ) tablets ; parthenolide , curcumin , and rosmarinic acid . When the (b ) capsules ; herbal medication created either synthetically or through extraction is a natural anti- inflammatory , the natural anti ( c) topical gels ; inflammatory can be selected from the group consisting of 10 ( d ) topical creams ; rhein and parthenolide . When the herbalmedication created ( e ) patches ; either synthetically or through extraction is an immunos ( f) suppositories ; and timulant , the immunostimulant can be a product found in or ( g ) lyophilized dosage fills . isolated from Echinacea . When the herbal medication cre Formulation of pharmaceutical compositions in tablets , ated either synthetically or through extraction is an anti - 15 capsules , and topical gels , topical creams or suppositories is microbial, the anti -microbial can be berberine. When the well known in the art and is described , for example , in herbal medication created either synthetically or through United States Patent Application Publication No. 2004 / extraction is a flavonoid or flavone , the flavonoid , isofla - 0023290 by Griffin et al. , incorporated herein by this refer vone, or flavone can be selected from the group consisting ence . of apigenin , genistein , apigenenin , genistein , genistin , 6 " - O - 20 Formulation of pharmaceutical compositions as patches malonylgenistin , 6 " - O - acetylgenistin , daidzein , daidzin , such as transdermal patches is well known in the art and is 6 " - O -malonyldaidzin , 6 " -O -acetylgenistin , glycitein , glyci- described , for example , in U .S . Pat. No. 7 ,728 , 042 to Eros tin , 6 " - O -malonylglycitin , and 6 - O - acetylglycitin . et al. , incorporated herein by this reference . When the improvement is made by a bulk drug product Lyophilized dosage fills are also well known in the art. improvement, the bulk drug product improvement can be , 25 One general method for the preparation of such lyophilized but is not limited to , a bulk drug product improvement dosage fills , applicable to dianhydrogalactitol and deriva selected from the group consisting of: tives thereof and to diacetyldianhydrogalactitol and deriva ( a ) salt formation ; tives thereof, comprises the following steps: ( b ) preparation as a homogeneous crystal structure ; ( 1 ) Dissolve the drug in water for injection precooled to ( c ) preparation as a pure isomer ; ( d ) increased purity ; 30 below 10° C . Dilute to final volume with cold water for ( e ) preparation with lower residual solvent content; and injection to yield a 40 mg/ mL solution . (f ) preparation with lower residual heavy metal content. (2 ) Filter the bulk solution through an 0 .2 -um filter into a When the improvement is made by use of a diluent , the receiving container under aseptic conditions. The formula diluent can be , but is not limited to , a diluent selected fromom 35 tontion and filtration should be completed in 1 hour. the group consisting of: ( 3 ) Fill nominal 1 . 0 mL filtered solution into sterilized (a ) an emulsion ; glass vials in a controlled target range under aseptic condi ( b ) dimethylsulfoxide (DMSO ); tions. ( c ) N -methylformamide (NMF ) ( 4 ) After the filling , all vials are placed with rubber ( d ) DMF ; 40 stoppers inserted in the " lyophilization position ” and loaded (e ) ethanol; in the prechilled lyophilizer. For the lyophilizer, shelf tem ( f) benzyl alcohol; perature is set at + 5° C . and held for 1 hour ; shelf tempera ( g ) dextrose - containing water for injection ; ture is then adjusted to - 5° C . and held for one hour, and the ( h ) Cremophor ; condenser , set to - 60° C ., turned on . ( i ) cyclodextrin ; and 45 ( 5 ) The vials are then frozen to 30° C . or below and held (j ) PEG . for no less than 3 hours , typically 4 hours . When the improvement is made by use of a solvent (6 ) Vacuum is then turned on , the shelf temperature is system , the solvent system can be , but is not limited to , a adjusted to - 5° C ., and primary drying is performed for 8 solvent system selected from the group consisting of: hours ; the shelf temperature is again adjusted to - 5° C . and ( a ) an emulsion ; 50 drying is carried out for at least 5 hours . ( b ) dimethylsulfoxide (DMSO ) ; ( 7 ) Secondary drying is started after the condenser (set at ( c ) N -methylformamide (NMF ) - 60° C . ) and vacuum are turned on . In secondary drying , the ( d ) DMF ; shelf temperature is controlled at + 5° C . for 1 to 3 hours , ( e ) ethanol; typically 1 . 5 hours , then at 25° C . for 1 to 3 hours , typically ( f) benzyl alcohol; 55 1. 5 hours, and finally at 35 -40° C . for at least 5 hours, ( g ) dextrose -containing water for injection ; typically for 9 hours , or until the product is completely dried . ( h ) Cremophor; ( 8 ) Break the vacuum with filtered inert gas ( e . g . , nitro ( i ) cyclodextrin ; and gen ) . Stopper the vials in the lyophilizer. (i ) PEG . ( 9 ) Vials are removed from the lyophilizer chamber and When the improvement is made by use of an excipient, 60 sealed with aluminum flip -off seals . All vials are visually the excipient can be , but is not limited to , an excipient inspected and labeled with approved labels . selected from the group consisting of: group consisting of: When the improvement is made by use of dosage kits and ( a ) mannitol; packaging , the dosage kits and packaging can be , but are not ( b ) albumin ; limited to , dosage kits and packaging selected from the ( C ) EDTA ; 65 group consisting of the use of amber vials to protect from ( d ) sodium bisulfite ; light and the use of stoppers with specialized coatings to ( e ) benzyl alcohol ; improve shelf - life stability . US 9 ,901 , 563 B2 55 56 When the improvement is made by use of a drug delivery Multivalent linkers are known in the art and are described , system , the drug delivery system can be, but is not limited for example , in United States Patent Application Publication to , a drug delivery system selected from the group consisting No. 2007 /0207952 by Silva et al. , incorporated herein by of : this reference . For example , multivalent linkers can contain ( a ) nanocrystals ; a thiophilic group for reaction with a reactive cysteine, and (b ) bioerodible polymers ; multiple nucleophilic groups ( such as NH or OH ) or elec ( c ) liposomes ; trophilic groups ( such as activated esters ) that permit attach ( d ) slow release injectable gels ; and ment of a plurality of biologically active moieties to the ( e ) microspheres. linker . Nanocrystals are described in U . S . Pat. No . 7 , 101, 576 to 10 Suitable reagents for cross - linking many combinations of Hovey et al ., incorporated herein by this reference . functional groups are known in the art . For example , elec Bioerodible polymers are described in U . S . Pat. No . trophilic groups can react with many functional groups , 7 ,318 , 931 to Okumu et al ., incorporated herein by this including those present in proteins or polypeptides. Various reference . A bioerodible polymer decomposes when placed combinations of reactive amino acids and electrophiles are inside an organism , as measured by a decline in the molecu - 15 known in the art and can be used . For example , N - terminal lar weight of the polymer over time. Polymer molecular cysteines, containing thiol groups, can be reacted with weights can be determined by a variety of methods including halogens or maleimides. Thiol groups are known to have size exclusion chromatography (SEC ) , and are generally reactivity with a large number of coupling agents , such as expressed as weight averages or number averages. A poly - alkyl halides , haloacetyl derivatives, maleimides, aziridines , mer is bioerodible if , when in phosphate buffered saline 20 acryloyl derivatives, arylating agents such as aryl halides, (PBS ) of pH 7 .4 and a temperature of 37° C ., its weight and others . These are described in G . T. Hermanson , “ Bio average molecular weight is reduced by at least 25 % over a conjugate Techniques ” ( Academic Press, San Diego , 1996 ) , period of 6 months as measured by SEC . Useful bioerodible pp . 146 - 150 , incorporated herein by this reference. The polymers include polyesters , such as poly (caprolactone ) , reactivity of the cysteine residues can be optimized by poly (glycolic acid ) , poly ( lactic acid ), and poly (hydroxy - 25 appropriate selection of the neighboring amino acid resi butryate ); polyanhydrides , such as poly ( adipic anhydride ) dues. For example , a histidine residue adjacent to the and poly (maleic anhydride ) ; polydioxanone; polyamines ; cysteine residue will increase the reactivity of the cysteine polyamides ; polyurethanes; polyesteramides; polyorthoe residue . Other combinations of reactive amino acids and sters ; polyacetals ; polyketals ; polycarbonates ; polyorthocar - electrophilic reagents are known in the art. For example , bonates; polyphosphazenes ; poly (malic acid ) ; poly ( amino 30 maleimides can react with amino groups , such as the acids) ; polyvinylpyrrolidone ; poly (methyl vinyl ether ) ; poly E - amino group of the side chain of lysine, particularly at (alkylene oxalate ) ; poly (alkylene succinate ); polyhy - higher pH ranges. Aryl halides can also react with such droxycellulose ; chitin ; chitosan ; and copolymers and mix - amino groups . Haloacetyl derivatives can react with the tures thereof. imidazolyl side chain nitrogens of histidine , the thioether Liposomes are well known as drug delivery vehicles . 35 group of the side chain of methionine , and the .epsilon . Liposome preparation is described in European Patent amino group of the side chain of lysine . Many other elec Application Publication No. EP 1332755 by Weng et al. , trophilic reagents are known that will react with the e - amino incorporated herein by this reference . group of the side chain of lysine , including, but not limited Slow release injectable gels are known in the art and are to , isothiocyanates, isocyanates , acyl azides, N -hydroxysuc described , for example , in B . Jeong et al. , “ Drug Release 40 cinimide esters, sulfonyl chlorides, epoxides , oxiranes, car from Biodegradable Injectable Thermosensitive Hydrogel of bonates , imidoesters, carbodiimides , and anhydrides. These PEG - PLGA - PEG Triblock Copolymers, " J. Controlled are described in G . T . Hermanson , “ Bioconjugate Tech Release 63: 155 - 163 ( 2000 ) . niques” (Academic Press, San Diego , 1996 ), pp . 137 - 146 , The use of microspheres for drug delivery is known in the incorporated herein by this reference . Additionally , electro art and is described , for example , in H . Okada & H . Taguchi, 45 philic reagents are known that will react with carboxylate “ Biodegradable Microspheres in Drug Delivery ,” Crit. Rev. side chains such as those of aspartate and glutamate , such as Ther. Drug Carrier Sys . 12 : 1 - 99 ( 1995 ) , incorporated herein diazoalkanes and diazoacetyl compounds, carbonyldiimida by this reference . zole , and carbodiimides. These are described in G . T . When the improvement is made by use of a drug conju - Hermanson , “ Bioconjugate Techniques ” ( Academic Press , gate form , the drug conjugate form can be , but is not limited 50 San Diego , 1996 ) , pp . 152 - 154 , incorporated herein by this to , a drug conjugate form selected from the group consisting reference . Furthermore , electrophilic reagents are known of: that will react with hydroxyl groups such as those in the side (a ) a polymer system ; chains of serine and threonine , including reactive haloalkane ( b ) polylactides; derivatives . These are described in G . T . Hermanson , “ Bio ( c ) polyglycolides ; 55 conjugate Techniques, ” ( Academic Press, San Diego , 1996 ), ( d ) amino acids ; pp. 154 - 158 , incorporated herein by this reference . In ( e ) peptides ; and another alternative embodiment, the relative positions of ( f ) multivalent linkers . electrophile and nucleophile ( i. e . , a molecule reactive with Polylactide conjugates are well known in the art and are an electrophile ) are reversed so that the protein has an amino described , for example , in R . Tong & C . Cheng, " Controlled 60 acid residue with an electrophilic group that is reactive with Synthesis of Camptothecin -Polylactide Conjugates and a nucleophile and the targeting molecule includes therein a Nanoconjugates, ” Bioconjugate Chem . 21: 111 - 121 ( 2010 ) , nucleophilic group . This includes the reaction of aldehydes incorporated by this reference . ( the electrophile) with hydroxylamine (the nucleophile ) , Polyglycolide conjugates are also well known in the art described above, but is more general than that reaction ; other and are described , for example , in PCT Patent Application 65 groups can be used as electrophile and nucleophile . Suitable Publication No . WO 2003 /070823 by Elmaleh et al. , incor groups are well known in organic chemistry and need not be porated herein by this reference . described further in detail . US 9 , 901 , 563 B2 57 58 Additional combinations of reactive groups for cross ( f ) use of topoisomerase inhibitors with non -overlapping linking are known in the art. For example , amino groups can side effects . be reacted with isothiocyanates , isocyanates, acyl azides, Multi- drug resistance inhibitors are described in U . S . Pat . N -hydroxysuccinimide (NHS ) esters, sulfonyl chlorides , No . 6 ,011 , 069 to Inomata et al. , incorporated herein by this aldehydes , glyoxals , epoxides, oxiranes , carbonates , alky - 5 reference . lating agents , imidoesters , carbodiimides , and anhydrides . Specific drug resistance inhibitors are described in T . Thiol groups can be reacted with haloacetyl or alkyl halide Hideshima et al ., “ The Proteasome Inhibitor PS - 341 Inhibits derivatives, maleimides, aziridines , acryloyl derivatives, Growth , Induces Apoptosis , and Overcomes Drug Resis acylating agents , or other thiol groups by way of oxidation tance in Human Multiple Myeloma Cells, ” Cancer Res. 61: and the formation of mixed disulfides. Carboxy groups can " 3071 - 3076 ( 2001 ) , incorporated herein by this reference . be reacted with diazoalkanes, diazoacetyl compounds, car- Repair inhibition is described in N . M . Martin , “ DNA bonyldiimidazole , or carbodiimides . Hydroxyl groups can Repair Inhibition and Cancer Therapy, ” J . Photochem . Pho be reacted with epoxides , oxiranes , carbonyldiimidazole , tobiol. B 63 : 162 - 170 ( 2001 ) , incorporated herein by this N , N -disuccinimidyl carbonate , N -hydroxysuccinimidyl 15 reference . chloroformate , periodate ( for oxidation ), alkyl halogens , or When the improvement is made by biotherapeutic isocyanates . Aldehyde and ketone groups can react with enhancement, the biotherapeutic enhancement can be per hydrazines, reagents forming Schiff bases, and other groups formed by use in combination as sensitizers /potentiators in reductive amination reactions or Mannich condensation with a therapeutic agent or technique that can be , but is not reactions. Still other reactions suitable for cross - linking 20 limited to , a therapeutic agent or technique selected from the reactions are known in the art. Such cross -linking reagents group consisting of: and reactions are described in G . T . Hermanson , “ Biocon ( a ) cytokines ; jugate Techniques ” ( Academic Press, San Diego , 1996 ) , ( b ) lymphokines ; incorporated herein by this reference . ( c ) therapeutic antibodies ; When the improvement is made by use of a compound 25 ( d ) antisense therapies ; analog , the compound analog can be , but is not limited to , ( e ) gene therapies; a compound analog selected from the group consisting of: ( f ) ribozymes ; and ( a ) alteration of side chains to increase or decrease lipo ( g ) RNA interference . philicity ; Antisense therapies are described , for example , in B . ( b ) addition of an additional chemical functionality to 30 Weiss et al. , “ Antisense RNA Gene Therapy for Studying alter a property selected from the group consisting of and Modulating Biological Processes ,” Cell. Mol. Life Sci . reactivity , electron affinity , and binding capacity ; and 55 : 334 - 358 ( 1999) , incorporated herein by this reference . ( c ) alteration of salt form . Ribozymes are described , for example , in S . Pascolo , When the improvement is made by use of a prodrug “ RNA - Based Therapies” in Drug Discovery Handbook ( S . system , the prodrug system can be, but is not limited to , a 35 C . Gad , ed ., Wiley - Interscience , Hoboken , N .J ., 2005 ), ch . prodrug system selected from the group consisting of: 27, pp . 1273 - 1278 , incorporated herein by this reference . ( a ) the use of enzyme sensitive esters ; RNA interference is described , for example , in S . Pascolo , ( b ) the use of dimers ; “ RNA - Based Therapies " in Drug Discovery Handbook (S . ( c ) the use of Schiff bases; C . Gad , ed ., Wiley - Interscience , Hoboken , N . J ., 2005 ) , ch . ( d ) the use of pyridoxal complexes ; and 40 27, pp . 1278 - 1283 , incorporated herein by this reference. ( e ) the use of caffeine complexes . When the biotherapeutic enhancement is use in combi The use of prodrug systems is described in T . Jarvinen et nation as sensitizers/ potentiators with a therapeutic anti al. , “ Design and Pharmaceutical Applications of Prodrugs” body, the therapeutic antibody can be, but is not limited to , in Drug Discovery Handbook ( S . C . Gad , ed . , Wiley - a therapeutic antibody selected from the group consisting of Interscience , Hoboken , N . J ., 2005 ) , ch . 17 , pp . 733 -796 , 45 bevacizumab ( Avastin ) , rituximab (Rituxan ) , trastuzumab incorporated herein by this reference . This publication (Herceptin ) , and cetuximab (Erbitux ) . describes the use of enzyme sensitive esters as prodrugs . The When the improvement is made by use of biotherapeutic use of dimers as prodrugs is described in U .S . Pat . No . resistance modulation , the biotherapeutic resistance modu 7 , 879 ,896 to Allegretti et al. , incorporated herein by this lation can be , but is not limited to , use against tumors reference . The use of peptides in prodrugs is described in S . 50 resistant to a therapeutic agent or technique selected from Prasad et al ., “ Delivering Multiple Anticancer Peptides as a the group consisting of: Single Prodrug Using Lysyl- Lysine as a Facile Linker, " J . (a ) biological response modifiers ; Peptide Sci. 13 : 458 -467 (2007 ) , incorporated herein by this ( b ) cytokines; reference. The use of Schiff bases as prodrugs is described ( c ) lymphokines ; in U . S . Pat. No. 7 ,619 , 005 to Epstein et al ., incorporated 55 ( d ) therapeutic antibodies ; herein by this reference . The use of caffeine complexes as ( e ) antisense therapies ; prodrugs is described in U . S . Pat . No. 6 ,443 , 898 to Unger et ( f) gene therapies; al. , incorporated herein by this reference. ( g ) ribozymes ; and When the improvement is made by use of a multiple drug ( h ) RNA interference . system , the multiple drug system can be , but is not limited 60 When the biotherapeutic resistance modulation is use to , a multiple drug system selected from the group consisting against tumors resistant to therapeutic antibodies, the thera of: peutic antibody can be , but is not limited to , a therapeutic ( a ) use of multi- drug resistance inhibitors ; antibody selected from the group consisting of bevacizumab ( b ) use of specific drug resistance inhibitors ; ( Avastin ), rituximab ( Rituxan ), trastuzumab (Herceptin ) , ( c ) use of specific inhibitors of selective enzymes ; 65 and cetuximab (Erbitux ). ( d ) use of signal transduction inhibitors ; When the improvement is made by radiation therapy ( e ) use of repair inhibition , and enhancement, the radiation therapy enhancement can be , but US 9 , 901, 563 B2 59 60 is not limited to , a radiation therapy enhancement agent or EGFR inhibition is described in G . Giaccone & J . A . technique selected from the group consisting of: Rodriguez , " EGFR Inhibitors: What Have We Learned from ( a ) hypoxic cell sensitizers ; the Treatment of Lung Cancer, ” Nat. Clin . Pract. Oncol. 11 : (b ) radiation sensitizers /protectors ; 554 - 561 ( 2005 ), incorporated herein by this reference . Pro (c ) photosensitizers ; tein kinase C inhibition is described in N . C . Swannie & S . ( d ) radiation repair inhibitors ; B . Kaye , “ Protein Kinase C Inhibitors, " Curr. Oncol. Rep . 4 : ( e ) thiol depleters ; 37 -46 ( 2002 ) , incorporated herein by this reference . Phos pholipase C downregulation is described in A . M . Martelli et ( f ) vaso - targeted agents ; al. , “ Phosphoinositide Signaling in Nuclei of Friend Cells : ( g ) DNA repair inhibitors ; 10 Phospholipase C B Downregulation Is Related to Cell Dif ( h ) radioactive seeds ; ferentiation , ” Cancer Res. 54 : 2536 - 2540 (1994 ) , incorpo ( i ) radionuclides; rated herein by this reference . Downregulation of Jun ( spe ( j) radiolabeled antibodies ; and cifically , c - Jun ) is described in A . A . P . Zada et al. , ( k ) brachytherapy. “ Downregulation of c - Jun Expression and Cell Cycle Regu Hypoxic cell sensitizers are described nlin C . C .. Ling et al. , 15 latory Molecules in Acute Myeloid Leukemia Cells Upon “ The Effect of Hypoxic Cell Sensitizers at Different Irra CD44 Ligation , ” Oncogene 22 : 2296 - 2308 ( 2003 ) , incorpo diation Dose Rates, " Radiation Res. 109 : 396 - 406 ( 1987 ) , rated herein by this reference . The role of histone genes as incorporated herein by this reference . Radiation sensitizers a target for therapeutic intervention is described in B . are described in T . S . Lawrence , “ Radiation Sensitizers and Calabretta et al. , “ Altered Expression of G1- Specific Genes Targeted Therapies ,” Oncology 17 (Suppl . 13 ) 23 - 28 ( 2003 ), 20 in Human MalignantMyeloid Cells ,” Proc . Natl. Acad . Sci. incorporated herein by this reference . Radiation protectors USA 83 : 1495 - 1498 ( 1986 ) , incorporated herein by this are described in S . B . Vuyyuri et al. , “ Evaluation of D -Me reference . The role of VEGF as a target for therapeutic thionine as a Novel Oral Radiation Protector for Prevention intervention is described in A . Zielke et al. , “ VEGF- Medi of Mucositis , " Clin . Cancer Res. 14 : 2161 - 2170 ( 2008 ) , ated Angiogenesis of Human Pheochromocytomas Is Asso incorporated herein by this reference . Photosensitizers are 25 ciated to Malignancy and Inhibited by anti -VEGF Antibod described in R . R . Allison & C . H . Sibata , "Oncologic ies in Experimental Tumors, ” Surgery 132 : 1056 - 1063 Photodynamic Therapy Photosensitizers : A Clinical (2002 ) , incorporated herein by this reference . The role of Review ,” Photodiagnosis Photodynamic Ther. 7 : 61 - 75 ornithine decarboxylase as a target for therapeutic interven ( 2010 ) , incorporated herein by this reference. Radiation tion is described in J . A . Nilsson et al. , “ Targeting Ornithine repair inhibitors and DNA repair inhibitors are described in 30 Decarboxylase in Myc - Induced Lymphomagenesis Prevents M . Hingorani et al. , “ Evaluation of Repair of Radiation Tumor Formation ,” Cancer Cell 7 : 433 -444 (2005 ) , incor Induced DNA Damage Enhances Expression from Replica - porated herein by this reference . The role of ubiquitin C as tion -Defective Adenoviral Vectors, ” Cancer Res. 68 : 9771 - a target for therapeutic intervention is described in C . 9778 ( 2008 ) , incorporated herein by this reference . Thiol Aghajanian et al. , “ A Phase I Trial of the Novel Proteasome depleters are described in K . D . Held et al. , “ Postirradiation 35 Inhibitor PS341 in Advanced Solid Tumor Malignancies, ” Sensitization of Mammalian Cells by the Thiol- Depleting Clin . Cancer Res. 8 : 2505 - 2511 ( 2002 ) , incorporated herein Agent Dimethyl Fumarate, ” Radiation Res. 127 : 75 - 80 by this reference . The role of Jun D as a target for therapeutic ( 1991) , incorporated herein by this reference . Vaso -targeted intervention is described in M . M . Caffarel et al. , “ JunD Is agents are described in A . L . Seynhaeve et al. , “ Tumor Involved in the Antiproliferative Effect of A9 - Tetrahydro Necrosis Factor a Mediates Homogeneous Distribution of 40 cannibinol on Human Breast Cancer Cells, ” Oncogene 27 : Liposomes in Murine Melanoma that Contributes to a Better 5033 -5044 ( 2008 ) , incorporated herein by this reference . Tumor Response ,” Cancer Res. 67 : 9455 - 9462 (2007 ) . The role of v - Jun as a target for therapeutic intervention is When the improvement is by use of a novel mechanism of described in M . Gao et al. , “ Differential and Antagonistic action , the novel mechanism of action can be , but is not Effects of v - Jun and c - Jun ,” Cancer Res. 56 : 4229 -4235 limited to , a novel mechanism of action that is a therapeutic 45 ( 1996 ) , incorporated herein by this reference . The role of interaction with a target or mechanism selected from the protein kinase A as a target for therapeutic intervention is group consisting of: described in P . C . Gordge et al. , " Elevation of Protein Kinase ( a ) inhibitors of poly - ADP ribose polymerase ; A and Protein Kinase C in Malignant as Compared with ( b ) agents that affect vasculature or vasodilation ; Normal Breast Tissue , ” Eur. J . Cancer 12 : 2120 - 2126 ( c ) oncogenic targeted agents ; 50 ( 1996 ), incorporated herein by this reference. The role of (d ) signal transduction inhibitors ; telomerase as a target for therapeutic intervention is ( e ) EGFR inhibition ; described in E . K . Parkinson et al . , “ Telomerase as a Novel ( f) protein kinase C inhibition ; and Potentially Selective Target for Cancer Chemotherapy, " ( g ) phospholipase C downregulation ; Ann. Med . 35 : 466 -475 (2003 ) , incorporated herein by this ( h ) Jun downregulation ; 55 reference . The role of histone deacetylase as a target for ( i) histone genes ; therapeutic intervention is described in A . Melnick & J . D . (j ) VEGF; Licht, “ Histone Deacetylases as Therapeutic Targets in ( k ) ornithine decarboxylase ; Hematologic Malignancies ," Curr. Opin . Hematol. 9 : 322 ( 1) ubiquitin C ; 332 (2002 ) , incorporated herein by this reference . ( m ) Jun D ; 60 When the improvement is made by use of selective target ( n ) v - Jun ; cell population therapeutics , the use of selective target cell ( 0 ) GPCRs; population therapeutics can be, but is not limited to, a use (p ) protein kinase A ; selected from the group consisting of: ( q ) protein kinases other than protein kinase A ; ( a ) use against radiation sensitive cells ; ( r ) prostate specific genes ; 65 ( b ) use against radiation resistant cells; (s ) telomerase ; and ( c ) use against energy depleted cells ; and ( t) histone deacetylase . ( d ) use against endothelial cells . US 9 , 901, 563 B2 62 As described above , the present invention also encom tive , analog or prodrug of the therapeutic agent or passes methods and compositions to improve the efficacy modified therapeutic agent possesses increased thera and / or reduce the side effects of suboptimally administered peutic efficacy or reduced side effects as compared with drug therapy of additional therapeutic agents , including, but an unmodified therapeutic agent; not limited to , Avastin (bevacizumab ), Rituxan (rituximab ), 5 ( ii ) a composition comprising: Nexavar ( sorafenib ) , dasatinib , nilotinib , Provenge ( sipuleu ( a ) a therapeutically effective quantity of a therapeutic cel- T ) , Tarceva ( erlotinib ) , and Iressa (gefitinib ) . agent, a modified therapeutic agent or a derivative , Avastin ( bevacizumab ) has a number of side effects analog , or prodrug of a therapeutic agent or modified associated with interference with angiogenesis , including therapeutic agent; and hypertension and increased risk of bleeding . This suggests 10 ( b ) at least one additional therapeutic agent, therapeutic possible use with antihypertensives , administration of plate agent subject to chemosensitization , therapeutic lets , or agents to improve wound healing . agent subject to chemopotentiation , diluent, excipi Rituxan (rituximab ) has side effects that include cardiac ent, solvent system , or drug delivery system , wherein arrest , infections, including viral infections and hepatitis B the composition possesses increased therapeutic effi reactivation , progressive multifocal encephalopathy, and 15 cacy or reduced side effects as compared with an tumor lysis syndrome . This suggests possible use with unmodified therapeutic agent; anti -virals , antibiotics , probenecid ( to treat hyperuricemia ) . ( iii ) a therapeutically effective quantity of a therapeutic Nexavar (sorafenib ) has side effects that include skin rash , agent, a modified therapeutic agent, or a derivative , skin reactions, diarrhea , and hypertension . This suggests analog , or prodrug of a therapeutic agent or modified possible use with antihypertensives or anti- inflammatory 20 therapeutic agent that is incorporated into a dosage agents . form , wherein the therapeutic agent, themodified thera Dasatinib has side effects that include neutropenia , peutic agent, or the derivative , analog , or prodrug of a myelosuppression , pleural effusions , headache , diarrhea , therapeutic agent or modified therapeutic agent incor and peripheral edema. This suggests possible use with porated into the dosage form possesses increased thera anti- inflammatory agents or agents that promote immune 25 peutic efficacy or reduced side effects as compared with function . Dasatinib has the property that patients with the an unmodified therapeutic agent ; T315L mutation in BCR ABL show resistance to dasatinib . ( iv ) a therapeutically effective quantity of a therapeutic This suggests genotypic analysis of patients to whom dasa agent, a modified therapeutic agent, or a derivative , tinib might be administered . analog , or prodrug of a therapeutic agent or modified Nilotinib has side effects that include possible heart 30 therapeutic agent that is incorporated into a dosage kit complications. Nilotinib also has the property that patients and packaging , wherein the therapeutic agent, the with the T315L mutation in BCR / ABL show resistance to modified therapeutic agent, or the derivative, analog , or nilotinib . This suggests genotypic analysis of patients to prodrug of a therapeutic agent or modified therapeutic whom nilotinib might be administered . agent incorporated into the dosage kit and packaging Provenge ( sipuleucel- T ) has side effects that include 35 possesses increased therapeutic efficacy or reduced side chills , fever, fatigue , nausea , headache , and rare cardiovas effects as compared with an unmodified therapeutic cular events . This suggests possible use with anti -inflam agent; and matory agents , anti - nausea agents, and anti -emetics . ( v ) a therapeutically effective quantity of a therapeutic Tarceva ( erlotinib ) has side effects that include rash , agent , a modified therapeutic agent , or a derivative , diarrhea , loss of appetite , fatigue , and interstitial pneumo - 40 analog , or prodrug of a therapeutic agent or modified nitis . This suggests possible use with anti - inflammatory therapeutic agent that is subjected to a bulk drug agents and anti - diarrhea agents . Tarceva only works with product improvement, wherein the therapeutic agent , patients that have an EGFR mutation , which suggests geno the modified therapeutic agent, or the derivative , ana typic analysis of patents to whom Tarceva might be admin log , or prodrug of a therapeutic agent or modified istered . Additionally , Tarceva has been found to be a potent 45 therapeutic agent subject to the bulk drug product inhibitor of the JAK2V617F mutant of the JAK2 tyrosine improvement possesses increased therapeutic efficacy kinase , and this mutation has been found to exist in most or reduced side effects as compared with an unmodified patients with polycythemia vera and many patients with therapeutic agent. other myeloproliferative disorders, including idiopathic Typically , the composition possesses increased efficacy or myelofibrosis and essential thrombocythemia . 50 reduced side effects for cancer therapy . Typically , the Iressa ( gefitinib ) is also an EGFR inhibitor, and thus its unmodified therapeutic agent is dianhydrogalactitol or mechanism of action is similar to Tarceva . Similarly , this diacetyldianhydrogalactitol, as described above. Alterna works with patients that have an EGFR mutation . This drug tively, the unmodified therapeutic agent can be selected from is particularly used in some types of non - small- cell lung the group consisting of Avastin (bevacizumab ) , Rituxan cancer, including adenocarcinoma. Side effects include acne , 55 ( rituximab ) , Nexavar (sorafenib ) , dasatinib , nilotinib , diarrhea , nausea, vomiting , anorexia , stomatitis , interstitial Provenge ( sipuleucel - T ) , Tarceva ( erlotinib ) , and Iressa ( ge lung disease , and other effects . Again , this suggests use with fitinib ) . anti - inflammatory agents , anti - diarrhea agents , and anti - In one alternative , the composition comprises a drug emetics . combination comprising : Another aspect of the present invention is a composition 60 ( i ) dianhydrogalactitol; and to improve the efficacy and /or reduce the side effects of ( ii ) an additional therapeutic agent selected from the suboptimally administered drug therapy comprising an alter group consisting of: native selected from the group consisting of: ( a ) topoisomerase inhibitors ; (i ) a therapeutically effective quantity of a modified ( b ) fraudulent nucleosides ; therapeutic agent or a derivative, analog, or prodrug of 65 (c ) fraudulent nucleotides ; a therapeutic agent or modified therapeutic agent, ( d ) thymidylate synthetase inhibitors ; wherein the modified therapeutic agent or the deriva ( e ) signal transduction inhibitors; US 9 , 901 ,563 B2 63 64 (f ) cisplatin or platinum analogs; (j ) berberine; ( g ) alkylating agents ; ( k ) apigenin ; ( h ) anti- tubulin agents ; ( 1 ) amonafide ; ( i ) antimetabolites ; ( m ) vinca alkaloids ; ( i ) berberine ; ( n ) 5 - fluorouracil ; ( k ) apigenin ; ( o ) curcumin ; (1 ) amonafide ; ( p ) NF -kB inhibitors ; (m ) vinca alkaloids; ( q ) rosmarinic acid ; ( n ) 5 - fluorouracil ; (r ) mitoguazone ; and ( o ) curcumin ; 10 ( S ) tetrandrine; ( p ) NF -kB inhibitors ; wherein the dianhydrogalactitol acts as a chemosensitizer. ( q ) rosmarinic acid ; In yet another alternative , the composition can comprise : ( r ) mitoguazone ; ( i ) diacetyldianhydrogalactitol; and (s ) tetrandrine ; and ( ii ) a therapeutic agent subject to chemosensitization (t ) an inhibitor of mutant isocitrate dehydrogenase 15 selected from the group consisting of: (IDH ) ; ( a ) topoisomerase inhibitors ; ( u ) a MGMT inhibitor; and ( b ) fraudulent nucleosides ; ( v ) an agent that inhibits NF -KB -enhanced expression (c ) fraudulent nucleotides ; of MGMT. ( d ) thymidylate synthetase inhibitors ; In another alternative of a composition according to the 20 (e ) signal transduction inhibitors ; present invention , the composition can comprise a drug ( f ) cisplatin or platinum analogs ; combination comprising: ( g ) alkylating agents ; (i ) diacetyldianhydrogalactitol ; and ( h ) anti - tubulin agents ; ( ii ) an additional therapeutic agent selected from the ( i ) antimetabolites; group consisting of: 25 (j ) berberine ; ( a ) topoisomerase inhibitors ; ( k ) apigenin ; (b ) fraudulent nucleosides ; ( 1 ) amonafide ; ( c ) fraudulent nucleotides ; ( m ) vinca alkaloids ; ( d ) thymidylate synthetase inhibitors ; ( n ) 5 - fluorouracil ; ( e ) signal transduction inhibitors ; 30 ( 0 ) curcumin ; ( f ) cisplatin or platinum analogs ; ( p ) NF -KB inhibitors ; ( g ) alkylating agents ; ( q ) rosmarinic acid ; ( h ) anti - tubulin agents ; ( r ) mitoguazone; and ( i) antimetabolites; ( s ) tetrandrine ; (i ) berberine ; 35 wherein the diacetyldianhydrogalactitol acts as a chemosen ( k ) apigenin ; sitizer . ( 1 ) amonafide; In still another alternative, the composition comprises: ( m ) vinca alkaloids ; ( i ) dianhydrogalactitol; and (n ) 5 - fluorouracil ; ( ii ) a therapeutic agent subject to chemopotentiation ( o ) curcumin ; 40 selected from the group consisting of: ( p ) NF -kB inhibitors ; ( a ) topoisomerase inhibitors ; ( q ) rosmarinic acid ; (b ) fraudulent nucleosides ; (r ) mitoguazone ; ( c ) fraudulent nucleotides ; ( s ) tetrandrine ; ( d ) thymidylate synthetase inhibitors ; (t ) an inhibitor of mutant isocitrate dehydrogenase 45 ( e ) signal transduction inhibitors ; ( IDH ) ; ( f ) cisplatin or platinum analogs; ( u ) a MGMT inhibitor; and ( g ) alkylating agents ; ( v ) an agent that inhibits NF -KB -enhanced expression ( h ) anti - tubulin agents ; of MGMT. ( i ) antimetabolites ; In these alternatives , when the additional therapeutic 50 (i ) berberine; agent is an alkylating agent, the alkylating agent can be , but ( k ) apigenin ; is not limited to , an alkylating agent selected from the group (1 ) amonafide ; consisting of BCNU , BCNU wafers , CCNU , bendamustine ( m ) vinca alkaloids; ( Treanda ) , and temozolomide ( Temodar) . ( n ) 5 - fluorouracil ; In another alternative , the composition comprises: 55 ( o ) curcumin ; ( i ) dianhydrogalactitol; and (p ) NF -kB inhibitors ; ( ii ) a therapeutic agent subject to chemosensitization ( q ) rosmarinic acid ; selected from the group consisting of: (r ) mitoguazone ; ( a ) topoisomerase inhibitors ; ( s ) tetrandrine ; and ( b ) fraudulent nucleosides ; 60 (t ) biotherapeutics ; ( c ) fraudulent nucleotides ; wherein the dianhydrogalactitol acts as a chemopotentiator. ( d ) thymidylate synthetase inhibitors ; In yet another alternative , the composition comprises : ( e ) signal transduction inhibitors ; ( i) diacetyldianhydrogalactitol; and (f ) cisplatin or platinum analogs ; ( ii ) a therapeutic agent subject to chemopotentiation ( g ) alkylating agents ; 65 selected from the group consisting of: ( h ) anti - tubulin agents ; ( a ) topoisomerase inhibitors ; ( i ) antimetabolites ; ( b ) fraudulent nucleosides ; US 9 , 901, 563 B2 65 66 ( c ) fraudulent nucleotides ; In yet another alternative, the therapeutic agent is dian ( d ) thymidylate synthetase inhibitors ; hydrogalactitol or diacetyldianhydrogalactitol and the com ( e ) signal transduction inhibitors ; position comprises an excipient, wherein the excipient is ( f ) cisplatin or platinum analogs ; selected from the group consisting of: ( g ) alkylating agents ; (a ) mannitol; ( h ) anti- tubulin agents ; ( b ) albumin ; ( i) antimetabolites; ( c ) EDTA ; (j ) berberine; ( d ) sodium bisulfite ; (k ) apigenin ; ( e ) benzyl alcohol; 10 ( f) a carbonate buffer; and ( 1 ) amonafide; ( g ) a phosphate buffer. ( m ) vinca alkaloids ; In still another alternative, the therapeutic agent is dian ( n ) 5 - fluorouracil ; hydrogalactitol or diacetyldianhydrogalactitol and the dian ( o ) curcumin ; hydrogalactitol or diacetyldianhydrogalactitol is incorpo ( p ) NF - kB inhibitors ; 15 rated into a dosage form selected from the group consisting ( q ) rosmarinic acid ; of: ( r ) mitoguazone; ( a ) tablets ; ( s ) tetrandrine ; and ( b ) capsules ; ( t ) biotherapeutics ; ( c ) topical gels ; wherein the diacetyldianhydrogalactitol acts as a chemopo - 20 ( d ) topical creams; tentiator. ( e ) patches ; In these alternatives, wherein the additional therapeutic ( f ) suppositories ; and agent is a biotherapeutic , the biotherapeutic can be , but is not ( g ) lyophilized dosage fills . limited to , a biotherapeutic selected from the group consist In yet another alternative , the therapeutic agent is dian ing of Avastin , Herceptin , Rituxan , and Erbitux . 25 hydrogalactitol or diacetyldianhydrogalactitol and the dian In yet another alternative , the therapeutic agent is dian - hydrogalactitol or diacetyldianhydrogalactitol is incorpo hydrogalactitol or diacetyldianhydrogalactitol and the dian rated into a dosage kit and packaging selected from the hydrogalactitol or diacetyldianhydrogalactitol is subjected group consisting of amber vials to protect from light and stoppers with specialized coatings to improve shelf - life to a bulk drug product improvement, wherein the bulk drug 30 stability . product improvement is selected from the group consistings In still another alternative, the therapeutic agent is dian of: hydrogalactitol or diacetyldianhydrogalactitol and the com ( a ) salt formation ; position comprises a drug delivery system selected from the ( b ) preparation as a homogeneous crystal structure ; group consisting of: (c ) preparation as a pure isomer ; ( a ) nanocrystals ; ( d ) increased purity ; ( b ) bioerodible polymers ; ( e ) preparation with lower residual solvent content; and ( c ) liposomes; ( f ) preparation with lower residual heavy metal content. ( d ) slow release injectable gels ; and In still another alternative , the therapeutic agent is dian ( e ) microspheres . hydrogalactitol or diacetyldianhydrogalactitol and the com - 40 In still another alternative , the therapeutic agent is dian position comprises a diluent, wherein the diluent is selected hydrogalactitol or diacetyldianhydrogalactitol and the dian from the group consisting of: hydrogalactitol or diacetyldianhydrogalactitol is present in ( a ) an emulsion ; the composition in a drug conjugate form selected from the ( b ) dimethylsulfoxide (DMSO ); group consisting of: ( c ) N -methylformamide (NMF ) 45 ( a ) a polymer system ; ( d ) DMF; (b ) polylactides ; ( e ) ethanol ; ( c ) polyglycolides ; ( f ) benzyl alcohol; ( d ) amino acids ; ( g ) dextrose -containing water for injection ; ( e ) peptides ; and 50 (f ) multivalent linkers . ( h ) Cremophor; In yet another alternative , the therapeutic agent is a ( i) cyclodextrin ; and modified dianhydrogalactitol or a modified diacetyldianhy (j ) PEG . drogalactitol and the modification is selected from the group In still another alternative , the therapeutic agent is dian consisting of: hydrogalactitol or diacetyldianhydrogalactitol and the com 55 ( a ) alteration of side chains to increase or decrease lipo position comprises a solvent system , wherein the solvent philicity ; system is selected from the group consisting of: ( b ) addition of an additional chemical functionality to ( a ) an emulsion ; alter a property selected from the group consisting of (b ) dimethylsulfoxide (DMSO ) ; reactivity , electron affinity , and binding capacity ; and ( c ) N -methylformamide (NMF ) 60 (c ) alteration of salt form . (d ) DMF; In still another alternative , the therapeutic agent is dian ( e ) ethanol; hydrogalactitol or diacetyldianhydrogalactitol and the dian ( f) benzyl alcohol; hydrogalactitol or diacetyldianhydrogalactitol is in the form ( g ) dextrose -containing water for injection ; of a prodrug system , wherein the prodrug system is selected ( h ) Cremophor; 65 from the group consisting of: (i ) cyclodextrin ; and ( a ) the use of enzyme sensitive esters ; (1 ) PEG . ( b ) the use of dimers ; US 9 , 901 ,563 B2 67 68 ( c ) the use of Schiff bases; cinnamic acid , a sulfonic acid , such as p - toluenesulfonic ( d ) the use of pyridoxal complexes ; and acid or ethanesulfonic acid , or the like . If the pharmacologi ( e ) the use of caffeine complexes . cally active compound has one or more acidic functional In yet another alternative, the therapeutic agent is dian groups, the desired pharmaceutically acceptable salt may be hydrogalactitol or diacetyldianhydrogalactitol and the com - 5 prepared by any suitable method available in the art , for position further comprises at least one additional therapeutic example , treatment of the free acid with an inorganic or agent to form a multiple drug system , wherein the at least organic base , such as an amine (primary , secondary or one additional therapeutic agent is selected from the group tertiary ), an alkali metal hydroxide or alkaline earth metal consisting of: hydroxide, or the like . Illustrative examples of suitable salts ( a ) an inhibitor of multi - drug resistance ; 10 include organic salts derived from amino acids, such as ( b ) a specific drug resistance inhibitor; glycine and arginine , ammonia , primary , secondary, and ( c ) a specific inhibitor of a selective enzyme ; tertiary amines , and cyclic amines , such as piperidine , ( d ) a signal transduction inhibitor ; morpholine and piperazine , and inorganic salts derived from ( e ) an inhibitor of a repair enzyme; and sodium , calcium , potassium , magnesium , manganese , iron , ( f ) a topoisomerase inhibitor with non -overlapping side 15 copper, zinc , aluminum and lithium . effects . In the case of agents that are solids, it is understood by When a pharmaceutical composition according to the those skilled in the art that the inventive compounds and present invention includes a prodrug , prodrugs and active salts may exist in different crystal or polymorphic forms, all metabolites of a compound may be identified using routine of which are intended to be within the scope of the present techniques known in the art. See , e . g . , Bertolini et al. , J . 20 invention and specified formulas . Med . Chem . , 40 , 2011 - 2016 ( 1997 ) ; Shan et al. , J . Pharm . The amount of a given pharmacologically active agent Sci. , 86 (7 ), 765 -767 ; Bagshawe , Drug Dev. Res ., 34 , that is included in a unit dose of a pharmaceutical compo 220 - 230 ( 1995 ) ; Bodor , Advances in Drug Res. , 13 , 224 - 331 sition according to the present invention will vary depending ( 1984 ) ; Bundgaard , Design of Prodrugs ( Elsevier Press upon factors such as the particular compound , disease con 1985 ) ; Larsen , Design and Application of Prodrugs, Drug 25 dition and its severity , the identity ( e . g . , weight ) of the Design and Development (Krogsgaard - Larsen et al. , eds. , subject in need of treatment, but can nevertheless be rou Harwood Academic Publishers, 1991 ); Dear et al. , J. Chro - tinely determined by one skilled in the art . Typically, such matogr. B , 748 , 281 - 293 ( 2000 ) ; Spraul et al . , J . Pharma - pharmaceutical compositions include a therapeutically ceutical & Biomedical Analysis , 10 , 601 -605 ( 1992 ) ; and effective quantity of the pharmacologically active agent and Prox et al. , Xenobiol. , 3 , 103 - 112 (1992 ) . 30 an inert pharmaceutically acceptable carrier or diluent. Typi When the pharmacologically active compound in a phar - cally, these compositions are prepared in unit dosage form maceutical composition according to the present invention appropriate for the chosen route of administration , such as possesses a sufficiently acidic , a sufficiently basic , or both a oral administration or parenteral administration . A pharma sufficiently acidic and a sufficiently basic functional group , cologically active agent as described above can be admin these group or groups can accordingly react with any of a 35 istered in conventional dosage form prepared by combining number of inorganic or organic bases , and inorganic and a therapeutically effective amount of such a pharmacologi organic acids , to form a pharmaceutically acceptable salt. cally active agent as an active ingredient with appropriate Exemplary pharmaceutically acceptable salts include those pharmaceutical carriers or diluents according to conven salts prepared by reaction of the pharmacologically active tional procedures. These procedures may involve mixing , compound with a mineral or organic acid or an inorganic 40 granulating and compressing or dissolving the ingredients as base , such as salts including sulfates , pyrosulfates , bisul- appropriate to the desired preparation . The pharmaceutical fates , sulfites, bisulfites, phosphates, monohydrogenphos - carrier employed may be either a solid or liquid . Exemplary phates , dihydrogenphosphates , metaphosphates , pyrophos - of solid carriers are lactose , sucrose , talc , gelatin , agar, phates, chlorides , bromides, iodides, acetates, propionates pectin , acacia , magnesium stearate , stearic acid and the like . decanoates , caprylates , acrylates , formates , isobutyrates , 45 Exemplary of liquid carriers are syrup , peanut oil, olive oil, caproates , heptanoates , propiolates , oxalates , malonates, water and the like . Similarly , the carrier or diluent may succinates , suberates , sebacates , fumarates , maleates , include time- delay or time- release material known in the art , butyne - 1 , 4 - dioates , hexyne - 1 , 6 - dioates , benzoates, chlo - such as glycerylmonostearate or glyceryl distearate alone or robenzoates , methyl benzoates, dinitrobenzoates, hydroxy - with a wax , ethylcellulose , hydroxypropylmethylcellulose , benzoates , methoxybenzoates, phthalates , sulfonates , xyle - 50 methylmethacrylate and the like . nesulfonates, phenylacetates , phenylpropionates , A variety of pharmaceutical forms can be employed . phenylbutyrates , citrates , lactates , B -hydroxybutyrates , gly . Thus , if a solid carrier is used , the preparation can be colates , tartrates , methane - sulfonates , propanesulfonates , tableted , placed in a hard gelatin capsule in powder or pellet naphthalene - 1 -sulfonates , naphthalene - 2 - sulfonates, and form or in the form of a troche or lozenge . The amount of mandelates. If the pharmacologically active compound has 55 solid carrier may vary, but generally will be from about 25 one or more basic functional groups, the desired pharma- mg to about 1 g . If a liquid carrier is used , the preparation ceutically acceptable salt may be prepared by any suitable will be in the form of syrup , emulsion , soft gelatin capsule , method available in the art, for example , treatment of the sterile injectable solution or suspension in an ampoule or free base with an inorganic acid , such as hydrochloric acid , vial or non -aqueous liquid suspension . hydrobromic acid , sulfuric acid , nitric acid , phosphoric acid 60 To obtain a stable water - soluble dose form , a pharmaceu and the like, or with an organic acid , such as acetic acid , tically acceptable salt of a pharmacologically active agent as maleic acid , succinic acid , mandelic acid , fumaric acid , described above is dissolved in an aqueous solution of an malonic acid , pyruvic acid , oxalic acid , glycolic acid , sali - organic or inorganic acid , such as 0 . 3 M solution of succinic cylic acid , a pyranosidyl acid , such as glucuronic acid or acid or citric acid . If a soluble salt form is not available , the galacturonic acid , an alpha -hydroxy acid , such as citric acid 65 agent may be dissolved in a suitable cosolvent or combina or tartaric acid , an amino acid , such as aspartic acid or t ions of cosolvents . Examples of suitable cosolvents include , glutamic acid , an aromatic acid , such as benzoic acid or but are not limited to , alcohol, propylene glycol, polyethyl US 9 , 901, 563 B2 69 70 ene glycol 300 , polysorbate 80 , glycerin and the like in Proper formulation is dependent upon the route of admin concentrations ranging from 0 -60 % of the total volume. In istration chosen . For injection , the agents of the invention an exemplary embodiment, a compound of Formula I is may be formulated into aqueous solutions , preferably in dissolved in DMSO and diluted with water. The composition physiologically compatible buffers such as Hanks ' s solution , may also be in the form of a solution of a salt form of the 5 Ringer' s solution , or physiological saline buffer. For trans active ingredient in an appropriate aqueous vehicle such as mucosal administration , penetrants appropriate to the barrier water or isotonic saline or dextrose solution . to be permeated are used in the formulation . Such penetrants It will be appreciated that the actual dosages of the agents are generally known in the art. used in the compositions of this invention will vary accord For oral administration , the compounds can be formulated ing to the particular complex being used , the particular 10 readily by combining the active compounds with pharma composition formulated , the mode of administration and the ceutically acceptable carriers known in the art. Such carriers particular site , host and disease and /or condition being enable the compounds of the invention to be formulated as treated . Actual dosage levels of the active ingredients in the tablets , pills , dragees , capsules , liquids, gels , syrups , slur pharmaceutical compositions of the present invention can be 15 riesa patient, solutions to be, suspensionstreated . Pharmaceutical and the like ,preparations for oral ingestion for oral by varied so as to obtain an amount of the active ingredient use can be obtained using a solid excipient in admixture with which is effective to achieve the desired therapeutic the active ingredient ( agent) , optionally grinding the result response for a particular subject, composition , and mode of ing mixture , and processing the mixture of granules after administration , without being toxic to the subject. The adding suitable auxiliaries , if desired , to obtain tablets or selected dosage level depends upon a variety of pharma- 20 dragee cores. Suitable excipients include : fillers such as cokinetic factors including the activity of the particular sugars , including lactose , sucrose, mannitol , or sorbitol; and therapeutic agent, the route of administration , the time of cellulose preparations , for example , maize starch , wheat administration , the rate of excretion of the particular com - starch , rice starch , potato starch , gelatin , gum , methyl cel pound being employed , the severity of the condition , other lulose , hydroxypropylmethyl- cellulose , sodium carboxym health considerations affecting the subject, and the status of 25 ethylcellulose , or polyvinylpyrrolidone ( PVP ) . If desired , liver and kidney function of the subject. It also depends on disintegrating agents may be added , such as crosslinked the duration of the treatment, other drugs, compounds and / or polyvinyl pyrrolidone , agar , or alginic acid or a salt thereof materials used in combination with the particular therapeutic such as sodium alginate . agent employed , as well as the age , weight, condition , Dragee cores are provided with suitable coatings. For this general health and prior medical history of the subject being 30 purpose , concentrated sugar solutions may be used , which treated , and like factors . Methods for determining optimal may optionally contain gum arabic , polyvinyl pyrrolidone , dosages are described in the art , e . g ., Remington : The Carbopol gel , polyethylene glycol, and / or titanium dioxide , Science and Practice of Pharmacy , Mack Publishing Co ., lacquer solutions , and suitable organic solvents or solvent 20th ed ., 2000 . Optimal dosages for a given set of conditions mixtures . Dyestuffs or pigments may be added to the tablets can be ascertained by those skilled in the art using conven - 35 or dragee coatings for identification or to characterize dif tional dosage - determination tests in view of the experimen - ferent combinations of active agents. tal data for an agent. For oral administration , an exemplary Pharmaceutical preparations which can be used orally daily dose generally employed is from about 0 .001 to about include push - fit capsules made of gelatin , as well as soft , 3000 mg/ kg of body weight, with courses of treatment sealed capsules made of gelatin and a plasticizer, such as repeated at appropriate intervals . In some embodiments , the 40 glycerol or sorbitol. The push - fit capsules can contain the daily dose is from about 1 to 3000 mg/ kg of body weight. active ingredients in admixture with fillers such as lactose , Typical daily doses in a patient may be anywhere between binders such as starches , and / or lubricants such as talc or about 500 mg to about 3000 mg, given once or twice daily , magnesium stearate , and , optionally , stabilizers . In soft e . g ., 3000 mg can be given twice daily for a total dose of capsules , the active agents may be dissolved or suspended in 6000 mg. In one embodiment, the dose is between about 45 suitable liquids, such as fatty oils, liquid paraffin , or liquid 1000 to about 3000 mg. In another embodiment , the dose is p olyethylene glycols . In addition , stabilizers may be added . between about 1500 to about 2800 mg. In other embodi- All formulations for oral administration should be in dos ments, the dose is between about 2000 to about 3000 mg. ages suitable for such administration . For buccal adminis Plasma concentrations in the subjects may be between tration , the compositions may take the form of tablets or about 100 uM to about 1000 uM . In some embodiments , the 50 lozenges formulated in conventional manner. plasma concentration may be between about 200 uM to Pharmaceutical formulations for parenteral administra about 800 uM . In other embodiments , the concentration is tion can include aqueous solutions or suspensions . Suitable about 300 uM to about 600 UM . In still other embodiments lipophilic solvents or vehicles include fatty oils such as the plasma concentration may be between about 400 to sesame oil or synthetic fatty acid esters , such as ethyl oleate about 800 uM . Administration of prodrugs is typically dosed 55 or triglycerides. Aqueous injection suspensions may contain at weight levels which are chemically equivalent to the substances which increase the viscosity of the suspension , weight levels of the fully active form . such as sodium carboxymethyl cellulose , sorbitol, or dex The compositions of the invention may be manufactured tran . Optionally , the suspension may also contain suitable using techniques generally known for preparing pharmaceu stabilizers or modulators which increase the solubility or tical compositions, e . g . , by conventional techniques such as 60 dispersibility of the composition to allow for the preparation mixing , dissolving, granulating, dragee -making , levitating , of highly concentrated solutions , or can contain suspending emulsifying , encapsulating, entrapping or lyophilizing . or dispersing agents . Pharmaceutical preparations for oral Pharmaceutical compositions may be formulated in a con use can be obtained by combining the pharmacologically ventional manner using one or more physiologically accept- active agent with solid excipients , optionally grinding a able carriers , which may be selected from excipients and 65 resulting mixture , and processing the mixture of granules, auxiliaries that facilitate processing of the active compounds after adding suitable auxiliaries , if desired , to obtain tablets into preparations, which can be used pharmaceutically. or dragee cores . Suitable excipients are , in particular , fillers US 9 , 901, 563 B2 71 72 such as sugars , including lactose , sucrose , mannitol, or fatty oils such as sesame oil , or synthetic fatty acid esters , sorbitol ; cellulose preparations such as , for example , maize such as ethyl oleate or triglycerides, or liposomes. Aqueous starch , wheat starch , rice starch , potato starch , gelatin , gum injection suspensions may contain substances that increase tragacanth , methyl cellulose , hydroxypropylmethyl - cellu the viscosity of the suspension , such as sodium carboxym lose , sodium carboxymethylcellulose , and / or polyvinylpyr - 5 ethyl cellulose , sorbitol, or dextran . Optionally , the suspen rolidone ( PVP ) . If desired , disintegrating modulators may be sion may also contain suitable stabilizers or agents , which added , such as the cross - linked polyvinyl pyrrolidone, agar , increase the solubility of the compounds to allow for the or alginic acid or a salt thereof such as sodium alginate . preparation of highly concentrated solutions. Other ingredients such as stabilizers , for example , anti- Alternatively , the active ingredient may be in powder oxidants such as sodium citrate , ascorbyl palmitate , propyl 10 form for constitution with a suitable vehicle , e . g . , sterile gallate , reducing agents , ascorbic acid , vitamin E , sodium pyrogen - free water , before use . The compounds may also be bisulfite , butylated hydroxytoluene , BHA , acetylcysteine , formulated in rectal compositions such as suppositories or monothioglycerol, phenyl - a -naphthylamine , or lecithin can retention enemas , e . g ., containing conventional suppository be used . Also , chelators such as EDTA can be used . Other bases such as cocoa butter or other glycerides. ingredients that are conventional in the area of pharmaceu - 15 In addition to the formulations described above , the tical compositions and formulations, such as lubricants in compounds may also be formulated as a depot preparation . tablets or pills , coloring agents , or flavoring agents , can be Such long - acting formulations may be administered by used . Also , conventional pharmaceutical excipients or car - implantation ( for example , subcutaneously or intramuscu riers can be used . The pharmaceutical excipients can larly ) or by intramuscular injection . Thus, for example , the include , but are not necessarily limited to , calcium carbon - 20 compounds may be formulated with suitable polymeric or ate , calcium phosphate , various sugars or types of starch , hydrophobic materials ( for example , as an emulsion in an cellulose derivatives , gelatin , vegetable oils , polyethylene acceptable oil ) or ion - exchange resins, or as sparingly glycols and physiologically compatible solvents . Other soluble derivatives , for example , as a sparingly soluble salt . pharmaceutical excipients are well known in the art. Exem An exemplary pharmaceutical carrier for hydrophobic plary pharmaceutically acceptable carriers include , but are 25 compounds is a cosolvent system comprising benzyl alco not limited to , any and / or all of solvents , including aqueous hol, a nonpolar surfactant, a water -miscible organic poly and non - aqueous solvents, dispersion media , coatings, anti - mer , and an aqueous phase . The cosolvent system may be a bacterial and / or antifungal agents , isotonic and /or absorption VPD co - solvent system . VPD is a solution of 3 % w / v benzyl delaying agents , and / or the like . The use of such media alcohol, 8 % w / v of the nonpolar surfactant polysorbate 80 , and/ or agents for pharmaceutically active substances is well 30 and 65 % w / v polyethylene glycol 300 , made up to volume known in the art . Except insofar as any conventional in absolute ethanol. The VPD co -solvent system (VPD :5W ) medium , carrier , or agent is incompatible with the active contains VPD diluted 1 : 1 with a 5 % dextrose in water ingredient or ingredients , its use in a composition according solution . This co - solvent system dissolves hydrophobic to the present invention is contemplated . Supplementary compounds well , and itself produces low toxicity upon active ingredients can also be incorporated into the compo - 35 systemic administration . Naturally , the proportions of a sitions, particularly as described above . For administration co - solvent system may be varied considerably without of any of the compounds used in the present invention , destroying its solubility and toxicity characteristics . Further preparations should meet sterility , pyrogenicity, general more , the identity of the co - solvent components may be safety , and purity standards as required by the FDA Office of varied : for example , other low - toxicity nonpolar surfactants Biologics Standards or by other regulatory organizations 40 may be used instead of polysorbate 80 ; the fraction size of regulating drugs . polyethylene glycol may be varied ; other biocompatible For administration intranasally or by inhalation , the com - polymers may replace polyethylene glycol, e . g . polyvinyl pounds for use according to the present invention are pyrrolidone ; and other sugars or polysaccharides may be conveniently delivered in the form of an aerosol spray substituted for dextrose . presentation from pressurized packs or a nebulizer, with the 45 Alternatively , other delivery systems for hydrophobic use of a suitable propellant, e .g ., dichlorodifluoromethane , pharmaceutical compounds may be employed . Liposomes trichlorofluoromethane, dichlorotetrafluoroethane , carbon and emulsions are known examples of delivery vehicles or dioxide or other suitable gas . In the case of a pressurized carriers for hydrophobic drugs . Certain organic solvents aerosol, the dosage unit may be determined by providing a such as dimethylsulfoxide also may be employed , although valve to deliver a metered amount. Capsules and cartridges 50 usually at the cost of greater toxicity . Additionally , the of gelatin for use in an inhaler or insufflator and the like may compounds may be delivered using a sustained -release be formulated containing a powder mix of the compound system , such as semipermeable matrices of solid hydropho and a suitable powder base such as lactose or starch . bic polymers containing the therapeutic agent. Various sus The compounds may be formulated for parenteral admin - tained - release materials have been established and are istration by injection , e . g ., by bolus injection or continuous 55 known by those skilled in the art. Sustained -release capsules infusion . Formulations for injection may be presented in may , depending on their chemical nature, release the com unit -dosage form , e . g . , in ampoules or in multi -dose con - pounds for a few weeks up to over 100 days. Depending on tainers , with an added preservative . The compositions may the chemical nature and the biological stability of the take such forms as suspensions , solutions or emulsions in therapeutic reagent, additional strategies for protein stabili oily or aqueous vehicles , and may contain formulatory 60 zation may be employed . agents such as suspending, stabilizing and / or dispersing The pharmaceutical compositions also may comprise suit agents . able solid - or gel -phase carriers or excipients . Examples of Pharmaceutical formulations for parenteral administra - such carriers or excipients include calcium carbonate , cal tion include aqueous solutions of the active compounds in cium phosphate , sugars , starches , cellulose derivatives , gela water- soluble form . Additionally , suspensions of the active 65 tin , and polymers such as polyethylene glycols . agents may be prepared as appropriate oily injection sus - A pharmaceutical composition can be administered by a pensions. Suitable lipophilic solvents or vehicles include variety of methods known in the art. The routes and /or US 9 ,901 , 563 B2 73 74 modes of administration vary depending upon the desired ration of symptoms of disease . Thereafter , the subject can be results . Depending on the route of administration , the phar - administered a prophylactic regime. macologically active agent may be coated in a material to For the purposes of the present application , treatment can protect the targeting composition or other therapeutic agent be monitored by observing one or more of the improving from the action of acids and other compounds that may 5 symptoms associated with the disease , disorder , or condition inactivate the agent. Conventional pharmaceutical practice being treated , or by observing one or more of the improving can be employed to provide suitable formulations or com - clinical parameters associated with the disease , disorder , or positions for the administration of such pharmaceutical condition being treated , as described above . compositions to subjects . Any appropriate route of admin Sustained - release formulations or controlled -release for to 10 mulations are well -known in the art . For example , the istration can be employed , for example, but not limited to , sustained - release or controlled - release formulation can be intravenous, parenteral, intraperitoneal, intravenous , trans ( 1 ) an oral matrix sustained - release or controlled - release cutaneous , subcutaneous , intramuscular, intraurethral, or formulation ; ( 2 ) an oral multilayered sustained -release or oral administration . Depending on the severity of the malig controlled -release tablet formulation ; ( 3 ) an oral multipar nancy or other disease , disorder, or condition to be treated ·, 15 ticulate sustained -release or controlled -release formulation ; as well as other conditions affecting the subject to be treated , ( 4 ) an oral osmotic sustained - release or controlled - release either systemic or localized delivery of the pharmaceutical formulation ; ( 5 ) an oral chewable sustained -release or con composition can be used in the course of treatment. The trolled - release formulation ; or ( 6 ) a dermal sustained - release pharmaceutical composition as described above can be or controlled - release patch formulation . administered together with additional therapeutic agents 20 The pharmacokinetic principles of controlled drug deliv intended to treat a particular disease or condition , which may ery are described , for example , in B . M . Silber et al. , be the same disease or condition that the pharmaceutical “ Pharmacokinetic /Pharmacodynamic Basis of Controlled composition is intended to treat , which may be a related Drug Delivery ” in Controlled Drug Delivery : Fundamentals disease or condition , or which even may be an unrelated and Applications ( J . R . Robinson & V . H . L . Lee , eds , 2d ed . , disease or condition . 25 Marcel Dekker , New York , 1987) , ch . 5 , pp . 213 -251 , Pharmaceutical compositions according to the present incorporated herein by this reference . invention can be prepared in accordance with methods well One of ordinary skill in the art can readily prepare known and routinely practiced in the art . See , e .g ., Reming formulations for controlled release or sustained release ton : The Science and Practice of Pharmacy , Mack Publish - comprising a pharmacologically active agent according to ing Co . , 20th ed ., 2000 ; and Sustained and Controlled 30 the present invention by modifying the formulations Release Drug Delivery Systems, J . R . Robinson , ed . , Marcel described above , such as according to principles disclosed in Dekker, Inc ., New York , 1978 . Pharmaceutical compositions V . H . K . Li et al, “ Influence of Drug Properties and Routes are preferably manufactured under GMP conditions. Formu of Drug Administration on the Design of Sustained and lations for parenteral administration may, for example , con - Controlled Release Systems” in Controlled Drug Delivery : tain excipients , sterile water, or saline , polyalkylene glycols 35 Fundamentals and Applications (J . R . Robinson & V . H . L . such as polyethylene glycol, oils of vegetable origin , or Lee , eds, 2d ed ., Marcel Dekker, New York , 1987 ) , ch . 1 , pp . hydrogenated naphthalenes . Biocompatible , biodegradable 3 -94 , incorporated herein by this reference. This process of lactide polymers, lactide/ glycolide copolymers , or polyoxy - preparation typically takes into account physicochemical ethylene -polyoxypropylene copolymers may be used to con properties of the pharmacologically active agent, such as trol the release of the compounds. Other potentially useful 40 aqueous solubility , partition coefficient, molecular size , sta parenteral delivery systems for molecules of the invention bility , and nonspecific binding to proteins and other biologi include ethylene -vinyl acetate copolymer particles , osmotic cal macromolecules. This process of preparation also takes pumps , and implantable infusion systems. Formulations for into account biological factors , such as absorption , distri inhalation may contain excipients , for example , lactose , or bution , metabolism , duration of action , the possible exis may be aqueous solutions containing, e . g . , polyoxyethylene - 45 tence of side effects , and margin of safety , for the pharma 9 - lauryl ether, glycocholate and deoxycholate , or can be oily cologically active agent. Accordingly , one of ordinary skill solutions for administration or gels. in the art could modify the formulations into a formulation Pharmaceutical compositions according to the present having the desirable properties described above for a par invention are usually administered to the subjects on mul ticular application . tiple occasions. Intervals between single dosages can be 50 U . S . Pat. No . 6 ,573 , 292 by Nardella , U . S . Pat. No . weekly , monthly or yearly . Intervals can also be irregular as 6 , 921 ,722 by Nardella , U . S . Pat. No . 7 ,314 ,886 to Chao et indicated by therapeutic response or other parameters well al. , and U .S . Pat. No . 7 ,446 , 122 by Chao et al. , which known in the art . Alternatively , the pharmaceutical compo - disclose methods of use of various pharmacologically active sition can be administered as a sustained release formula agents and pharmaceutical compositions in treating a num tion , in which case less frequent administration is required . 55 ber of diseases and conditions, including cancer , and meth Dosage and frequency vary depending on the half- life in the ods of determining the therapeutic effectiveness of such subject of the pharmacologically active agent included in a pharmacologically active agents and pharmaceutical com pharmaceutical composition . The dosage and frequency of positions, are all incorporated herein by this reference . administration can vary depending on whether the treatment is prophylactic or therapeutic . In prophylactic applications , 60 ADVANTAGES OF THE INVENTION a relatively low dosage is administered at relatively infre quent intervals over a long period of time. Some subjects The present invention provides more effective and effi may continue to receive treatment for the rest of their lives . cient methods of using therapeutic drugs that have previ In therapeutic applications , a relatively high dosage at ously been evaluated for treatment of a number of diseases relatively short intervals is sometimes required until pro - 65 and conditions, especially hyperproliferative disorders, but gression of the disease is reduced or terminated , and pref- whose evaluations resulted in a premature conclusion of lack erably until the subject shows partial or complete amelio - of sufficient efficacy or of occurrence of side effects suffi US 9 ,901 , 563 B2 75 76 cient to prevent the use of the therapeutic drug . Such more (iii ) fraudulent nucleotides; effective and efficient methods of therapeutic drugs will ( iv ) thymidylate synthetase inhibitors ; improve efficacy, prevent or reduce the occurrence of sig ( v ) signal transduction inhibitors ; nificant side effects , and will identify categories of patients (vi ) cisplatin or platinum analogs ; and situations in which such drugs can be effectively 5 ( vii ) alkylating agents ; employed . These therapeutic drugs include , but are not (viii ) anti - tubulin agents ; limited to , dianhydrogalactitol and diacetyldianhydrogalac ( ix ) antimetabolites ; titol. ( x ) berberine; Methods according to the present invention possess indus (xi ) apigenin ; trial applicability for the preparation of a medicament for the 10 ( xii ) amonafide ; treatment of a number of diseases and conditions, especially (xiii ) vinca alkaloids ; hyperproliferative diseases , and compositions according to (xiv ) 5 - fluorouracil; the present invention possess industrial applicability as (xv ) curcumin ; pharmaceutical compositions. (xvi ) NF -kB inhibitors ; The inventions illustratively described herein can suitably 15 (xvii ) rosmarinic acid ; be practiced in the absence of any element or elements , (xviii ) mitoguazone ; and limitation or limitations, not specifically disclosed herein . ( xix ) tetrandrine . Thus, for example , the terms " comprising ," " including, " 2 . A composition to improve the efficacy and /or reduce the " containing , " etc . shall be read expansively and without side effects of suboptimally administered drug therapy , limitation . Additionally , the terms and expressions 20 wherein the composition possesses increased efficacy or employed herein have been used as terms of description and reduced side effects for cancer therapy , wherein the com not of limitation , and there is no intention in the use of such position comprises : terms and expressions of excluding any equivalents of the ( a ) dianhydrogalactitol or diacetyldianhydrogalactitol; future shown and described or any portion thereof, and it is and recognized that various modifications are possible within the 25 ( b ) a therapeutic agent subject to chemosensitization scope of the invention claimed . Thus , it should be under selected from the group consisting of: stood that although the present invention has been specifi (i ) topoisomerase inhibitors ; cally disclosed by preferred embodiments and optional ( ii) fraudulent nucleosides ; features, modification and variation of the inventions herein ( iii ) fraudulent nucleotides ; disclosed can be resorted by those skilled in the art, and that 30 ( iv ) thymidylate synthetase inhibitors ; such modifications and variations are considered to be ( v ) signal transduction inhibitors ; within the scope of the inventions disclosed herein . The (vi ) cisplatin or platinum analogs ; inventions have been described broadly and generically ( vii ) alkylating agents ; herein . Each of the narrower species and subgeneric group ( viii ) anti - tubulin agents ; ings falling within the scope of the generic disclosure also 35 ( ix ) antimetabolites ; form part of these inventions. This includes the generic ( x ) berberine; description of each invention with a proviso or negative ( xi) apigenin ; limitation removing any subject matter from the genus, (xii ) amonafide ; regardless of whether or not the excised materials specifi (xiii ) vinca alkaloids ; cally resided therein . 40 (xiv ) 5 - fluorouracil; In addition , where features or aspects of an invention are ( xv ) curcumin ; described in terms of the Markush group , those schooled in ( xvi) NF -kB inhibitors ; the art will recognize that the invention is also thereby (xvii ) rosmarinic acid ; described in terms of any individualmember or subgroup of (xviii ) mitoguazone ; and members of the Markush group . It is also to be understood 45 (xix ) tetrandrine ; that the above description is intended to be illustrative and wherein the dianhydrogalactitol or diacetyldianhydrogalac not restrictive . Many embodiments will be apparent to those titol acts as a chemosensitizer. of in the art upon reviewing the above description . The scope 3 . A composition to improve the efficacy and /or reduce the of the invention should therefore , be determined not with side effects of suboptimally administered drug therapy, reference to the above description , but should instead be 50 wherein the composition possesses increased efficacy or determined with reference to the appended claims, along reduced side effects for cancer therapy, wherein the com with the full scope of equivalents to which such claims are position comprises : entitled . The disclosures of all articles and references, (a ) dianhydrogalactitol or di acetyl dianhydrogalactitol ; including patent publications, are incorporated herein by and reference . 55 (b ) a therapeutic agent subject to chemopotentiation What is claimed is : selected from the group consisting of: 1 . A composition to improve the efficacy and /or reduce the (i ) topoisomerase inhibitors ; side effects of suboptimally administered drug therapy, ( ii ) fraudulent nucleosides ; wherein the composition possesses increased efficacy or (iii ) fraudulent nucleotides ; reduced side effects for cancer therapy , wherein the com - 60 ( iv ) thymidylate synthetase inhibitors ; position comprises a drug combination comprising : ( v ) signal transduction inhibitors ; (a ) dianhydrogalactitol or diacetyldianhydrogalactitol; ( vi) cisplatin or platinum analogs; and ( vii ) alkylating agents ; ( b ) an additional therapeutic agent selected from the (viii ) anti - tubulin agents ; group consisting of: 65 ( ix ) antimetabolites ; (i ) topoisomerase inhibitors ; ( x ) berberine; ( ii ) fraudulent nucleosides; (xi ) apigenin ; US 9 , 901 ,563 B2 78 (xii ) amonafide ; 7 . A composition to improve the efficacy and / or reduce the ( xiii ) vinca alkaloids; side effects of suboptimally administered drug therapy, (xiv ) 5 - fluorouracil ; wherein the composition possesses increased efficacy or (xv ) curcumin ; reduced side effects for cancer therapy, wherein the com ( xvi ) NF -KB inhibitors ; 5 position comprises a therapeutic agent that is dianhydroga (xvii ) rosmarinic acid ; lactitol or diacetyldianhydrogalactitol and wherein the dian (xviii ) mitoguazone; hydrogalactitolor diacetyldianhydrogalactitolis ( xix ) tetrandrine ; and ( xx ) biotherapeutics ; incorporated into a dosage form selected from the group wherein the dianhydrogalactitol or diacetyldianhydrogalac - 10 consisting of: titol acts as a chemopotentiator. ( i ) tablets ; 4 . A composition to improve the efficacy and / or reduce the ( ii ) capsules; side effects of suboptimally administered drug therapy , ( iii ) topical gels ; wherein the composition possesses increased efficacy or ( iv ) topical creams; reduced side effects for cancer therapy, wherein the com - 15 ( v ) patches ; position comprises a therapeutic agent that is dianhydroga (vi ) suppositories; and lactitol or diacetyldianhydrogalactitol and the composition ( vii ) lyophilized dosage fills . also comprises a diluent, wherein the diluent is selected from 8 . A composition to improve the efficacy and /or reduce the the group consisting of: side effects of suboptimally administered drug therapy , (i ) an emulsion ; wherein the composition possesses increased efficacy or (ii ) N -methylformamide (NMF ) ; reduced side effects for cancer therapy , wherein the com ( iii ) DMF ; position comprises a therapeutic agent that is dianhydroga ( iv ) ethanol; lactitol or diacetyldianhydrogalactitol and the composition ( v ) benzyl alcohol1 .; also comprises a drug delivery system selected from the ( vi) dextrose -containing water for injection ; 25 group consisting of: ( vii ) Cremophor ; ( i) nanocrystals ; (viii ) cyclodextrin ; and ( ii) bioerodible polymers ; ( ix ) PEG . ( iii ) liposomes ; 5 . A composition to improve the efficacy and /or reduce the ( iv ) slow release injectable gels ; and side effects of suboptimally administered drug therapy, 30 (v ) microspheres . wherein the composition possesses increased efficacy or 9 . A composition to improve the efficacy and/ or reduce the reduced side effects for cancer therapy, wherein the com side effects of suboptimally administered drug therapy, position comprises a therapeutic agent that is dianhydroga wherein the composition possesses increased efficacy or lactitol or diacetyldianhydrogalactitol and the composition reduced side effects for cancer therapy, wherein the com also comprises a solvent system , wherein the solvent system 35 position comprises a therapeutic agent that is dianhydroga lactitol or diacetyldianhydrogalactitol and the dianhydroga is selected from the group consisting of: lactitol or diacetyldianhydrogalactitol is present in the ( i) an emulsion ; composition in a drug conjugate form selected from the ( ii ) N -methylformamide ( NMF) ; group consisting of: ( iii) DMF; ( i ) a polymer system ; ( iv ) ethanol; 40 (v ) benzyl alcohol; ( ii ) polylactides; ( vi) dextrose - containing water for injection ; ( iii) polyglycolides; (vii ) Cremophor ; ( iv ) amino acids; ( viii ) cyclodextrin ; and ( v ) peptides; and ( ix ) PEG . 45 ( vi) multivalent linkers . 6 . A composition to improve the efficacy and /or reduce the 10 . A composition to improve the efficacy and / or reduce side effects of suboptimally administered drug therapy, the side effects of suboptimally administered drug therapy , wherein the composition possesses increased efficacy or wherein the composition possesses increased efficacy or reduced side effects for cancer therapy, wherein the com reduced side effects for cancer therapy, wherein the com position comprises a therapeutic agent that is dianhydroga - 50 position comprises a therapeutic agent that is dianhydroga lactitol or diacetyldianhydrogalactitol and the composition lactitol or diacetyldianhydrogalactitol and the dianhydroga also comprises an excipient, wherein the excipient is lactitol or diacetyldianhydrogalactitol is in the form of a selected from the group consisting of: prodrug system , wherein the prodrug system is selected ( i ) mannitol; from the group consisting of: ( ii) albumin ; 55 ( i ) the use of enzyme sensitive esters ; ( iii) EDTA ; ( ii ) the use of dimers ; ( iv ) sodium bisulfite ; ( iii) the use of Schiff bases ; ( v ) benzyl alcohol; ( iv ) the use of pyridoxal complexes; and ( vi) a carbonate buffer ; and ( v ) the use of caffeine complexes . ( vii ) a phosphate buffer . * * * * *