Preclinical evaluation of WR-151327: an orally active chemotherapy protector.
Clinical trials are in progress to evaluate radio- and chemoprotection by the aminothiol 2-[(3-aminopropyl)amino]ethanethiol-dihydrogen phosphate ester (WR-2721; amifostine). Phase II and III clinical studies have demonstrated that i.v. administered WR-2721 protects against the toxicities of cis-diamminedichloroplatinum (II) and cyclophosphamide. In preclinical murine studies, we have now further characterized the chemoprotective properties of WR-2721, and have evaluated the protective ability of the related aminothiol S-3-(3-methylaminopropylamino)propylphosphorothioic acid (WR-151327) following p.o. administration. The P388 leukemia (i.p. tumor-i.p. cytotoxic drug on Day 1 after tumor) was used to determine antitumor efficacy. Single dose pretreatment with i.p. WR-2721 protects normal mouse tissues against the chemotoxicities of mitomycin C, cis-diammine(cyclobutanedicarboxylato)platinum (II), and doxorubicin. Bone marrow suppression and cytotoxic drug-induced lethality were reduced, without compromising P388 antitumor activity. Pretreatment with a single p.o. dose of WR-151327 was as effective as i.p. WR-2721 in protecting against the myelotoxicity and lethality of mitomycin C, cis-diamminedichloroplatinum (II), and cis-diammine(cyclobutanedicarboxylato)platinum (II), while P388 antitumor activity was maintained. These data support the clinical development of WR-151327 as a p.o. administered chemotherapy protector.
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Vincent T. Lombardi Cancer Research Center, Georgetown University Medical Center, Washington, DC 20007.
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Schein
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D000284:Administration, Oral; D004999:Amifostine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007941:Leukemia P388 / Q000188:drug therapy; D007962:Leukocytes / Q000187:drug effects; D007970:Leukopenia / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009946:Organothiophosphorus Compounds; D011837:Radiation-Protective Agents; C048392:WR 151327; D004999:Amifostine