USOO6693125B2 (12) United States Patent (10) Patent No.: US 6,693,125 B2 Borisy et al. (45) Date of Patent: Feb. 17, 2004

(54) COMBINATIONS OF DRUGS (E.G., A Fraser et al., “Endo-Exonuclease of Human Leukaemic BENZIMIDAZOLE AND PENTAMIDINE) Cells: Evidence for a Role in Apoptosis,” J. Cell Sci., FOR THE TREATMENT OF NEOPLASTIC 109:2343-2360, 1996. DSORDERS Gambari et al., “ DNA-Binding Activity and Biological effects of Aromatic Polyamidines,” Biochem Pharmacol, (75) Inventors: Alexis Borisy, Boston, MA (US); 47:599–610, 1994. Curtis Keith, Boston, MA (US); Klemes et al., “Inhibition of Phorbol-Ester-Induced Adhe Michael A. Foley, Chestnut Hill, MA sion of Differentiating Human Myeloid Leukemic Cells by (US); Brent R. Stockwell, Boston, MA Pentamidine-Isethionate,” Differentiation, 27:141-145, (US) 1984. Kopac, M.J., “Section of Biology,” The New York Academy (73) Assignee: CombinatoRx Incorporated, Boston, of Sciences, 5-10, 1945. MA (US) Kopac, M.J., “Some Cellular and Surface Chemical Aspects of Tumor Chemotherapy,” Approaches to Tumor Chemo (*) Notice: Subject to any disclaimer, the term of this therapy ed. F.R. Moulton, AAAS, Washington, D.C. 1947. patent is extended or adjusted under 35 Libby et al., “Inhibition of Enzymes of Polyamine Back U.S.C. 154(b) by 0 days. Conversion by Pentamidine and Berenil,” Biochemical Pharmacology, 44:830–832, 1992. (21) Appl. No.: 09/768,870 Luck et al., “Interaction of Nonintercalative Antitumour Drugs SN-6999 and SN-18071 with DNA: Influence of (22) Filed: Jan. 24, 2001 Ligand Structure on the Binding Specificity,” Journal of (65) Prior Publication Data Biomolecular Structure & Dynamics 4:1079–1094, 1987. NastruZZi et al., “Inhibition of “In Vitro Tumor Cell Growth US 2002/0165261 A1 Nov. 7, 2002 by Aromatic Polyamidines Exhibiting Antiproteinase Activ (51) Int. Cl." ...... A61K 31/415; A61K 31/155 ity,” Clin. Expl. Metastasis, 7:25-39, 1989. (52) U.S. Cl...... 514/388; 514/631 Nastruzzi et al., “Differential Effects of Benzamidine Derivatives on the Expression of C-MYC and HLA-DRC. (58) Field of Search ...... 514/388, 631 Genes in a Human B-Lymphoid Tumor Cell Line,” Cancer (56) References Cited Letters, 38:297-305, 1988. Nishimura et al., “A Serine Protease-Inhibitory Benzami U.S. PATENT DOCUMENTS dine Derivative Inhibits the Growth of Human Colon Car 5,770.585 A 6/1998 Kaufman et al. cinoma Cells,” Jpn. J. Cancer Res., 83:723–728, 1992. 6,280,768 B1 * 8/2001 McDevitt ...... 424/464 Osei et al., “Diabetogenic Effect of Pentamidine,” Am. J. Med., 77:41-46, 1984. FOREIGN PATENT DOCUMENTS Perez et al., “Binding of Pt-Pentamidine to Nucleosomal GB 1288376 9/1972 DNA. Studies of the Antiproliferative Activity of the Drug WO WO O1/35935 5/2001 ...... 31/155 Against Human Cancer Cells,” Chemico-Biological Inter actions, 89:61-72, 1993. OTHER PUBLICATIONS Perez et al., “DNA Binding Properties and Antileukemic The Merck Index, eleventh edition, 1989, Merck & Co., Inc., (L1210) Activity of A Pt-Pentamidine Complex,” Chem. Rayway, N.J., p. 1128, No. 7071.* Biol. Interactions, 77:341–355, 1991. Anees et al., “Inhibition of a Tumor Protease with Reddy et al., “Synthetic DNA Minor Groove-Binding 3,4-Dichloroisocoumarin, Pentamidine-Isethionate and Drugs.” Pharmacology & Therapeutics, 84:1-111, 1999. Guanidino Derivatives,” J. Enzyme Inhibition, 8:213-221, Sands et al., “Pentamidine: A Review,” Reviews of Infectious 1994. Diseases, 7.625-634, 1985. Bailly et al., “Sequence-Selective Binding to DNA of Sansom et al., “Structural Studies on Bio-Active Com Bis(Amidinophenoxy)Alkanes Related to Propamidine and pounds. Part XIV. Molecular Modelling of the Interactions Pentamidine,” Biochem J., 323:23–31, 1997. Between Pentamidine and DNA,” Anti-Cancer Drug Barrett et al., “Anti-Sleeping SickneSS Drugs and Cancer Design, 5:243–248, 1990. Chemotherapy,” Parasitology Today, 16:7-9, 2000. (List continued on next page.) Bornstein et al., “An Evalution of the Mechanism of Action of Pentamidine Isethionate,” Journal of Surgical Oncology, Primary Examiner Jerome D. Goldberg 2:393-398, 1970. (74) Attorney, Agent, or Firm-Clark & Elbing LLP Cresson et al., “ In Vitro Inhibition of Human Sarcoma (57) ABSTRACT Cells Invasive Ability by Bis(5-Amidino-2-Benzimidazolyl) Methane-a novel The invention features a method for treating a patient having esteroprotease inhibitor,” Am. J. Pathol. 123:46-56, 1986. a cancer or other neoplasm, by administering to the patient Ferroni et al., “N1-Substituted Benzamidines: Synthesis, (i) a benzimidazole or a metabolite or analog thereof, and (ii) Antiproteinase Activity and Inhibition of Tumor Cell pentamidine or a metabolite or analog thereof Simulta Growth,” II Farmaco, 46:1311–1321, 1991. neously or within 14 days of each other in amounts Sufficient Fibach et al., “Phorbol Ester-Induced Adhesion of Murine to inhibit the growth of the neoplasm. Erythroleukemia Cells: Possible Involvement of Cellular Proteases,” Carcinogenesis, 4:1395–1399, 1983. 43 Claims, No Drawings US 6,693,125 B2 Page 2

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Antiproteinase Activity and Inhibition of Tumor Cell Turner et al., “The Mutagenic Properties of DNA Minor Growth” Farmaco 46:1311–21 (1991). Groove Binding Ligands,” Mutation Research, Gupta, “Cross-Resistance of Nocodazole-Resistant 355:141-169, 1996. Mutants of CHO Cells Toward Other Microtubule Inhibi Van Wauwe et al., “The Inhibitory Effect of Pentamidine on tors:Similar Mode of Action of Benzimidizole Carbamate the Production of Chemotactic Cytokines by In Vitro Stimu Derivatives and NSC 181928 and TN-16' Mol. Pharmacol. lated Human Blood Cells,” Inflamm. Res. 45:357-363, 1996. 30:142–148 (1986). 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Albendazole Sulfoxide in Patients with Neurocysticercosis” Benaim et al., “A Calmodulin-Stimulated Ca2+ Pump in Chirality 11:218–223 (1999). Plasma-Membrane Vesicles from Trypanosoma brucei; Mesa-Valle et al., “In Vitro Action of Platinum (II) and Selective Inhibition by Pentamidine” Biochem. J, Platinum (IV) Complexes on Trypanosoma cruzi and Leish 296:759–763 (1993). mania donovani" Arzneimittelforschung 39:838-42 (1989). Capece et al., “Pharmacokinetic Behaviour of Albendazole Mesa-Valle et al., “In Vitro and In Vivo Activity of Two Sulphoxide Enantiomers in Male and Female Sheep” Vet. Pt(IV) Salts Against Leishmania donovanl" Pharmacology, Res. Commun. 24:339–48 (2000). 57:160-172 (1998). Chen et al., “Anti-Tumor Necrosis Factor Properties of Mesa-Valle CM et al., “Action of New Organometallic Non-Peptide Drugs in Acute-Phase Responses” Eur. J. Complexes Against Leishmania donovani' J. Antimicrob. Pharmacol 271:319-327 (1994). Chemother. 40:47–57 (1997). Chiap et al., “Determination of Albendazole and Its Main Monglardo et al., “Pentamidine Salts' Lancet 2:108 (1989). Metabolites in Ovine Plasma by Liquid Chromatography with Dialysis as an Integrated Sample Preparation Tech Morgan et al., “Activities of Several Benzimidazoles and nique” J. Chromatogr: A, 870: 121-34 (2000). Tubulin Inhibitors Against Giardia spp. In Vitro” Antimi Corsini et al., “Induction of Tumor Necrosis Factor-Alpha crob. Agents Chemother, 37:328–31 (1993). In Vivo by a Skin Irritant, Tributy tin, Through Activation of Navas et al., “Structural Determinants of Putrescine Uptake Transcription Factors: Its Pharmacological Modulation by Inhibition Produced by Cationic Diamidines in the Model of Anti-Inflammatory Drugs' J. Invest. Dermatol. Trypanosomatid Crithidla Fasciculata' Biol. Chem, 108:892–896 (1997). 377:833-6 (1996). Cubria et al., “Aromatic Diamidines are Reversible Inhibi Nunn et al., “Sequence-Dependent Drug Binding to the tors of Porcine Kidney Diamine Oxidase” Biochem. Phar Minor Groove of DNA; Crystal Structure of the DNA macol. 45:1355–7 (1993). Dodecamar d(CGCAAATTTGCG) Complexed with Pro Dautzenberg et al., “Pentamidine Aerosol in the Preventive pamidine” J. Med. Chem. 28:2317–2325 (1995). Treatment of Pheumocystosis in AIDS Patients. Comparison Perez et al., “DNA Binding Properties and Antileukemic of Two Salts and Two Nebulizers’ Presse Med. (L1210) Activity of Pt-Pentamidine Complex” Chem. Biol. 20:1117–1120 (1991). Interact. 77:341-55 (1991). US 6,693,125 B2 Page 3

Perez et al., “Binding of Pt-Pentamidine to Nucleosomal Tidwell et al., "Analogues of DNA. Studies of the Antiproliferative Activity of the Drug 1.5-Bis(4-amidlnophenoxy)pentane (Pentamidine) in the Against Human Cancer Cells” Chemico-Biological Inter Treatment of Experimental Pneumocystis carinii Pneumo actions 89:61-72 (1993). nia” J. Med. Chem. 33:1252–1257 (1990). Ramanathan et al., “Determination of the Antifiarial Drug UMF-078 and its Metabolites UMF-080 and Flubendazole Van Wauwe et al., “The Inhibitory Effect of Pentamidine on in Whole Blood Using High-Performance Liquid Chroma the Production of Chemotactic Cytokines by In Vitro Stimu tography” J. Chromatogr: B Biomed. Appl, 655:269-273 lated Human Blood Cells” Inflamm. Res. 45:357-363 (1994). (1996). Redondo et al., “Influence of Surfactants on Oral Bioavail ability of Albendazole Based on the Formation of the Whittaker et al., “Effects of Benzimidazole Analogs on Sulphoxide Metabolites in Rats' Biopharm. Drug Dispos., Cultures of Differentiating Rodent Embryonic Cells' Toxi 19:65-70 (1998). col. Appl. Pharmacol. 113: 144–51 (1992). Rolin et al., “Study of the In Vitro Bioactivation of Albenda Zakrzewska et al., “The Solvation Contribution to the Bind Zole in Human Liver Microsomes and Hepatoma Cell Lines' ing Energy of DNA with Non-Intercalating Antibiotics” Cell Biol. Toxicol. 5:1-14 (1998). Nucleic Acids Res. 12:6559–74 (1984). Rosenthal et al., “Pentamidine: An inhibitor of Interleukin-1 that Acts Via a Post-Translational Event Toxicol. App. Mesa-Valle et al., “In Vitro and In Vivo Activity of Two Pharmacol. 107:555–561 (1991). Pl(IV) Salts Against Leishmania donovanl" Pharmacology, Shapiro et al., “Selective Cleavage of Kinetoplast DNA 57:160-172 (1998). Minicircles Promoted by Antitrypanosomal Drugs’ Proc. Natl. Acad. Sci. USA, 87:950-954 (1990). * cited by examiner US 6,693,125 B2 1 2 COMBINATIONS OF DRUGS (E.G., A Preferably, the two compounds are administered within BENZIMIDAZOLE AND PENTAMIDINE) ten days of each other, more preferably within five days of FOR THE TREATMENT OF NEOPLASTIC each other, and most preferably within twenty-four hours of DISORDERS each other or even Simultaneously. The cancer treated according to any of the methods of the invention, described below, can be lung cancer (Squamous cell carcinoma, BACKGROUND OF THE INVENTION adenocarcinoma, or large cell carcinoma), brain cancer, The invention relates to the treatment of neoplastic dis breast cancer, cerVical cancer, colon cancer, gastric cancer, orderS Such as cancer. kidney cancer, leukemia, liver cancer, lymphoma, ovarian Cancer is a disease marked by the uncontrolled growth of cancer, pancreatic cancer, prostate cancer, rectal cancer, abnormal cells. The abnormal cells may no longer do the Sarcoma, Skin cancer, testicular cancer, or uterine cancer. work of normal cells, and they crowd out and destroy In a related aspect, the invention also features a method healthy tissue. for treating a patient having a neoplasm Such as cancer. In Lung cancer is the most common cancer-related cause of 15 this method, the patient is administered (a) a first compound death among men and women. It is the Second most com Selected from albendazole, albendazole Sulfonate, albenda monly occurring cancer among men and women; it has been Zole Sulfone, albendazole Sulfoxide, astemizole, benomyl, estimated that there will be more than 164,000 new cases of 2-benzimidazolylurea, benzthiaZuron, cambendazole, lung cancer in the U.S. in the year 2000 alone. While the rate cyclobendazole, domperidone, droperidol, fenbendazole, of lung cancer cases is declining among men in the U.S., it flu bendazole, frentizole, 5-hydroxy mebendazole, continues to increase among women. Lung cancer can be lob end a Zole, lu Xab end a Zole, me bend a Zole, lethal; according to the American Lung ASSociation, an methabenzthiaZuron, mercazole, midefradil, nocodoZole, estimated 156,900 Americans are expected to die due to lung omeprazole, Oxfendazole, OXibendazole, parbendazole, cancer in 2000. pimozide, and tioxidazole (or a Salt of any of the above), NSC 181928 (ethyl 5-amino-1,2-dihydro-3-(N- Cancers that begin in the lungs are divided into two major 25 methylanilino)methyl-pyrido3,4-bipyrazin-7- types, non-Small cell lung cancer and Small cell lung cancer, ylcarbamate), and TN-16 (3-(1-anilinoethylidene)-5-benzyl depending on how the cells appear under a microScope. pyrrodiline-2,4-dione); and (b) a Second compound Selected Non-Small cell lung cancer (Squamous cell carcinoma, from pentamidine, propamidine, butamidine, heptamidine, adenocarcinoma, and large cell carcinoma) generally nonamidine, Stilb amidine, hydroxy Stilb amidine, Spreads to other organs more slowly than does Small cell dimina Zene, ben Zamidine, phen a midine, lung cancer. Small cell lung cancer is the leSS common type, dibrom prop a midine, 1,3-bis(4- a mid in o-2- accounting for about 20% of all lung cancer. methoxyphenoxy)propane, phenamidine, and amicarbalide Other cancers include brain cancer, breast cancer, cervical (or a salt of any of the above). Alternatively, the Second cancer, colon cancer, gastric cancer, kidney cancer, 35 compound can be a functional analog of pentamidine, Such leukemia, liver cancer, lymphoma, ovarian cancer, pancre as netropsin, distamycin, bleomycin, actinomycin, or dauno atic cancer, prostate cancer, rectal cancer, Sarcoma, skin rubicin. The first and Second compounds are preferably cancer, testicular cancer, and uterine cancer. These cancers, administered simultaneously or within 14 days of each other like lung cancer, are Sometimes treated with chemotherapy. and in amounts sufficient to inhibit the growth of the Chemotherapeutic drugs currently in use or in clinical neoplasm. trials include paclitaxel, docetaxel, tamoxifen, Vinorelbine, 40 gemcitabine, cisplatin, etoposide, topotecan, irinotecan, In another related aspect, the invention also features a an astro Zole, rituximab, trastu Zumab, fludarabine, method for treating a patient having a neoplasm Such as cyclophosphamide, gentuzumab, carboplatin, interferon, cancer by administering the following: and doxorubicin. The most commonly used anticancer agent a) a first compound having the formula (I): is paclitaxel, which is used alone or in combination with 45 other chemotherapy drugs. Such as: 5-FU, doxorubicin, (I) Vinorelbine, cytoxan, and cisplatin. R4 N, , SUMMARY OF THE INVENTION 1. 50 2 R2 We have discovered that the combination of one of the antihelmintic drugs albendazole, mebendazole, or OXibenda R N Zole and the antiprotozoal drug pentamidine exhibits Sub Stantial antiproliferative activity against cancer cells. Struc wherein: tural and functional analogs of each of these compounds are 55 known, and any of these analogs can be used in the anti R is Selected from the group consisting of proliferative combinations of the invention. Metabolites of albendazole and pentamidine are also known. Many of these (A-1) metabolites share one or more biological activities with the O parent compound and, accordingly, can also be used in the 60 antiproliferative combinations of the invention. ... --~" Accordingly, the invention features a method for treating a (A-2) patient having a cancer or other neoplasm, by administering O to the patient (i) albendazole, mebendazole, or oxibenda N 65 Zole; and (ii) pentamidine Simultaneously or within 14 days ul N -N-N-1 of each other in amounts sufficient to inhibit the growth of H the neoplasm. US 6,693,125 B2 3 4 -continued -continued (A-3) O (B-13) O

usO O and 5 ----N --- O N-1\o-1Ne. (A-4) ----H; each of R and R is independently Selected from the R is Selected from the group consisting of 1O group consisting of:

(B-1) (C-1) - - -NH CH - - - - C NH (C-2) O 15 1-N-CH3 B-2 - - -NH (B-2) 1-N-CH3 (C-3) y-NH - - - -S O 2O CH (C-4) 1N1 3 C-5 (B-3) ----OCH, (C-5) NH2 NH (B-4) as O O (C-6) -N-K \/ NH2 - - - - O (B-5) - - -NH 3O R) y- CH (C-7) O O --NH (B-6) ) OH 35 o O Na

H (B-7) (C-8)C-8 --N O CH O r N1 40 M - - - -N O V (B-8) O --S (C-9) \ /CH 45 S N VCH () H (B-9) - - - -N OS-CH3 50 O (C-10) M O - - - -S

- - -NH (B-10) y-NH. 55 O (B-11) ----CH (C-11) O X-N O (C-12) --N CH 60 V CH (B-12) N -N1-( D and 65 US 6,693,125 B2 S 6 -continued -continued O (C-13) (C-26) (C-27)

and b) a second compound having the formula (II): F (II) (C-14) OH / \ Y-(CH2) -Z y-Rs

15 Rs R6

(C-15) wherein each of Y and Zis, independently, O or N; each O. O of Rs and R is, independently, -H, -OH, -halogen, \/ -O-Co alkyl, -OCF, -NO, or NH; n is an integer between 2 and 6, inclusive; and each of R7 and Rs is, independently, at the meta or para position and is Selected from the group consisting of: (D-1) R F 25 NH (C-16) O

(D-2) NOH SN2 (C-17) NH2 (D-3) 35

'. (D-4) (C-18) OSa O ----O1 N1\ct, 40 (C-19) --N-Cls (D-5) y 45 (C-20) O CH

O (C-21) 50 O wherein the first and Second compounds are adminis M tered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neo VO plasm. (C-22) In another related aspect, the invention also features a 55 method for treating a patient having a neoplasm Such as (C-23) cancer by administering the following: - - - -CH a) a first compound having the formula (III): (C-24) O (III) 60 R11 A. 1. 2 R9 3 ON2 R16 N (C-25) - - - - O 65 N1)-ct, wherein: A is Selected from the group consisting of O, S, and NR;

US 6,693,125 B2 9 10 -continued bination therapy may be given in on-and-off cycles that (D-4) include rest periods So that the patient's body has a chance N to build healthy new cells and regain Strength. -( D and Depending on the type of cancer and its Stage of N development, the combination therapy can be used to treat M cancer, to Slow the Spreading of the cancer, to Slow the HC cancer's growth, to kill or arrest cancer cells that may have (D-5) Spread to other parts of the body from the original tumor, to NN relieve Symptoms caused by the cancer, or to prevent cancer in the first place. Combination therapy can also help people -(N-N live more comfortably by eliminating cancer cells that cause H pain or discomfort. As used herein, the terms “alkyl,” “alkenyl,” and the wherein the first and Second compounds are adminis prefix “alk-” are inclusive of both straight chain and tered simultaneously or within 14 days of each other in 15 branched chain groups and of cyclic groups, i.e., cycloalkyl amounts sufficient to inhibit the growth of the neo and cycloalkenyl groups. Cyclic groups can be monocyclic plasm. or polycyclic and preferably have from 3 to 10 ring carbon In any of the foregoing treatment methods, both com atoms, inclusive. Exemplary cyclic groups include pounds are preferably together in a pharmaceutical compo cyclopropyl, cyclopentyl, cyclohexyl, and adamanty1 Sition that also includes a pharmaceutically acceptable car groupS. rier. A benzimidazole is preferably administered at a dosage The term “aryl' includes carbocyclic aromatic rings or of 1 to 2500 milligrams and pentamidine is preferably ring Systems. Examples of aryl groups include phenyl, administered at a dosage of 1 to 1000 milligrams. Suitable naphthyl, biphenyl, fluorenyl, and indenyl groups. The term modes of administration include intravenous, intramuscular, "heteroaryl' includes aromatic rings or ring Systems that inhalation, and oral administration. 25 contain at least one ring hetero atom (e.g., O, S, N). The antiproliferative combinations of the invention can Heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, also be provided as components of a pharmaceutical pack. tetrazolyl, and imidazo groups. The two drugs can be formulated together or Separately and “Hetercyclyl includes non-aromatic rings or ring Sys in individual dosage amounts. tems that contain at least one ring hetero atom (e.g., O, S, N). It will be understood by those in the art that the com Heterocyclic groups include, for example, pyrrolidinyl, pounds are also useful when formulated as Salts. For tetrahydrofuranyl, morpholinyl, thiazolidinyl, and imidazo example, as is described herein, the isethionate Salt of lidinyl groupS. pentamidine exhibits Synergistic antiproliferative activity The aryl, heteroaryl, and heterocyclyl groups may be when combined with a benzimidazole. Other salts of pen unsubstituted or substituted by one or more substituents tamidine include the platinum Salt, the dihydrochloride Salt, 35 Selected from the group consisting of Co alkyl, hydroxy, and the dimethaneSulfonate Salt (see, for example, Mongia halo, nitro, Co alkoxy, Co alkylthio, trihalomethyl, rdo et al., Lancet 2:108, 1989). Similarly, benzimidazole Co acyl, arylcarbonyl, heteroarylcarbonyl, nitrile, Co Salts include, for example, halide, Sulfate, nitrate, phosphate, alkoxycarbonyl, Oxo, arylalkyl (wherein the alkyl group has phosphinate Salts. from 1 to 10 carbon atoms) and heteroarylalkyl (wherein the The invention also features a method for identifying 40 alkyl group has from 1 to 10 carbon atoms). compounds useful for treating a patient having a neoplasm. Compounds useful in the invention include those The method includes the Steps of: contacting cancer cells in described herein in any of their pharmaceutically acceptable vitro with (i) pentamidine or a benzimidazole (or an analog forms, including isomerS Such as diastereomers and of pentamidine or a benzimidazole) and (ii) a candidate enantiomers, Salts, Solvates, and polymorphs, thereof, as compound, and determining whether the cancer cells grow 45 well as racemic mixtures of the compounds described more slowly than (a) cancer cells contacted with the benz herein. imidazole or pentamidine but not contacted with the candi Other features and advantages of the invention will be date compound, and (b) cancer cells contacted with the apparent from the following detailed description, and from candidate compound but not with the benzimidazole or the claims. pentamidine. A candidate compound that, when combined 50 with the benzimidazole or pentamidine, reduces cell prolif DETAILED DESCRIPTION OF THE eration but, in the absence of the benzimidazole or INVENTION pentamidine, does not is a compound that is useful for We have discovered that the antihelmentic drugs treating a patient having a neoplasm. albendazole, mebendazole, or oxibendazole in combination Combination therapy according to the invention may be 55 with the antiprotozoal drug pentamidine exhibit Substantial provided wherever chemotherapy is performed: at home, the antiproliferative activity against cancer cells. Concentra doctor's office, a clinic, a hospital's outpatient department, tions that exhibited maximal antiproliferative activity or a hospital. Treatment generally begins at a hospital So that against cancer cells were not toxic to normal cells. Thus, this the doctor can observe the therapy’s effects closely and drug combination is useful for the treatment of cancer and make any adjustments that are needed. The duration of the 60 other neoplasms. We have also discovered that the combi combination therapy depends on the kind of cancer being nation of pentamidine isethionate with either exhibits similar treated, the age and condition of the patient, the Stage and antiproliferative activity. type of the patient's disease, and how the patient's body Based on known properties that are shared among responds to the treatment. Drug administration may be albendazole, mebendazole, and OXibendazole, their performed at any of various intervals (e.g., daily, weekly, or 65 metabolites, and other benzimidazoles, as well as those monthly) and the dosage, frequency, and mode of adminis shared among pentamidine and its analogs and metabolites, tration of each agent can be determined individually. Com it is likely that Structurally related compounds can be US 6,693,125 B2 11 12 Substituted for albendazole, mebendazole, and OXibendazole -continued and for pentamidine in the antiproliferative combinations of the invention. Information regarding each of the drugs and (B-8) its analogs and metabolites is provided below. - - - -S Benzimidazoles Benzimidazoles that are useful in the antiproliferative y H. N combination of the invention are compounds having the V general formula (I): CH

R (I) (B-9) 1. R4 \ ---- O CH 1. r N1 3 2 R 2 15 O R N

(B-10) wherein: - - - -NH R is Selected from the group consisting of H and Co alkyl or Coalkenyl that is unsubstituted or Substi tuted by one or more substituents selected from the OX-Nil, group consisting of -aryl, -heteroaryl, -heterocyclyl, (B-11) -O-Co alkyl, -O-(C-o)--aryl, -O-(Co O alkyl)o-hetero aryl, -O-(Co alkyl)o- 25 )-NV heterocyclyl, -Co alkoxycarbonyl, -SO)-2-C. - - - -N CH V 10 alkyl, -S(O)o-2-(Co alkyl)0-1-aryl, CH -S(O)o-2-(Co alkyl)o-heteroaryl, -SO)o-2- (B-12) (Clo alkyl)--heterocyclyl, -N (R), -OR, N -oxo, -cyano, -halo, -NO, -OH, and -SH; R is Selected from the group consisting of -N1-( D and O (B-13) O (B-1) - - - -NH CH 35 ... -- O N-1\o-1Ne. X-réNH O each of R and R is independently selected from the (B-2) 40 group consisting of -H, -halo, -NO, -OH, -SH, - - - -NH -O-Co alkyl, -O-(C-o)-1-aryl, -O-(Co y-Nil alkyl)o-hetero aryl, -O-(Co alkyl)-1- O heterocyclyl, -Co alkoxycarbonyl, -SO)--C- 45 10 alkyl, -S(O)o-2-(Co alkyl)-1-aryl, -SO)o- (C11o alkyl)o-heteroaryl, -S(O)o-2-(C-1o alkyl)o- 1-heterocyclyl, and -Co alkyl or -Co alkenyl (B-3) ----NH that is unsubstituted or substituted by one or more (B-4) Substituents Selected from the group consisting of-aryl, NH 50 -heteroaryl, -heterocyclyl, -O-Co alkyl, -O- -N1-( (Clio alkyl)-1-aryl, -O-(Co alkyl)o-heteroaryl, NH2 -O-(Co alkyl)--heterocyclyl, -Co (B-5) alkoxycarbonyl, -S(O)o-Co alkyl, -SO)o- - - - -NH 55 (C11o alkyl)o-1-aryl, -S(O)o-2-(C1-io alkyl)o-1- X- CH heteroaryl, -SO)-(Co alkyl)--heterocyclyl, O -N(R), -OR-, -oxo, -cyano, -halogen, -NO, (B-6) -OH, and -SH; and - - - -NH each R is Selected from the group consisting of H and y- OH 60 Co alkyl or Co alkenyl that is unsubstituted or O Substituted by one or more substituents selected from (B-7) the group consisting of-aryl, -heteroaryl, -heterocyclyl, O CH N1 3 -O-Co alkyl, -O-(C-o)-1-aryl, -O-(Co 65 alkyl)o-hetero aryl, -O-(Co alkyl)o- O heterocyclyl, -Co alkoxycarbonyl, -oxo, -cyano, -halo, -NO, -OH, and -SH.

US 6,693,125 B2 15 16 -continued -continued (C-24) (B-4) O -N-KNH NH2 (B-5) On 2 - - - -NH (C-25) CH - - - - O O N1)-ct, (B-6) (C-26) - - - -NH F (C-27) ----Br; y-on O 15 (B-7) One of the most commonly prescribed members of the ---- O CH benzimidazole family is albendazole, which has the Struc N1 '3 ture: O (B-8) (E-1) - - - -S \ \ y H. N V CH 25 (B-9) ---- O n1'3CH Albendazole is currently available as an oral Suspension and in tablets. O (B-10) Albendazole Metabolites - - - -NH Albendazole undergoes metabolic transformation into a number of metabolites that may be therapeutically active; X-Nil, O these metabolites may be substituted for albendazole in the (B-11) antiproliferative combination of the invention. The metabo 35 O lism of albendazole can yield, for example, albendazole Sulfonate, albendazole Sulfone, and albendazole Sulfoxide. )-NV - - - -N CH BenZimidazole Analogs V CH Analogs of benzimidazoles include benzothioles and ben 40 (B-12) Zoxazoles having the structure of formula IV: N (IV) -N-( D and R11 B O 1. (B-13) 2X-R 45 O R16 N ... -- O N-1\o-1Ne. wherein: 50 and each of Ro and R is independently Selected from B is O or S; the group consisting of -H, -halo, -NO, -OH, -SH, -O-Co alkyl, -O-(C-o)--aryl, -O- Ro is Selected from the group consisting of (Clio alkyl)o-heteroaryl, -O-(Co alkyl)o-- (B-1) heterocyclyl, -Co alkoxycarbonyl, -SO) - - - -NH CH 55 -Co alkyl, -S(O)o-2-(Co alkyl)o-1-aryl, -S(O)o-2-(Co alkyl)o-heteroaryl, -S(O)o-2-(C. NH 10 alkyl)o-heterocyclyl, and -Co alkyl or -Co O alkenyl that is unsubstituted or substituted by one or (B-2) - - - -NH more Substituents Selected from the group consisting of 60 -aryl, -heteroaryl, -heterocyclyl, -O-C alkyl, y-Nil -O-(Co alkyl)o-aryl, -O-(Co alkyl)-1- O heteroaryl, -O-(Co alkyl)o-heterocyclyl, -Co alkoxycarbonyl, -S(O)o-Co alkyl, -SO)o- (C11o alkyl)o-1-aryl, -S(O)o-2-(C1-io alkyl)o-1- (B-3) 65 heteroaryl, -SO)-(Co alkyl)--heterocyclyl, - - - -NH2 -N(R), -OR-, -oxo, -cyano, -halogen, -NO, -OH, and -SH; and US 6,693,125 B2 17 18 each R is independently Selected from the group con and the protozoan Crithidia Oncopelti indicate that the drug Sisting of H and Co alkyl or Coalkenyl that is interferes with nuclear metabolism, causing inhibition of the unsubstituted or substituted by one or more substituents synthesis of DNA, RNA, phospholipids, and proteins. Selected from the group consisting of-aryl, -heteroaryl, -heterocyclyl, -O-Co alkyl, -O-(C-o)-1-aryl, Little is also known about the drug's pharmacokinetics. In -O-(Co alkyl)-heteroaryl, -O-(Coalkyl)- one published Study, Seven patients treated with daily i.m. 1-heterocyclyl, -Co alkoxycarbonyl, -oxo, -cyano, doses of pentamidine at 4 mg/kg for 10 to 12 days were -halo, -NO, -OH, and -SH. found to have plasma concentrations between 0.3 and 0.5 Suitable benzimidazoles and benzimidazole analogs for tug/mL. The patients continued to excrete decreasing use in the methods of the invention include astemizole, amounts of pentamidine in urine up to Six to eight weeks be nomyl, 2-ben Zimidazolylu rea, ben Zthia Zuron, after cessation of treatment. cambendazole, cyclobendazole, domperidone, droperidol, Tissue distribution of pentamidine has been studied in fe nb end a Zole, flub endazole, fre n ti Zole, mice given a single intraperitoneal injection of pentamidine 5-hydroxymebendazole, lobendazole, luxabendazole, at 10 mg/kg. The concentration in the kidneys was the mebendazole, methabenzthiaZuron, mercazole, midefradil, highest, followed by that in the liver. In mice, pentamidine nocodozole, omeprazole, Oxfendazole, OXibendazole, 15 was excreted unchanged, primarily via the kidneys with parbendazole, pimozide, and tioxidazole. Some elimination in the feces. The ratio of amounts excreted Some benzimidazoles and benzimidazole analogs fit the in the urine and feces (4:1) was constant over the period of following formula (III). Study. Pentamidine Analogs (III) Aromatic diamidino compounds can replace pentamidine R11 A. 1. in the antiproliferative combination of the invention. These 2 R compounds are referred to as pentamidine analogs. } 9 Examples are propamidine, butamidine, heptamidine, and R16 N nonamidine, all of which, like pentamidine, exhibit 25 antipathogenic or DNA binding properties. Other analogs wherein: (e.g., Stilbamidine and indole analogs of Stilbamidine, A is selected from the group consisting of O, S, and NR; hydroxy Stilb amidine, dimina Zene, ben Zamidine, Ro Ro, R, and R are as described above for formula dibrom prop a midine, 1,3-bis(4- a mid in o-2- (IV); methoxyphenoxy) propane (DAMP), metropsin, distamycin, R is selected from the group consisting of -H and phenamidine, amicarbalide, bleomycin, actinomycin, and -Co alkylor-Coalkenyl that is unsubstituted or daunorubicin) also exhibit properties in common with pen Substituted by one or more Substituents selected from tamidine. It is likely that these compounds will have anti the group consisting of-aryl, -heteroaryl, -heterocyclyl, proliferative activity when administered in combination -O-Co alkyl, -O-(C-o)-1-aryl, -O-(Co 35 with a benzimidazole (or an analog or metabolite of a alkyl)--hetero aryl, -O-(Co alkyl)-1- benzimidazole). heterocyclyl, -Co alkoxycarbonyl, -SO)-2-C. Suitable analogs are those falling within formula (II). 10 alkyl, -S(O)-(Co alkyl)-1-aryl, -SO)-- (C-1o alkyl)o-1-heteroaryl, -S(O)o-2 (II) -(Co alkyl)o-heterocyclyl, -N(R), -OR, 40 -oxo, -cyano, -halo, -NO, -OH, and -SH; and Y-(CH2) Pentamidine Pentamidine is currently used for the treatment of Pneu mocystis carinii, Leishmania donovani, TrypanoSoma Rs R6 brucei, T. gambiense, and T. rhodesiense infections. The 45 Structure of pentamidine is: wherein each of Y and Z is, independently, -O-or-N-; each of Rs and R is, independently, -H, -OH, -Cl, (F-1) Br, -F, -OCH, -OCF, -NO, or -NH; n is an NH NH integer between 2 and 6, inclusive, and each of R7 and Rs 50 is, independently, at the meta or para position and is Selected HN NH2 from the group consisting of: 1n 1-1N (D-1) 55 It is available formulated for injection or inhalation. For d" injection, pentamidine is packaged as a nonpyrogenic, lyo NH2 philized product. After reconstitution, it is administered by (D-2) intramuscular or intravenous injection. Pentamidine isethionate is a white, crystalline powder 60 " Soluble in water and glycerin and insoluble in ether, acetone, NH2 and chloroform. It is chemically designated 4,4'-diamidino diphenoxypentane di(B-hydroxyethaneSulfonate). The (D-3) molecular formula is CHNOS and the molecular weight is 592.68. 65 The antiprotozoal mode of action of pentamidine is not fully understood. In vitro Studies with mammalian tissues US 6,693,125 B2 19 20 -continued -continued (D- (H-3) HN

HN)-( )—on (H-4) (D-5) NH NOH

1-1-1aO (H-5) Other Suitable pentamidine analogs include Stilbamidine NH NH (G-1) and hydroxyStilbamidine (G-2), and their indole ana 15 logs (e.g., G-3): (G-1) HN ~~~O OH ( ) NH (H-6) NH NH NH2 (G-2) 25 OH HN ~N~O (H-7) ( ) v. NH NH NOH NH2 and (G-3) NH 1a1a1aO HN N 35 Therapy ( ) NH2. The combinations of compounds of the invention are HN useful for the treatment of neoplasms. Combination therapy may be performed alone or in conjunction with another therapy (e.g., Surgery, radiation, chemotherapy, biologic Each amidine moiety may independently be replaced with 40 therapy). Additionally, a person having a greater risk of one of the moieties depicted as D-2, D-3, D-4, or D-5, above. developing a neoplasm (e.g., one who is genetically predis AS is the case for the benzimidazoles and pentamidine, Salts posed or one who previously had a neoplasm) may receive of stilbamidine, hydroxystilbamidine, and their indole prophylactic treatment to inhibit or delay neoplastic forma derivatives are also useful in the method of the invention. tion. Preferred salts include, for example, dihydrochloride and 45 The dosage and frequency of administration of each methaneSulfonate Salts. component of the combination can be controlled indepen dently. For example, one compound may be administered Pentamidine Metabolites orally three times per day, while the Second compound may Pentamidine metabolites are also useful in the antiprolif be administered intramuscularly once per day. The com erative combination of the invention. Pentamidine is rapidly 50 pounds may also be formulated together Such that one metabolized in the body to at least Seven primary metabo administration delivers both compounds. Formulations and lites. Some of these metabolites share one or more activities dosages are described further below. with pentamidine. It is likely that Some pentamidine metabo Formulation of Pharmaceutical Compositions lites will exhibit antiproliferative activity when combined The administration of each compound of the combination with a benzimidazole or an analog thereof. 55 may be by any Suitable means that results in a concentration Seven pentamidine metabolites are shown below. of the compound that, combined with the other component, is anti-neoplastic upon reaching the target region. The (H-1) compound may be contained in any appropriate amount in HN any Suitable carrier Substance, and is generally present in an O(CH2)COOH 60 amount of 1-95% by weight of the total weight of the HN composition. The composition may be provided in a dosage (H-2) form that is Suitable for the oral, parenteral (e.g., HN intravenously, intramuscularly), rectal, cutaneous, nasal, O(CH2)4CH2OH vaginal, inhalent, skin (patch), or ocular administration 65 route. Thus, the composition may be in form of, e.g., tablets, HN capsules, pills, powders, granulates, Suspensions, emulsions, Solutions, gels including hydrogels, pastes, ointments, US 6,693,125 B2 21 22 creams, plasters, drenches, delivery devices, Suppositories, alginates, or alginic acid), binding agents (e.g., Sucrose, enemas, injectables, implants, sprays, or aeroSols. The phar glucose, Sorbitol, acacia, alginic acid, Sodium alginate, maceutical compositions may be formulated according to gelatin, Starch, pregelatinized Starch, microcrystalline conventional pharmaceutical practice (see, e.g., Remington. cellulose, magnesium aluminum Silicate, carboxymethylcel The Science and Practice of Pharmacy, (19th ed.) ed. A. R. lulose Sodium, methylcellulose, hydroxypropyl Gennaro, 1995, Mack Publishing Company, Easton, Pa. and methylcellulose, ethylcellulose, polyvinylpyrrolidone, or Encyclopedia of Pharmaceutical Technology, eds. J. Swar polyethylene glycol); and lubricating agents, glidants, and brick and J. C. Boylan, 1988-1999, Marcel Dekker, New antiadhesives (e.g., magnesium Stearate, Zinc Stearate, York. Stearic acid, Silicas, hydrogenated vegetable oils, or talc). Pharmaceutical compositions according to the invention Other pharmaceutically acceptable excipients can be may be formulated to release the active compound Substan colorants, flavoring agents, plasticizers, humectants, buffer tially immediately upon administration or at any predeter ing agents, and the like. mined time or time period after administration. The latter The tablets may be uncoated or they may be coated by types of compositions are generally known as controlled known techniques, optionally to delay disintegration and release formulations, which include (i) formulations that 15 absorption in the gastrointestinal tract and thereby providing create a Substantially constant concentration of the drug a Sustained action over a longer period. The coating may be within the body over an extended period of time; (ii) adapted to release the active drug Substance in a predeter formulations that after a predetermined lag time create a mined pattern (e.g., in order to achieve a controlled release Substantially constant concentration of the drug within the formulation) or it may be adapted not to release the active body over an extended period of time; (iii) formulations that drug Substance until after passage of the stomach (enteric Sustain drug action during a predetermined time period by coating). The coating may be a Sugar coating, a film coating maintaining a relatively, constant, effective drug level in the (e.g., based on hydroxypropyl methylcellulose, body with concomitant minimization of undesirable side methylcellulose, methyl hydroxyethylcellulose, effects associated with fluctuations in the plasma level of the hydroxypropylcellulose, carboxymethylcellulose, acrylate active drug Substance (Sawtooth kinetic pattern); (iv) for 25 co polymers, polyethylene gly cols and/or mulations that localize drug action by, e.g., Spatial place polyvinylpyrrolidone), or an enteric coating (e.g., based on ment of a controlled release composition adjacent to or in the methacrylic acid copolymer, cellulose acetate phthalate, diseased tissue or organ; and (v) formulations that target hydroxypropyl methylcellulose phthalate, hydroxypropyl drug action by using carriers or chemical derivatives to methylcellulose acetate Succinate, polyvinyl acetate deliver the drug to a particular target cell type. phthalate, shellac, and/or ethylcellulose). Furthermore, a Administration of compounds in the form of a controlled time delay material Such as, e.g., glyceryl monoStearate or release formulation is especially preferred in cases in which glyceryl distearate may be employed. the compound, either alone or in combination, has (i) a The Solid tablet compositions may include a coating narrow therapeutic index (i.e., the difference between the adapted to protect the composition from unwanted chemical plasma concentration leading to harmful Side effects or toxic 35 changes, (e.g., chemical degradation prior to the release of reactions and the plasma concentration leading to a thera the active drug Substance). The coating may be applied on peutic effect is Small; in general, the therapeutive index, TI, the Solid dosage form in a similar manner as that described is defined as the ratio of median lethal dose (LDso) to in Encyclopedia of Pharmaceutical Technology, Supra. median effective dose (EDso)); (ii) a narrow absorption The two drugs may be mixed together in the tablet, or may window in the gastro-intestinal tract; or (iii) a very short 40 be partitioned. In one example, the first drug is contained on biological half-life So that frequent dosing during a day is the inside of the tablet, and the Second drug is on the outside, required in order to Sustain the plasma level at a therapeutic Such that a Substantial portion of the Second drug is released level. prior to the release of the first drug. Any of a number of Strategies can be pursued in order to Formulations for oral use may also be presented as obtain controlled release in which the rate of release out 45 chewable tablets, or as hard gelatin capsules wherein the weighs the rate of metabolism of the compound in question. active ingredient is mixed with an inert Solid diluent (e.g., In one example, controlled release is obtained by appropriate potato Starch, lactose, microcrystalline cellulose, calcium Selection of various formulation parameters and ingredients, carbonate, calcium phosphate or kaolin), or as Soft gelatin including, e.g., various types of controlled release compo capsules wherein the active ingredient is mixed with water Sitions and coatings. Thus, the drug is formulated with 50 or an oil medium, for example, peanut oil, liquid paraffin, or appropriate excipients into a pharmaceutical composition olive oil. Powders and granulates may be prepared using the that, upon administration, releases the drug in a controlled ingredients mentioned above under tablets and capsules in a manner. Examples include Single or multiple unit tablet or conventional manner using, e.g., a mixer, a fluid bed appa capsule compositions, oil Solutions, Suspensions, emulsions, ratus or a Spray drying equipment. microcapsules, microSpheres, nanoparticles, patches, and 55 Controlled Release Oral Dosage Forms liposomes. Controlled release compositions for oral use may, e.g., be Solid Dosage Forms for Oral Use constructed to release the active drug by controlling the Formulations for oral use include tablets containing the dissolution and/or the diffusion of the active drug Substance. active ingredient(s) in a mixture with non-toxic pharmaceu Dissolution or diffusion controlled release can be tically acceptable excipients. These excipients may be, for 60 achieved by appropriate coating of a tablet, capsule, pellet, example, inert diluents or fillers (e.g., Sucrose, Sorbitol, or granulate formulation of compounds, or by incorporating Sugar, mannitol, microcrystalline cellulose, Starches includ the compound into an appropriate matrix. A controlled ing potato Starch, calcium carbonate, Sodium chloride, release coating may include one or more of the coating lactose, calcium phosphate, calcium Sulfate, or Sodium Substances mentioned above and/or, e.g., shellac, beeswax, phosphate); granulating and disintegrating agents (e.g., cel 65 glycowax, castor wax, carnauba wax, Stearyl alcohol, glyc lulose derivatives including microcrystalline cellulose, eryl mono Stearate, glyceryl diste a rate, glycerol Starches including potato Starch, croScarmellose Sodium, palmitoStearate, ethylcellulose, acrylic resins, d1-polylactic US 6,693,125 B2 23 24 acid, cellulose acetate butyrate, polyvinyl chloride, polyvi AS indicated above, the pharmaceutical compositions nyl acetate, Vinyl pyrrollidone, polyethylene, according to the invention may be in the form Suitable for poly me thacrylate, methyl me thacrylate, Sterile injection. To prepare Such a composition, the Suitable 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 buty active drug(s) are dissolved or Suspended in a parenterally lene glycol, ethylene glycol methacrylate, and/or polyeth acceptable liquid vehicle. Among acceptable vehicles and ylene glycols. In a controlled release matrix formulation, the Solvents that may be employed are water, water adjusted to matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and Stearyl alcohol, carbopol a Suitable pH by addition of an appropriate amount of 934, Silicone, glyceryl tristearate, methyl acrylate-methyl hydrochloric acid, sodium hydroxide or a suitable buffer, methacrylate, polyvinyl chloride, polyethylene, and/or halo 1,3-butanediol, Ringer's Solution, and isotonic Sodium chlo genated fluorocarbon. ride Solution. The aqueous formulation may also contain one A controlled release composition containing one or more or more preservatives (e.g., methyl, ethyl or n-propyl of the compounds of the claimed combinations may also be p-hydroxybenzoate). In cases where one of the compounds in the form of a buoyant tablet or capsule (i.e., a tablet or is only sparingly or slightly Soluble in water, a dissolution capsule that, upon oral administration, floats on top of the enhancing or Solubilizing agent can be added, or the Solvent gastric content for a certain period of time). Abuoyant tablet 15 may include 10-60% w/w of propylene glycol or the like. formulation of the compound(s) can be prepared by granu Controlled Release Parenteral Compositions lating a mixture of the drug(s) with excipients and 20-75% Controlled release parenteral compositions may be in w/w of hydrocolloids, such as hydroxyethylcellulose, form of aqueous Suspensions, microSpheres, microcapsules, hydroxypropylcellulose, or hydroxypropylmethylcellulose. magnetic microSpheres, oil Solutions, oil Suspensions, or The obtained granules can then be compressed into tablets. emulsions. Alternatively, the active drug(s) may be incor On contact with the gastric juice, the tablet forms a Sub porated in biocompatible carriers, liposomes, nanoparticles, Stantially water-impermeable gel barrier around its Surface. implants, or infusion devices. This gel barrier takes part in maintaining a density of leSS Materials for use in the preparation of microSpheres than one, thereby allowing the tablet to remain buoyant in and/or microcapsules are, e.g., biodegradable/bioerodible the gastric juice. 25 polymerS Such as polyglactin, poly-(isobutyl cyanoacrylate), Liquids for Oral Administration poly(2-hydroxyethyl-L-glutamnine) and, poly(lactic acid). Powders, dispersible powders, or granules Suitable for Biocompatible carriers that may be used when formulating preparation of an aqueous Suspension by addition of water a controlled release parenteral formulation are carbohy are convenient dosage forms for oral administration. For drates (e.g., dextrans), proteins (e.g., albumin), lipoproteins, mulation as a Suspension provides the active ingredient in a or antibodies. mixture with a dispersing or wetting agent, Suspending Materials for use in implants can be non-biodegradable agent, and one or more preservatives. Suitable dispersing or (e.g., polydimethyl siloxane) or biodegradable (e.g., poly Wetting agents are, for example, naturally-occurring phos (caprolactone), poly(lactic acid), poly(glycolic acid) or poly phatides (e.g., lecithin or condensation products of ethylene (ortho esters)). oxide with a fatty acid, a long chain aliphatic alcohol, or a 35 Rectal Compositions partial ester derived from fatty acids) and a hexitol or a For rectal application, Suitable dosage forms for a com hexitol anhydride (e.g., polyoxyethylene Stearate, polyoxy position include Suppositories (emulsion or Suspension ethylene Sorbitol monooleate, polyoxyethylene Sorbitan type), and rectal gelatin capsules (Solutions or Suspensions). monooleate, and the like). Suitable Suspending agents are, In a typical Suppository formulation, the active drug(s) are for example, Sodium carboxy methylcellulose, 40 combined with an appropriate pharmaceutically acceptable methylcellulose, Sodium alginate, and the like. Suppository base Such as cocoa butter, esterified fatty acids, Parenteral Compositions glycerinated gelatin, and various water-Soluble or disperS The pharmaceutical composition may also be adminis ible bases like polyethylene glycols and polyoxyethylene tered parenterally by injection, infusion or implantation Sorbitan fatty acid esters. Various additives, enhancers, or (intravenous, intramuscular, Subcutaneous, or the like) in 45 Surfactants may be incorporated. dosage forms, formulations, or via Suitable delivery devices Compositions for Inhalation or implants containing conventional, non-toxic pharmaceu For administration by inhalation, typical dosage forms tically acceptable carriers and adjuvants. The formulation include nasal Sprays and aerosols. In a typically nasal and preparation of Such compositions is well-known to those formulation, the active ingredient(s) are dissolved or dis skilled in the art of pharmaceutical formulation. Formula 50 persed in a Suitable vehicle. The pharmaceutically accept tions can be found in Remington. The Science and Practice able vehicles and excipients (as well as other pharmaceuti of Pharmacy, Supra. cally acceptable materials present in the composition Such as Compositions for parenteral use may be provided in unit diluents, enhancers, flavoring agents, and preservatives) are dosage forms (e.g., in Single-dose ampoules), or in Vials Selected in accordance with conventional pharmaceutical containing Several doses and in which a Suitable preservative 55 practice in a manner understood by the perSons skilled in the may be added (see below). The composition may be in form art of formulating pharmaceuticals. of a Solution, a Suspension, an emulsion, an infusion device, Percutaneous and Topical Compositions or a delivery device for implantation, or it may be presented The pharmaceutical compositions may also be adminis as a dry powder to be reconstituted with water or another tered topically on the skin for percutaneous absorption in Suitable vehicle before use. Apart from the active drug(s), 60 dosage forms or formulations containing conventionally the composition may include Suitable parenterally accept non-toxic pharmaceutical acceptable carriers and excipients able carriers and/or excipients. The active drug(s) may be including microSpheres and liposomes. The formulations incorporated into microSphere S, micro capsules, include creams, ointments, lotions, liniments, gels, nanoparticles, liposomes, or the like for controlled release. hydrogels, Solutions, Suspensions, Sticks, Sprays, pastes, Furthermore, the composition may include Suspending, 65 plasters, and other kinds of transdermal drug delivery Sys Solubilizing, Stabilizing, pH-adjusting agents, and/or dis tems. The pharmaceutically acceptable carriers or excipients persing agents. may include emulsifying agents, antioxidants, buffering US 6,693,125 B2 25 26 agents, preservatives, humectants, penetration enhancers, is formed by Substantially homogeneously dispersing the chelating agents, gelforming agents, ointment bases, active drug Substance in a hydrophilic or lipophilic polymer perfumes, and skin protective agents. matrix and then molding the drug-containing polymer into a Examples of emulsifying agents are naturally occurring disc with a Substantially well-defined Surface area and gums (e.g., gum acacia or gum tragacanth) and naturally thickness. The adhesive polymer is spread along the circum occurring phosphatides (e.g., Soybean lecithin and Sorbitan ference to form a Strip of adhesive around the disc. monooleate derivatives). Examples of antioxidants are buty In a microreservoir System, the reservoir of the active lated hydroxy anisole (BHA), ascorbic acid and derivatives Substance is formed by first Suspending the drug Solids in an thereof, tocopherol and derivatives thereof, butylated aqueous Solution of water-Soluble polymer, and then dis hydroxy anisole, and cysteine. Examples of preservatives persing the drug Suspension in a lipophilic polymer to form are parabens, Such as methyl or propyl p-hydroxybenzoate, a plurality of microscopic spheres of drug reservoirs. and benzalkonium chloride. Examples of humectants are Dosages glycerin, propylene glycol, Sorbitol, and urea. Examples of The dosage of each compound of the claimed combina penetration enhancers are propylene glycol, DMSO, tions depends on Several factors, including: the administra trie thanolamine, N,N-dimethylace tamide, N,N- 15 tion method, the disease to be treated, the Severity of the dimethylformamide, 2-pyrrolidone and derivatives thereof disease, whether the disease is to be treated or prevented, tetrahydrofurfuryl alcohol, and AZONET.M. Examples of and the age, weight, and health of the person to be treated. chelating agents are Sodium EDTA, citric acid, and phos The compounds are preferably administered in an amount phoric acid. Examples of gel forming agents are of about 0.1-30 mg/kg body weight per day, and more CARBOPOLTM, cellulose derivatives, bentonite, alginates, preferably in an amount of about 0.5-15 mg/kg body weight gelatin and polyvinylpyrrollidone. Examples of ointment per day. AS described above, the compound in question may bases are beeswax, paraffin, cetyl palmitate, vegetable oils, be administered orally in the form of tablets, capsules, Sorbitan esters of fatty acids (Span), polyethylene glycols, elixirs or Syrups, or rectally in the form of Suppositories. and condensation products between Sorbitan esters of fatty Parenteral administration of a compound is Suitably acids and ethylene oxide (e.g., polyoxyethylene Sorbitan 25 performed, for example, in the form of Saline Solutions or monooleate (TWEENTM)). with the compound incorporated into liposomes. In cases The pharmaceutical compositions described above for where the compound in itself is not sufficiently soluble to be topical administration on the Skin may also be used in dissolved, a Solubilizer Such as ethanol can be applied. connection with topical administration onto or close to the Below, for illustrative purposes, the dosages for benzimida part of the body that is to be treated. The compositions may Zoles and pentamidine are described. One in the art will be adapted for direct application or for introduction into recognize that if a Second compound is Substituted for either relevant orifice(s) of the body (e.g., rectal, urethral, vaginal a benzimidazole or pentamidine, the correct dosage can be or oral orifices). The composition may be applied by means determined by examining the efficacy of the compound in of Special drug delivery devices Such as dressings or alter cell proliferation assays, as well as its toxicity in humans. natively plasters, pads, Sponges, Strips, or other forms of 35 Oral Administration Suitable flexible material. For a benzimidazole adapted for oral administration for Controlled Release Percutaneous and Topical Compositions Systemic use, the dosage is normally about 1 mg to 1000 mg There are Several approaches for providing rate control per dose administered (preferably about 5 mg to 500 mg, and over the release and transdermal permeation of a drug, more preferably about 10 mg to 300 mg) one to ten times including: membrane-moderated Systems, adhesive 40 daily (preferably one to five times daily) for one day to one diffusion-controlled Systems, matrix dispersion-type year, and may even be for the life of the patient, because the Systems, and microreservoir Systems. A controlled release combinations of the invention function primarily as cyto percutaneous and/or topical composition may be obtained by Static rather than cytotoxic agents, and exhibit low toxicity, using a Suitable mixture of the above-mentioned approaches. chronic, long-term administration will be indicated in many In a membrane-moderated System, the active drug is 45 cases. Dosages up to 8 g per day may be necessary. present in a reservoir which is totally encapsulated in a For pentamidine, the dosage is normally about 0.1 mg to shallow compartment molded from a drug-impermeable 300 mg per dose administered (preferably about 1 mg to 100 laminate, Such as a metallic plastic laminate, and a rate mg) one to four times daily for one day to one year, and, like controlling polymeric membrane Such as a microporous or a a benzimidazole, may be administered for the life of the non-porous polymeric membrane (e.g., ethylene-Vinyl 50 patient. Administration may also be given in cycles, Such acetate copolymer). The active compound is only released that there are periods during which time pentamidine is not through the rate-controlling polymeric membrane. In the administered. This period could be, for example, about a drug reservoir, the active drug Substance may either be day, a week, a month, or a year or more. dispersed in a Solid polymer matrix or Suspended in a Rectal Administration Viscous liquid medium Such as Silicone fluid. On the external 55 For compositions adapted for rectal use for preventing Surface of the polymeric membrane, a thin layer of an disease, a Somewhat higher amount of a compound is adhesive polymer is applied to achieve an intimate contact usually preferred. Thus a dosage of a benzimidazole is of the transdermal system with the skin surface. The adhe normally about 5 mg to 2000 mg per dose (preferably about Sive polymer is preferably a hypoallergenic polymer that is 10 mg to 1000 mg, more preferably about 25 mg to 500 mg) compatible with the active drug. 60 administered one to four times daily. Treatment durations are In an adhesive diffusion-controlled System, a reservoir of as described for oral admininstration. The dosage of penta the active drug is formed by directly dispersing the active midine is as described for orally admininstered pentamidine. drug in an adhesive polymer and then spreading the adhesive Parenteral Administration containing the active drug onto a flat sheet of Substantially For intravenous or intramuscular administration of a drug-impermeable metallic plastic backing to form a thin 65 benzimidazole, a dose of about 0.1 mg/kg to about 100 drug reservoir layer. A matrix dispersion-type System is mg/kg body weight per day is recommended, a dose of about characterized in that a reservoir of the active drug Substance 1 mg/kg to about 25 mg/kg is preferred, and a dose of 1 US 6,693,125 B2 27 28 mg/kg to 10 mg/kg is most preferred. Pentamidine is admin opaque polystyrene cell culture treated Sterile 384-well plate istered at a dose of about 0.1 mg/kg to about 20 mg/kg, (NalgeNunc #164610) using a multidrop (Labsystems) to preferably at a dose of about 0.5 mg/kg to about 10 mg/kg, give a density of 3000 cells per well. Fifteen microliters of and more preferably at a dose of about 1 mg/kg to about 4 the 4x compound mixture matrix was added to each well of mg/kg. the plate containing the cells. The compound mixture matrix Each compound is usually administered daily for up to was transferred using a 16-channel pipettor (Finnpipette). In about 6 to 12 months or more. It may be desirable to addition, control wells with paclitaxel (final concentration administer a compound over a one to three hour period; this 4.6 uM), podophyllotoxin (9.6 uM), and quinacrine (8.5uM) period may be extended to last 24 hours or more. AS is were added to each plate. Each experiment was conducted in described for oral administration, there may be periods of triplicate plates. about one day to one year or longer during which at least one After incubation for 48 hours at 37 C., BrdU was added of the drugs is not administered. to each well at a concentration of 10 M. After 16 hours, the Inhalation media was aspirated and the cells were fixed by the addition For inhalation, a benzimidazole is administered at a dose of 70% ethanol and phosphate-buffered saline (PBS) at room of about 1 mg to 1000 mg daily, and preferably at a dose of 15 temperature for 1 hour. The fixative was aspirated and 2N about 10 mg to 500 mg daily. For pentamidine, a dose of HCl with Tween 20 (polyoxyethylene sorbitan monolaurate) about 10 mg to 1000 mg, and preferably at a dose of 30 mg was added to each well and the plates were incubated for 20 to 600 mg, is administered daily. minutes at room temperature. The HCl was neutralized with Percutaneous Administration a solution of 2N NaOH and the cells were washed twice with For topical administration of either compound, a dose of Hank's Balanced Salt Solution (HBSS) and once with PBS about 1 mg to about 5 g administered one to ten times daily containing 0.5% bovine serum albumin (BSA) and 0.1% for one week to 12 months is usually preferable. Tween 20. The wash Solution was removed and mouse The following examples are to illustrate the invention. anti-BrdU primary antibody (PharMingen #555627) was They are not meant to limit the invention in any way. diluted 1:1000 in PBS containing BSA, Tween 20, and 25 secondary antibody at a dilution of 1:2000 (Amersham EXAMPLE 1. #NA931). The secondary antibody recognizes the mouse antibody and is conjugated to the enzyme horseradish per Preparation of the Albendazole/Pentamidine oxidase (HRP). After one hour of incubation, the antibody Isethionate Dilution Matrix Solution was removed and the cells washed once with PBS. Stock Solutions of albendazole and pentamidine isethion After the PBS wash, the HRP substrate (which contains ate (Sigma catalog number A4673 and P0547, respectively) luminol, hydrogen peroxide, and an enhancer Such as para were made in dimethylsulfoxide (DMSO) at concentrations iodophenol) was added to each well. The plates were read of 15.07 mM and 6.74 mM respectively. An 8x stock using an LJL Analyst. All aspirations as well as the washes solution (128 uM) of each individual compound was made with PBS and HBSS were performed using a TECANTM in Dulbecco's Modified Eagle Medium (DMEM) (Gibco 35 Power Washer 384. The amount of light output from each 11995-040) containing 10% fetal bovine serum (FBS), 200 well indicates the amount of DNA synthesis that occurred in mM L-glutamine, and 1% antibiotic/antimycotic Solution. that well. Decreased light indicates antiproliferative action From this a 2-fold dilution series was made in DMEM. This of the compounds. Series provided nine concentrations ranging from 64 uM to Luminescence for each position in the albendazole/ 240 nM, and one concentration of O M. The compound 40 pentamidine isethionate dilution matrix was divided into the mixture matrix was prepared by filling columns of a 384 luminescence values for A549 cells treated with only DMSO well plate with the dilution Series of pentamidine isethionate vehicle, providing antiproliferative ratioS for each position (first column: 32 uM; second column: 16 uM; third column: in the albendazole/pentamidine isethionate dilution matrix. 8 uM; fourth column: 4 uM; fifth column: 2 uM; sixth Antiproliferative ratioS were also calculated for paclitaxel, column: 1 uM; seventh column: 500 nM; eighth column: 45 podophyllotoxin, and quinacrine and used for comparison. 250 nM; ninth column: 125 nM; and tenth column: no compound) and filling the rows with the dilution series of TABLE 1. albendazole (first row: 32 uM; second row: 16 uM; third Albendazole row: 8 uM; fourth row: 4 uM; fifth row: 2 uM; sixth row: 1 Concentrations Pentamidine Isethionate Concentrations (LM uM; seventh row: 500 nM; eighth row: 250 nM; ninth row: 50 125 nM; and tenth row: no compound) using a 16-channel (uM) 8 4 2 1 0.5 O.25 O.13 O.O6 O.O3 O pipettor (Finnpipette). This compound mixture plate pro 8 7.4 8.O 5.7 5.2 6.2 6.5 4.5 4.1 4.3 3.1 Vided 4x concentrations of each compound that are trans 4 9.9 9.5 9.4 8.9 6.8 4.9 3.7 3.O 2.4 2.4 ferred to assay plates. The dilution matrix thus contained 2 8.7 5.8 7.O 5.1 4.3 4.O 3.2 2.8 3.1 2.5 55 1. 6.6 5.7 5.5 4.6 3.4 3.1 2.9 2.1 1.9 1.4 100 different points-81 wells where varying amounts of a 0.5 6.9 5.9 4.8 3.9 2.3 1.7 1.9 1.5 13 1.2 benzimidazole and pentamidine were present, as well as a O.25 5.5 5.5 4.9 3.1 1.9 1.5 1.4 1.4 1.2 1.3 ten-point dilution Series (2-fold) for each individual com O.13 4.5 4.2 3.0 1.8 1.4 1.2 1.2 1.2 1.1 1.2 pound. O.O6 3.3 3.2 2.2 1.5 1.1 1.0 1.1 1.O 11 O.9 O.O3 4.O 3.2 2.O 14 13 1.4 1.2 12 10 1.3 O 2.5 2.2 1.9 1.3 1.1 1.2 0.9 1.O 1.O. O.9 EXAMPLE 2 60 Assay for Antiproliferative Activity of Albendazole At 2.0 uM, pentamidine isethionate alone yields an anti and Pentamidine Isethionate proliferative ratio of 1.9 (i.e., inhibition of 47% of growth) The compound dilution matrix was assayed using the and this increases to a ratio of 2.2 (inhibition of 55% of A549 bromodeoxyuri dine (BrdU) cytoblot method. Forty 65 growth) when the concentration is doubled to 4.0 uM. Two five microliters of a Suspension containing A549 lung adeno micromolar albendazole yields a ratio of 2.5 (inhibition of carcinoma cells (ATCC# CCL-185) was seeded in a white 60% of growth), and this is increased no further by doubling US 6,693,125 B2 29 30 the concentration to 4.0 uM. When 2.0 uM pentamidine The combination of thiabendazole and pentamidine isethionate is tested in combination with 2.0 uMalbendazole isethionate did not result in greater antiproliferative activity (4.0 uM total compound species), an antiproliferative ratio than either drug alone (Table 4). These results are consistent with the findings by Gupta (Mol. Pharmacol. 30:142-148, of 7.0 is achieved (inhibition of 85.7% of growth). Thus, a 1986) of a lack of cross-resistance of the nocodozole combination of albendazole and pentamidine isethionate resistant NocR and Podrii6 cell lines to thiabendazole (but yields an antiproliferative ratio higher than that seen for not to other benzimidazoles tested), indicating that the paclitaxel (4.0), an effect that was not achieved by either mechanism of action of this compound is different from that drug alone. of other benzimidazoles.

TABLE 2 Mebendazole Pentamidine Isethionate Concentrations (LM Concentrations (uM) 4 2 1. O.S. O.25 O.13 O.O6 O.O3 OO15 O 4 12.2 9.8 6.2 4.5 5.1 4.6 4.9 5.0 4.5 4.4 2 14.3 12.2 6.7 5.5 4.7 5.4 5.0 6.O 5.1 5.0 1. 8.9 10.9 7.8 4.1 3.7 3.6 3.7 3.9 3.9 3.4 10.2 11.5 6.5 4.7 3.3 3.4 3.0 3.1 3.0 2.8 6.6 5.9 3.8 1.7 1.5 1.5 1.4 1.5 1.6 1.5 5.7 4.6 2.4 1.5 1.3 1.3 1.2 1.4 1.4 1.5 4.5 3.4 1.9 1.1 1.O 1.O 1.1 O.9 1.2 1.O 5.4 5.1 2.3 1.5 1.4 1.3 1.3 1.4 1.3 1.4 5.1 3.2 1.9 1.1 1.1 1.O 1.O O.9 1.2 1.O 5.7 4.1 2.4 1.5 1.2 1.4 1.2 1.4 1.6 1.7

TABLE 3 Oxibendazole Pentamidine Isethionate Concentrations (LM Concentrations (uM) 4 2 1. O.S. O.25 O.13 O.O6 O.O3 OO15 O 4 6.7 6.6 4.6 3.7 3.9 3.6 3.7 3.8 3.7 3.6 2 6.3 6.6 4.9 3.5 3.0 2.8 2.5 3.5 2.9 3.2 1. 5.2 6.4 4.8 3.2 3.1 2.7 3.0 3.1 3.3 2.9 5.0 5.8 3.9 2.7 2.6 2.8 15 1.7 1.7 1.6 5.0 4.1 3.5 1.5 1.2 1.2 1.1 1.O 1.2 1.O 4.0 3.8 2.1 1.2 1.1 1.1 1.1 1.1 1.O 1.1 3.6 3.0 18 1.O 1.O 1.1 1.1 1.O 1.3 1.O 3.5 3.0 1.7 1.2 1.O 1.1 1.O 1.2 O.9 1.1 3.9 2.8 1.9 1.1 1.O 1.O 1.O O.9 1.O 1.O 4.1 2.9 1.6 1.3 O.9 1.1 1.1 1.O 1.1 1.2

40 In another analysis, the potency of the Single compounds is shifted by the presence of the other compound. The TABLE 4 maximal antiproliferative ratio achieved by albendazole Thiabendazole Pentamidine Isethionate Concentrations (uM) alone was 3.1 (at 8.0 uM). A similar antiproliferative ratio 45 was observed when 1 uM pentamidine isethionate was Concentrations (uM) 4 2 1. 0.5 0.25 O combined with albendazole at concentrations as low as 250 nM, Significantly reducing the total drug Species needed to 4 4.1 2.4 1.5 1.2 1.2 1.2 2 4.5 3.0 1.4 1.1 1.1 1.2 achieve this effect. 1. 4.1 2.9 1.8 1.O 1.2 1.2 50 0.5 3.3 3.1 1.6 1.O 1.3 1.2 EXAMPLE 3 O.25 3.5 3.4 1.4 1.1 1.1 1.2 O 3.7 3.0 1.7 1.1 1.1 1.2 Assay for Antiproliferative Activity of Pentamidine Isethionate in Combination with Albendazole 55 Sulfoxide, Mebendazole, Oxibendazole, or TABLE 5 Thiabendazole Albendazole Because albendazole shares antihelmentic activity with Sulfoxide Pentamidine Sethionate Concentrations (LM other benzimidazoles, we tested the combination of penta 60 Concentrations (uM) 4 2 1. 0.5 0.25 O midine isethionate with benzimidazoles mebendazole, 8 3.7 3.2 2.5 1.2 1.1 1.4 OXibendazole, albendazole Sulfoxide, and thiabendazole 4 2.7 2.7 1.6 1.3 1.2 1.4 (Tables 2-5). The assays were performed as described in 2 2.5 1.9 1.7 1.1 1.1 1.2 1. 18 2.4 1.4 1.O 1.O 1.1 Example 2, above. In the case of mebendazole and 0.5 18 18 1.6 1.1 O.9 1.2 oxibendazole, the combination of the benzimidazole with 65 O 1.9 2.1 1.6 O.9 1.1 1.O pentamidine resulted in greater antiproliferative activity than that that achieved by either drug alone (Tables 2 and 3). US 6,693,125 B2 31 32 The anti-proliferative effect demonstrated with A459 cells 8. The composition of claim 1, wherein said drug (i) is can be similarly demonstrated using other cancer cell lines, pentamidine isethionate and said drug (ii) is albendazole such as MCF7 mammary adenocarcinoma, PA-1 ovarian Sulfone. teratocarcinoma, HT29 colorectal adenocarcinoma, H1299 9. The composition of claim 1, wherein said drug (i) is large cell carcinoma, U-2 OS osteogenic Sarcoma, U-373 pentamidine isethionate and said drug (ii) is albendazole MG glioblastoma, Hep-3B hepatocellular carcinoma, Sulfoxide. BT-549 mammary carcinoma, T-24 bladder cancer, C-33A 10. A method for treating a patient having a cancer cervical carcinoma, HT-3 metastatic cervical carcinoma, Selected from the group consisting of brain cancer, breast SiHa Squamous cervical carcinoma, CaSki epidermoid cer cancer, cervical cancer, colon cancer, gastric cancer, kidney vical carcinoma, NCI-H292 mucoepidermoid lung cancer, leukemia, liver cancer, lymphoma, Ovarian cancer, carcinoma, NC-2o.o. non Small cell lung carcinoma, HeLa, pancreatic cancer, prostate cancer, rectal cancer, Sarcoma, epithelial cervical adenocarcinoma, KB epithelial mouth skin cancer, testicular cancer, or uterine cancer, Said method carcinoma, HT1080 epithelial fibrosarcoma, Saos-2 epithe comprising administering to said patient the drugs (i) pen lial osteogenic Sarcoma, PC3 epithelial prostate tatnidine or a Salt thereof, and (ii) albendazole, albendazole adenocarcinoma, SW480 colorectal carcinoma, CCL-228, Salfonate, albendazole Sulfone, or albendazole Sulfoxide, and MS-751 epidermoid cervical carcinoma cell lines. 15 wherein the drugs (i) and (ii) are administered simulta Specificity can be tested by using cells such as NHLF lung neously or within 14 days of each other, in amounts Suffi fibroblasts, NHDF dermal fibroblasts, HMEC mammary cient to inhibit the growth of Said cancer in Said patient. epithelial cells, PrEC prostate epithelial cells, HRE renal 11. The method of claim 10, wherein drugs (i) and (ii) are epithelial cells, NHBE bronchial epithelial cells, CoSmC administered within ten days of each other. Colon Smooth muscle cells, CoEC colon endothelial cells, 12. The method of claim 11, wherein drugs (i) and (ii) are NHEK epidermal keratinocytes, and bone marrow cells as administered within five days of each other. control cells. 13. The method of claim 12, wherein drugs (i) and (ii) are Other Embodiments administered within twenty-four hours of each other. All publications and patents mentioned in the above 14. The method of claim 13, wherein said cancer is lung Specification are herein incorporated by reference. Various 25 CCC. modifications and variations of the described method and 15. The method of claim 14, wherein said lung cancer is system of the invention will be apparent to those skilled in Selected from the group consisting of Squamous cell the art without departing from the Scope and Spirit of the carcinoma, adenocarcinoma, and large cell carcinoma. invention. Although the invention has been described in 16. The method of claim 13, wherein said cancer is connection with Specific preferred embodiments, it should Selected from the group consisting of colon cancer, breast be understood that the invention as claimed should not be cancer, and prostate cancer. unduly limited to Such specific embodiments. Indeed, vari 17. The method of claim 13, wherein said drug (i) is ous modifications of the described modes for carrying out pentamidine isethionate and said drug (ii) is albendazole. the invention that are obvious to those skilled in molecular 18. The method of claim 13, wherein said drug (i) is biology or related fields are intended to be within the scope 35 pentamidine isethionate and said drug (ii) is albendazole of the invention. Sulfonate. What is claimed is: 19. The method of claim 13, wherein said drug (i) is 1. A pharmaceutical composition comprising a pharma pentamidine isethionate and said drug (ii) is albendazole ceutically acceptable carrier and the drugs (i) pentamidine or Sulfone. a Salt thereof, and (ii) albendazole, albendazole Sulfonate, 40 20. The method of claim 13, wherein said drug (i) is albendazole Sulfone, or albendazole Sulfoxide, wherein pentamidine isethionate and said drug (ii) is albendazole drugs (i) and (ii) are each present in a Synergistically Sulfoxide. effective amount that, when administered together to a 21. The method of claim 1, wherein Said cancer is lung patient having a cancer Selected from the group consisting of CCC. brain cancer, breast cancer, cervical cancer, colon cancer, 45 22. The method of claim 21, wherein Said lung cancer is gastric cancer, kidney cancer, leukemia, liver cancer, Selected from the group consisting of Squamous cell lymphoma, OVarian cancer, pancreatic cancer, prostate carcinoma, adeno carcinoma, and large cell carcinoma. cancer, rectal cancer, Sarcoma, Skin cancer, testicular cancer, 23. The method of claim 10, wherein drugs (i) and (ii) are or uterine cancer, inhibits the growth of Said cancer. administered to Said patient by intravenous, intramuscular, 2. The composition of claim 1, wherein drug (ii) is present 50 inhalation, rectal, or oral administration. in said composition in an amount of 10 to 2500 milligrams 24. The method of claim 1, wherein said drug (i) is and drug (i) is present in said composition in an amount of pentamidine isethionate, pentamidine platinum, pentami 1 to 1000 milligrams. dine dihydrochioride or pentamidine dimethaneSulfonate. 3. The method of claim 2, wherein drug (ii) is present in 25. The method of claim 10, wherein said drug (i) is said composition in an amount of 50 to 1000 milligrams and 55 pentamidine isethionate and said drug (ii) is albendazole. drug (i) is present in said composition in an amount of 10 to 26. The method of claim 10, wherein said drug (i) is 250 milligrams. pentamidine isethionate and said drug (ii) is albendazole 4. The composition of claim 1, wherein Said composition Sulfonate. is formulated for intravenous, intramuscular, rectal, 27. The method of claim 10, wherein said drug (i) is inhalation, or oral administration. 60 pentamidine isethionate and said drug (ii) is albendazole 5. The composition of claim 1, wherein said drug (i) is Sulfone. pentamidine isethionate. 28. The method of claim 10, wherein said drug (i) is 6. The composition of claim 1, wherein said drug (i) is pentamidine isethionate and said drug (ii) is albendazole pentamidine isethionate and Said drug (ii) is albendazole. Sulfoxide. 7. The composition of claim 1, wherein said drug (i) is 65 29. The method of claim 10, wherein said cancer is pentamidine isethionate and said drug (ii) is albendazole Selected from the group consisting of colon cancer, breast Sulfonate. cancer, and prostate cancer. US 6,693,125 B2 33 34 30. A method for treating a patient having a cancer 36. The method of claim 30, wherein said drug (i) is Selected from the group consisting of brain cancer, breast pentamidine isethionate and said drug (ii) is albendazole cancer, cervical cancer, colon cancer, gastric cancer, kidney Sulfonate. cancer, leukemia, liver cancer, lymnphoma, Ovarian cancer, 37. The method of claim 30, wherein said drug (i) is pancreatic cancer, prostate cancer, rectal cancer, Sarcoma, pentamidine isethionate and said drug (ii) is albendazole skin cancer, testicular cancer, or uterine cancer, Said method Sulfone. comprising administering to Said patient a pharmaceutical 38. The method of claim 30, wherein said drug (i) is composition comprising a pharmaceutically acceptable car pentamidine isethionate and said drug (ii) is albendazole Sulfoxide. rier and the drugs (i) pentamidine or a salt thereof, and (ii) 39. The method of claim 30, wherein said cancer is lung albendazole, albendazole Sulfonate, albendazole Sulfone, or CCC. albendazole Sulfoxide, at dosages that together inhibit the 40. The method of claim 39, wherein said lung cancer is growth of Said cancer in Said patient. Selected from the group consisting of Squamous cell 31. The method of claim 30, wherein drug (ii) is present carcinoma, adenocarcinoma, and large cell carcinoma. in said composition in an amount of 10 to 2500 milligrams 41. The method of claim 30, wherein said cancer is and drug (i) is present in said composition in an amount of 15 Selected from the group consisting of colon cancer, breast 1 to 1000 milligrams. cancer, and prostate cancer. 32. The method of claim 31, wherein drug (ii) is present 42. A method of treating a patient having lung cancer, Said in said composition in an amount of 50 to 1000 milligrams method comprising administering to Said patient the drugs and drug (i) is present in said composition in an amount of pentamidine isethionate and albendazole, wherein Said pen 10 to 250 milligrams. tamidine isethionate and albendazole are administered 33. The method of claim 30, wherein said composition is within twenty-four hours of each other, in amounts Sufficient administered to Said patient by intravenous, intramuscular, to inhibit the growth of Said lung cancer in Said patient. inhalation, rectal, or oral administration. 43. The method of claim 42, wherein said pentamidine 34. The method of claim 30, wherein said drug (i) is isethionate and albendazole are administered simulta pentamidine isethionate. 25 neously. 35. The method of claim 30, wherein said drug (i) is pentamidine isethionate and Said drug (ii) is albendazole.