DOCSLIB.ORG

Effect of the Chemoprotective Agent WR-2721 on Disposition and Biotransformations of Ormaplatin in the Fischer 344 Rat Bearing a Fibrosarcoma1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Effect of the Chemoprotective Agent WR-2721 on Disposition and Biotransformations of Ormaplatin in the Fischer 344 Rat Bearing a Fibrosarcoma1 [CANCERRESEARCH55, 2837—2846,July1. 1995] Effect of the Chemoprotective Agent WR-2721 on Disposition and Biotransformations of Ormaplatin in the Fischer 344 Rat Bearing a Fibrosarcoma1 D. CharlesThompson,StevenD. Wyrick, David J. Holbrook, and StephenG. Chane? Curriculum in Toxicology (D. C. T.. D. J. H., S. G. C.] and Department of Biochemistry and Biophysics ID. J. H., S. G. CI, School of Medicine, and Division of Medicinal Chemistry and Natural Products [S. D. WI, School of Pharmacy, University ofNorth Carolina, Chapel Hill, North Carolina 27599-7260 ABSTRA4@T be selective for nontumor tissues (4, 5). The proposed mechanism for this selectivity is a relative lack of alkaline phosphatase activity in The effects of the phosphorothloate agent, WR-2721, have been Eaves tumor tissues as compared to normal tissues and the lesser conversion ligated with respect to the biotransformations oformaplatin in the Fischer of the inactive parent compound, WR-2721, to its postulated active 344 rat bearinga transplantedfibrosarcoma.A number of different paradigms ofdosing route and schedule for the administration of the two thiol metabolite, WR-1065, within tumor tissues. Because WR-1065 agents have been investigated. In the first group ofexperiments, WR.2721 is postulated to bind to reactive platinum species within the cell, this (200mg/kg, l.p.) wasadministered30 mis beforeormaplatin (12.5mg/kg, would provide a mechanistic basis for selective protection of normal i.p.), and then peritoneal fluid, plasma, and tissues were harvested at 30 tissues as compared to tumor tissues (3, 6, 7). This hypothesis has mm after the ormaplatin administration. Our results suggest that a sig never been tested directly. Ormaplatin (formerly tetraplatin) is a nificant interaction between WR-2721 and ormaplatin is occurring in the platinum(IV) analogue of cisplatin recently in Phase I clinical trials @tonea1cavity.The interaction was evident in terms of both effects on (8—10).This laboratory has previously reported investigations of the distribution and disposition of total platinum and in alterations of the biotransformations of ormaplatin under a variety of conditions in vitro profilesof biotransformation products formed in the various tissues and (1 1), in cell culture (12, 13), and in vivo (14—16).These studies have fluids. Plasma protein binding oformaplatin was decreased by 50% in the shown that ormaplatin is very rapidly (t½‘@3s) reduced to the presence ofWR-2721. Total platinum in the spleen was decreased by 66% and In the liver by 50%. There were no trends among the findings that corresponding platinum(II) complex, Pt(dach)C12, in the presence of would indicate any selectivity between tumor and nontumor tissue with plasma protein sulfhydryl (1 1), and that subsequent biotransforma respect to the effects of WR-2721 on the parameters measured. Subse tions of this complex appear to be similar to those reported for quent investigations examined the effects of dosing the WR-2721 by the cisplatin (17, 18). The previous studies have also shown that the LV. rOute while continuing with the i.p. administration of the ormaplatin. intracellular biotransformations of ormaplatin in vivo are very similar WR-2721 was administered either 30 or 5 mm before the ormaplatin, and in all tissues examined to date (19). The present report discusses the plasma and tissues were harvested at 15, 30, or 60 mm after ormapla investigations into the effects of WR-2721 on ormaplatin biotransfor tin administration. The reverse-phase HPLC peak, which behaved chro mations in tumor-bearing male rats as a direct test of the proposed matographically as a Pt(dach)(WR-1065) standard, was less prominent mechanism of action of WR-2721. after the Lv. administration of WR-2721 than It was after i.p. administra lion under any of the paradigms tested. There was again no evidence for selectivity between tumor and nontumor tissue in the findings from any of MATERIALS AND METHODS the paradigms. It is concluded that If WR-2721 is capable of selectively protecting nontumor tissue from the toxicities of platinum-based chemo Materials. [4,5-3H2(n)]Ormaplatin (formerly tetraplatin) was prepared in therapy, It is doing so by some mechanism other than its selective uptake the Radiosynthesis Laboratory, Division of Medicinal Chemistry and Natural Into normal tissue and subsequent nonspecific inactivation of any reactive Products, School of Pharmacy, at the University of North Carolina at Chapel cytosolic platinum species formed. Other possible mechanisms are briefly Hill with a specific activity of 0.520 Ci/mmol. The synthesis and purity of this compound have been described elsewhere (20). Reductive tritiation of the cyclohexene ring yields a radiolabel that is not chemically exchangeable (20). INTRODUCTION Preparation of a solution of the drug for administration was as described previously (14). WR-2721 and its corresponding free thiol, WR-1065, were WR-27213 is a phosphorothioate compound currently in Phase III obtained from US Bioscience (West Conshohocken, PA). This is different clinical trials investigating its efficacy at reducing the adverse side from the clinical formulation available through the National Cancer Institute, effects of both radiotherapy and alkylating agent chemotherapy of which contains a 1:1 mix by weight of WR-2721 and mannitol. The drug was neoplastic disease (1—3).This chemoprotective effect is purported to dissolved either in H20 (20 mg/ml) for i.p. injection or in PBS (pH 7.5; 100 mg/mi) for iv. injection and filtered immediately before use. YMT ultrafil tration membranes (M, cutoff, 30,000) were purchased from Amicon (Danvers, Received 2/6/95; accepted 5/3/95. Thecostsof publicationofthisarticleweredefrayedinpartby thepaymentofpage MA). HPLC grade reagents were obtained from commercial sources, and charges. This article must therefore be hereby marked advertisement in accordance with solutions were filtered and degassed before use. A Barnstead Nanopure water 18 U.S.C. Section 1734 solely to indicate this fact. purification system with an organics filter provided the water used with I This work was supported by NIH Grants CA55326 and ES07126. solvents and for dissolution. All other general laboratory reagents were com 2 To whom requests for reprints should be addressed, at Department of Biochemistry and Biophysics, 502 FLOB CB# 7260, University of North Carolina, Chapel Hill, NC mercial reagent grade or better and were used without additional purification. 27599-7260. Animals. Male Fischer 344 adult rats (150—200 g) were obtained from 3 ‘FIse abbreviations and trivial names used are: WR-2721, S-2-(3-aminopropyl Charles River Breeding Laboratories (Raleigh, NC) and housed in clear plastic amino)ethylphosphorothioicacid(Ethiofos,Amifostine,Ethyol);WR-1065,S-2-(3-ami cages on a 12-h light/12-h dark cycle with access to water and Purina rodent nopropylamino)ethanethiol, the thiol metabolite of WR-2721; cisplatin, cis [PtCl2(NH3)2J, cis-diamminedichloroplatinum(!I) (cDDP); ormaplatin (formerly called chow ad libitum. Room temperature was maintained at approximately 22°C. tetraplatin), (d@l)trans-1,2-diaminocyclohexanetetrachloroplatinum(!V);dach,(d,l)trans Animals were allowed at least a 1-week acclimatization period before use in 1,2-diaminocyclohexane; Pt(dach)Cl2, (cU)trans-1,2-diaminocyclohexanedichloroplati experiments. A transplantable fibrosarcoma (originally induced by methylchol num(ll); P2, reverse phase; SCX, strong cation exchange chromatography; AAS, flame anthrene) was obtained from Dr. M. W. Dewhirst (Duke University Medical less atomic absorption spectroscopy; LSC, liquid scintillation counting; GSH, reduced glutathione. Platinum(II) complexes with various amino acids are indicated as: Pt Center, Durham, NC) with permission from Dr. J. M. C. Bull (University of (dachXaminoacid)orPt(aminoacid)@;inmostcases,theexactstoichiometryorchargeof Texas Health Science Center, Houston, TX), who originally developed the the complex is not known. tumor (21). The tumor was maintained via regular passage involving s.c. hind 2837 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1995 American Association for Cancer Research. WR-2721 AND ORMAPLATIN BIOTRANSFORMATIONSIN F344 RATS flank implantation of solid donor tumor (“100mm3) under ketamine-xylazine material, the reaction products formed were identical.4 Henceforth, only the anesthesia. Experiments were routinely performed at 10 days posttransplanta Pt(dach)(WR-1065) was used in column standardization, along with the other tion, at which time tumor volume was on average 2.5—3.0cm3. standards routinely tested: Pt(dach@cysteine),Pt(dachXGSH),Pt(dachXmethi Methods. Animals were administered WR-2721 or corresponding vehicle onine), Pt(dachXserine),and the free dach ligand. These were the standards the by either of two protocols. For most of the experiments, a dual i.p. paradigm chromatographic characteristics of which most closely approximated those of was used, in which case the WR-2721 (20 mg/mI and 200 mg/kg; @34-fold the RP HPLC peaks that appeared routinely in greatest abundance in the molar excess to platinum on a per kg body weight basis) or H20 vehicle was biological samples. administered i.p. under light ether anesthesia at time zero (4). At t 30 mm, Statistics. Independent (unpaired) t tests on control (ormaplatin only) ormaplatin was administered (12.5 mg/kg, i.p.), also under light ether anes and treated (WR-2721 plus ormaplatin) variables were performed with the thesia. These animals were all then sacrificed at t = 60 mm. The second SYSTAT statisticalpackage (SYSTAT, Inc., Evanston,IL). Assessment of the significance of any effect of WR-2721 treatment on ormaplatin disposition protocol used an i.v./i.p. paradigm in which the WR-2721 (100 mg/ml in PBS, or biotransformation was at the P = 0.05 level. pH 7.5 vehicle, 200 mg/kg) was administered iv. via the lateral vein under light ether anesthesia at time zero. For this protocol, ormaplatin (12.5 mg/kg i.p.) was administered at either t = 5 mm or t = 30 mm. These animals were RESULTS then sacrificed at either 15, 30, or 60 mm after ormaplatin administration.
Load more

Recommended publications
  • Selective Protection of Normal Cells During Chemotherapy by RY4 Peptides
    Published OnlineFirst May 29, 2014; DOI: 10.1158/1541-7786.MCR-13-0425 Molecular Cancer Cell Death and Survival Research Selective Protection of Normal Cells during Chemotherapy by RY4 Peptides Xiao-Rong Wu, Lihua Liu, Zhi-Fu Zhang, Bing Zhang, Hongzhe Sun, Gerald L. Chan, and Na Li Abstract Mitochondrial targeted Szeto-Schiller (SS) peptides have recently gained attention for their antioxidative stress ability; however, the functional variations between normal and cancer cells have not been determined. Here, we report the results of such experiments conducted with a newly designed class of peptide called RY4, which is based on SS peptide sequence characteristics. The RY4 peptide exhibits distinct differences in antioxidative stress response between normal and cancer cells when challenged with chemotherapeutics like the glycolytic inhibitor dichlor- oacetate (DCA), the platinating agent carboplatin, and the DNA damage inducer doxorubicin. Interestingly, only normal human cells were protected by the RY4 peptide and catalase (CAT) activity was significantly enhanced in normal but not tumor cells when incubated with RY4. Pull-down, coimmunoprecipitation, and LC/MS-MS proteomic analysis demonstrated that RY4 and catalase are capable of forming protein complexes. Finally, in vivo efficacy was evaluated by intraperitoneal administration of RY4 into a lung cancer xenograft model, which revealed significant myocardiocyte protection from doxorubicin-induced cardiotoxicity without diminishing doxorubicin's tumoricidal effects. Taken together, RY4 offers selective protection to normal cells from chemotherapy-induced toxicity by enhancing the activity of cellular antioxidant enzymes. Implications: RY4 peptides selectively reduce chemotherapeutic-induced oxidative stress and represent a new class of chemoprotective agents with clinical potential.
    [Show full text]
  • Mesna: Drug Information
    Official reprint from UpToDate® www.uptodate.com ©2017 UpToDate® Mesna: Drug information Copyright 1978-2017 Lexicomp, Inc. All rights reserved. (For additional information see "Mesna: Patient drug information" and see "Mesna: Pediatric drug information") For abbreviations and symbols that may be used in Lexicomp (show table) Brand Names: US Mesnex Brand Names: Canada Mesna for injection; Uromitexan Pharmacologic Category Antidote; Chemoprotective Agent Dosing: Adult Note: Mesna dosing schedule should be repeated each day ifosfamide is received. If ifosfamide dose is adjusted (decreased or increased), the mesna dose should also be modified to maintain the mesna-to-ifosfamide ratio. Prevention of ifosfamide-induced hemorrhagic cystitis: Standard-dose ifosfamide (manufacturer’s labeling): IV: Mesna dose is equal to 20% of the ifosfamide dose given for 3 doses: With the ifosfamide dose, hour 4, and at hour 8 after the ifosfamide dose (total daily mesna dose is 60% of the ifosfamide dose) Oral mesna (following IV mesna; for ifosfamide doses ≤2 g/m2/day): Mesna dose (IV) is equal to 20% of the ifosfamide dose at hour 0, followed by mesna dose (orally) equal to 40% of the ifosfamide dose given 2 and 6 hours after the ifosfamide dose (total daily mesna dose is 100% of the ifosfamide dose). Note: If the oral mesna dose is vomited within 2 hours of administration, repeat the dose or administer IV mesna. Short infusion standard-dose ifosfamide (<2.5 g/m2/day): ASCO guidelines: IV: Total mesna dose is equal to 60% of the ifosfamide dose, in 3 divided
    [Show full text]
  • Tuning the Metabolism of the Anticancer Drug Cisplatin with Chemoprotective Agents to Improve Cite This: Metallomics, 2016, 8, 1170 Its Safety and Efficacy
    Metallomics View Article Online MINIREVIEW View Journal | View Issue Tuning the metabolism of the anticancer drug cisplatin with chemoprotective agents to improve Cite this: Metallomics, 2016, 8, 1170 its safety and efficacy Melani Sooriyaarachchi,a Graham N. George,bcd Ingrid J. Pickering,bcd e a Aru Narendran and Ju¨rgen Gailer* Numerous in vivo studies have shown that the severe toxic side-effects of intravenously administered cisplatin can be significantly reduced by the co-administration of sulfur-containing ‘chemoprotective agents’. Using a metallomics approach, a likely biochemical basis for these potentially useful observations Received 18th August 2016, was only recently uncovered and appears to involve the reaction of chemoprotective agents with cisplatin- Accepted 8th September 2016 derived Pt-species in human plasma to form novel platinum–sulfur complexes (PSC’s). We here reveal DOI: 10.1039/c6mt00183a aspects of the structure of two PSC’s and establish the identification of an optimal chemoprotective agent to ameliorate the toxic side-effects of cisplatin, while leaving its antineoplastic activity largely intact, as a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. www.rsc.org/metallomics feasible research strategy to transform cisplatin into a safer and more effective anticancer drug. Introduction Severe toxic side-effects of CP The serendipitous discovery of the antiproliferative effects of In contrast to so-called ‘molecularly targeted’ anticancer drugs cis-diaminedichloroplatinum(II) or cisplatin [CP] on E.
    [Show full text]
  • Vernonia Cinerea) in Human Embryonic Kidney (HEK293
    Review Article Clinician’s corner Images in Medicine Experimental Research Case Report Miscellaneous Letter to Editor DOI: 10.7860/JCDR/2019/40242.12624 Original Article Postgraduate Education Cytoprotective Activity of Neichitti (Vernonia Case Series cinerea) in Human Embryonic Kidney (HEK293) Section Normal Cells and Human Cervix Epitheloid Short Communication Carcinoma (HeLa) Cells against Cisplatin Complementary/Alternative Medicine Induced Toxicity: A Comparative Study ARUL AMUTHAN1, VASUDHA DEVI2, CHANDRASHEKARA SHASTRY SHREEDHARA3, VENKATA RAO4, RICHARD LOBO5 ABSTRACT statistically compared using One-Way ANOVA, followed by Introduction: Traditional Siddha Medicine literatures suggest Dunnett’s (2-sided) post-hoc test. to use the decoction of Vernonia cinerea (VC) to alleviate toxic Results: Aqueous fraction showed 2.8 times higher effects caused by metals. Cisplatin, a metal used in cancer cytoprotection (improvement in cell viability by 54%) than treatment is known to cause nephrotoxicity. CAE against cisplatin induced toxicity in HEK293 cells. BF did Aim: To evaluate and compare protective activity of aqueous not show protective activity in HEK293 cells. In HELA cells, extract and fractions of VC in Human Embryonic Kidney AF showed 1.73 times higher cytoprotection than CAE and (HEK293) cells and Human Cervix Epitheloid Carcinoma (HELA) 1.55 times higher cytoprotection than BF against cisplatin, as cell lines against cisplatin induced cytotoxicity. evidenced by improvement in cell viability by 30%, 11% and 13% in AF, CAE and BF respectively. AF exhibited 80% higher Materials and Methods: The Crude Aqueous Extract (CAE) cytoprotection against cisplatin cytotoxicity in normal HEK293 was obtained from whole plant of VC. CAE was fractioned using than cancer HELA cells.
    [Show full text]
  • 703.Full.Pdf
    Vol. 9, 703–710, February 2003 Clinical Cancer Research 703 Phase I Clinical and Pharmacologic Study of Weekly Cisplatin and Irinotecan Combined with Amifostine for Refractory Solid Tumors1 Abdul-Kader Souid, Ronald L. Dubowy, Conclusion: The combination of cisplatin and irinote- Susan M. Blaney, Linda Hershon, Jim Sullivan, can administered weekly for 4 weeks in children with re- Wendy D. McLeod, and Mark L. Bernstein1 fractory cancer is well tolerated. Amifostine offers some myeloprotection, likely permitting >30% dose escalation for Departments of Pediatric Hematology/Oncology, State University of irinotecan, when administered in a combination regimen New York Upstate Medical University, Syracuse, New York 13210 [A-K. S., R. L. D.]; Texas Children’s Cancer Center, Houston, Texas with cisplatin. However, effective antiemetics and calcium 77030 [S. M. B.]; Sainte-Justine Hospital, H3T 1C5, Canada [L. H., supplementation are necessary with the use of amifostine. M. L. B.]; and the Statistical Office, Children Oncology Group, Further escalation of irinotecan dosing, using these precau- Gainesville, Florida 32601 [J. S., W. D. M.] tions for amifostine administration, may be possible. ABSTRACT INTRODUCTION Purpose: This Phase I study was designed primarily to Irinotecan (Camptosar, CPT-11, 7-ethyl-10-[4-(1-piper- determine the maximum tolerated dose (MTD) and dose- idino)-1-piperidino]carbonyloxycamptothecin) is a water-solu- limiting toxicities (DLTs) of irinotecan and cisplatin with ble derivative of camptothecin, an alkaloid extracted
    [Show full text]
  • A Solid Phase Assay for Topoisomerase I Interfacial Poisons and Catalytic Inhibitors
    University of Central Florida STARS Electronic Theses and Dissertations, 2004-2019 2011 A Solid Phase Assay For Topoisomerase I Interfacial Poisons And Catalytic Inhibitors Vidusha Cyril University of Central Florida Part of the Molecular Biology Commons Find similar works at: https://stars.library.ucf.edu/etd University of Central Florida Libraries http://library.ucf.edu This Masters Thesis (Open Access) is brought to you for free and open access by STARS. It has been accepted for inclusion in Electronic Theses and Dissertations, 2004-2019 by an authorized administrator of STARS. For more information, please contact [email protected]. STARS Citation Cyril, Vidusha, "A Solid Phase Assay For Topoisomerase I Interfacial Poisons And Catalytic Inhibitors" (2011). Electronic Theses and Dissertations, 2004-2019. 1836. https://stars.library.ucf.edu/etd/1836 A SOLID PHASE ASSAY FOR TOPOISOMERASE I INTERFACIAL POISONS AND CATALYTIC INHIBITORS by VIDUSHA CYRIL B.Tech. Sathyabama University, 2009 A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Molecular and Microbiology in the Burnett School of Biomedical Sciences in the College of Sciences at the University of Central Florida Orlando, Florida Fall Term 2011 Major Professor: Mark. T. Muller © 2011 Vidusha Cyril ii ABSTRACT We report a mechanism based screening technique to rapidly identify eukaryotic topoisomerase I targeting agents. The method is based on genetic tagging of topoisomerase I to immobilize the enzyme on a solid surface in a microtiter well format. DNA is added to the wells and retained DNA is detected by Picogreen fluorescence. Compounds that result in an increase in Picogreen staining represent potential topoisomerase interfacial poisons while those that reduce fluorescence report catalytic inhibitors; therefore, the solid phase assay represents a „bimodal‟ readout that reveals mechanisms of action.
    [Show full text]
  • Interaction of Mesna with Platinum Chemotherapy Agents Cisplatin and Carboplatin: Chemistry, in Vitro, in Vivo, and Clinical Pharmacokinetics
    University of Calgary PRISM: University of Calgary's Digital Repository Graduate Studies Legacy Theses 2001 Interaction of Mesna with platinum chemotherapy agents Cisplatin and Carboplatin: chemistry, in vitro, in vivo, and clinical pharmacokinetics Kangarloo, Shahbal B. Kangarloo, S. B. (2001). Interaction of Mesna with platinum chemotherapy agents Cisplatin and Carboplatin: chemistry, in vitro, in vivo, and clinical pharmacokinetics (Unpublished master's thesis). University of Calgary, Calgary, AB. doi:10.11575/PRISM/16467 http://hdl.handle.net/1880/41240 master thesis University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission. Downloaded from PRISM: https://prism.ucalgary.ca The author of this thesis has granted the University of Calgary a non-exclusive license to reproduce and distribute copies of this thesis to users of the University of Calgary Archives. Copyright remains with the author. Theses and dissertations available in the University of Calgary Institutional Repository are solely for the purpose of private study and research. They may not be copied or reproduced, except as permitted by copyright laws, without written authority of the copyright owner. Any commercial use or publication is strictly prohibited. The original Partial Copyright License attesting to these terms and signed by the author of this thesis may be found in the original print version of the thesis, held by the University of Calgary Archives.
    [Show full text]
  • Novel Small-Molecule TNF-Α Modulators As Chemoprotective
    Reducing the side-effects of chemotherapy Medicinal chemist and cancer researcher Dr JiaJiu Shaw discusses the need to develop novel DR JIAJIU SHAW chemoprotective agents, and shares the details of his own work towards accomplishing this goal which is known to be associated with several the elevated levels of TNF-α and TGF-β. This is potential side-effects. This is why we did not another promising area we may pursue. conduct many chemoprotective studies on UTL-4 compounds. One of the main reasons Do you have any results from the SBIR phase we pursued UTL-5g as a chemoprotector is that II study? most of the UTL-5 compounds are associated with very low acute toxicity and UTL-5g shows In addition to further confirming that UTL-5g the highest potency among them. reduces the side-effects induced by cisplatin, we have investigated the metabolic behaviour of What are the benefits of taking a UTL-5g, ultimately finding that it is dramatically collaborative approach to your project? In different from a structurally similar drug, particular, how did your collaborations with leflunomide. I believe this difference is one Drs Frederick Valeriote and Ben Chen help of the main reasons that UTL-5g has a lower move your study in the right direction? acute toxicity than leflunomide. This was a significant finding and it formed the basis of Dr Valeriote has more than 35 years of a published review paper. Another important experience in cancer research. He also finding originated from the repeat dose toxicity has extensive research experience in study, in which we treated mice with up to radioprotection, which is another potential 1,500 mg/kg per day orally for seven days; there Could you introduce your current research application of UTL-5g.
    [Show full text]
  • A Phase I Trial of Amifostine (WR-2721) and Melphalan in Children with Refractory Cancer Peter C
    (CANCER RESEARCH 55. 406M-4072. Seplcmbtr 15. I9M5| A Phase I Trial of Amifostine (WR-2721) and Melphalan in Children with Refractory Cancer Peter C. Adamson,1 Frank M. Balis, Jean E. Belasco, Beverly Lange, Stacey L. Berg,2 Susan M. Blaney,2 Catherine Craig,2 and David G. Poplack2 Pediatrie Branch, National Cancer Institute, Bethesda, Maryland 20M2 ¡P.C. A.. F. M. B., C. G., S. L B., S. M. B.. D. G. P./, unti Children's Hospital of Philadelphia. Philadelphia, Pennsylvania 19104 ¡J.E. B.. B. L.¡ ABSTRACT The use of colony-stimulating factors, an approach that has been successful with other anticancer drugs, did not prevent severe myelo Melphalan has a steep dose-response curve, but the use of high doses suppression from melphalan, a stem-cell poison (3). An alternative results in unacceptable myelosuppression. Strategies to circumvent this approach is to administer a chemoprotective agent. Amifostine (WR- dose-limiting myelosuppression would allow for the administration of higher, more effective doses of melphalan. Amifostine (WR-2721) has been 2721) is an organic thiophosphate that selectively protects against the shown in preclinical studies to protect the bone marrow from the myelo- cytotoxicity of alkylating agents. In preclinical studies, amifostine toxicity of melphalan, and in clinical trials, to protect from the myelotox- protects the bone marrow from the myelotoxicity of melphalan (4), icity of other alkylating agents. A Phase 1 trial of the combination of and in clinical trials it appears to circumvent the myelotoxicity of amifostine and melphalan was performed in children with refractory other alkylating agents (5-10).
    [Show full text]
  • Amifostine (WR-2721), a Cytoprotective Agent During High-Dose Cyclophosphamide Treatment of Non-Hodgkin’S Lymphomas: a Phase II Study
    Brazilian Journal of Medical and Biological Research (2000) 33: 791-798 Amifostine and high-dose cyclophosphamide for NHL 791 ISSN 0100-879X Amifostine (WR-2721), a cytoprotective agent during high-dose cyclophosphamide treatment of non-Hodgkin’s lymphomas: a phase II study C.A. De Souza1, G. Santini2, 1Centro de Hematologia e Hemoterapia, Unidade de Transplante de Medula, G. Marino2, S. Nati2, Universidade Estadual de Campinas, Campinas, SP, Brasil A.M. Congiu2, A.C. Vigorito1 2Department of Hematology, San Martino Hospital, Genoa, Italy and E. Damasio2 Abstract Correspondence Clinical trials indicate that amifostine may confer protection on Key words C.A. De Souza various normal tissues without attenuating anti-tumor response. When · Amifostine Centro de Hematologia e administered prior to chemotherapy or radiotherapy, it may provide a · Cytoprotection Hemoterapia broad spectrum of cytoprotection including against alkylating drugs. · Non-Hodgkin’s lymphoma Unidade de Transplante de Medula The mechanism of protection resides in the metabolism at normal · High-dose cyclophosphamide UNICAMP · tissue site by membrane-bound alkaline phosphatase. Toxicity of this Peripheral blood progenitor 13083-080 Campinas, SP cell mobilization Brasil drug is moderate with hypotension, nausea and vomiting, and hypo- Fax: +55-19-788-8750 calcemia being observed. We report a phase II study using amifostine E-mail: [email protected] as a protective drug against high-dose cyclophosphamide (HDCY) (7 g/m2), used to mobilize peripheral blood progenitor cells (PBPC) and Publication supported by FAPESP. to reduce tumor burden. We enrolled 29 patients, 22 (75.9%) affected by aggressive and 7 (24.1%) by indolent non-Hodgkin’s lymphoma (NHL), who were submitted to 58 infusions of amifostine and com- Received August 10, 1999 pared them with a historical group (33 patients) affected by aggressive Accepted March 9, 2000 NHL and treated with VACOP-B followed by HDCY.
    [Show full text]
  • Pharmacokinetics and Therapeutic Uses of Mesna
    Western University Scholarship@Western Electronic Thesis and Dissertation Repository November 2010 Pharmacokinetics and Therapeutic Uses of Mesna Murray J. Cutler The University of Western Ontario Supervisor Dr. David J. Freeman The University of Western Ontario Graduate Program in Pharmacology and Toxicology A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Murray J. Cutler 2010 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Pharmacology Commons Recommended Citation Cutler, Murray J., "Pharmacokinetics and Therapeutic Uses of Mesna" (2010). Electronic Thesis and Dissertation Repository. 28. https://ir.lib.uwo.ca/etd/28 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. PHARMACOKINETICS AND THERAPEUTIC USES OF MESNA (Spine Title: Pharmacokinetics and Therapeutic Uses of Mesna) (Thesis Format: Integrated-Article) By Murray J. Cutler Department of Physiology and Pharmacology Graduate Program In Pharmacology and Toxicology Submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy School of Graduate and Postdoctoral Studies The University of Western Ontario London, Ontario November, 2010 © Murray J. Cutler, 2010 THE UNIVERSITY OF WESTERN ONTARIO SCHOOL OF GRADUATE AND POSTDOCTORAL STUDIES CERTIFICATE
    [Show full text]
  • OCN Review Course About the Audience… Disclosures Plan for The
    About the audience… OCN Review Course • When will you take the exam? – Now anytime- 3 months post the sign up • Is anyone in the group, just contemplating taking the test? Chris Rimkus RN, MSN, AOCN • Anyone in here to get CEU’s? • The goal of the OCN test is to validate that you are a well rounded oncology nurse Plan for the day Disclosures • Goal of this course is to do snapshot review • I am on a couple speakers bureaus, but this – For those taking it soon- validate what you know will not impact anything I teach today – For those considering, shows what you need to – Onyx/Amgen focus on – Genentech • I will question you to see what you know and maybe show you where you need to focus attention • It is possible for me to discuss some off • Stay on track!! label information – This may take some work for me/you • There will be a lot of info and to be efficient – With an open question/answer, sometimes time with your time, it is likely the breaks are not gets away enough for appropriate adult learning • Get through all material theory • Get done ON TIME!!!!!!!!!!!! ONCC.ORG 1 ONS.ORG Resources to use • ONCC Website – 50 free questions- OCN – Other- do as many as you can • Core Curriculum- outdated but still recommended by those who take the test • ONS standards of professional practice • ONCC practice tests • Guidelines for practice from ONS • Other textbooks Do as many of the free tests as Do both versions of OCN, CBCN, you can!!! BMTCN, AOCNS 2 Books I Know… These books are still relevant… These are new editions this year $65-80 $55.86-
    [Show full text]