Preclinical evaluation of WR-151327: an orally active chemotherapy protector

Abstract

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.