WR-2721: inhibitor of cisplatin-induced micronuclei.

Abstract

The modulatory effect of S-2-/3-aminopropylamino/ethyl-phosphorothioic acid, (WR-2721, Amifostine) on induction of micronuclei by cis-diamminedichloroplatinum[II] (CDDP) was studied. The adult, male Swiss mice were treated with WR-2721, at a dose of 200 mg/kg or 400 mg/kg body weight, and/or with CDDP, at a dose 5 mg/kg or 10 mg/kg body weight. WR-2721 was given alone or 30 min before CDDP administration. The frequency of micronucleated polychromatic erythrocytes (MNPCEs) and also the number of polychromatic erythrocytes (PCEs) in the bone marrow and peripheral blood, at 24 h after the drug application, were determined. After administration of CDDP, the frequency of MNPCEs distinctly increased, and the number of PCEs decreased. As compared with the animals injected with CDDP only, in mice treated with WR-2721 before CDDP application, the number of MNPCEs was reduced and the frequency of PCEs was increased. However, WR-2721 given alone, without subsequent administration of cis-diamminedichloroplatinum[II], caused an increase in the number of micronucleated polychromatic erythrocytes and a decrease in the number of PCEs. The geno- and cyto-toxicity and chemoprotection were dependent on the doses of the agents WR-2721 and CDDP applied. In mice injected with CDDP and/or WR-2721, the patterns of changes in the frequency of MNPCEs and PCEs were similar in the bone marrow and peripheral blood, respectively. The protective effect of the aminothiol compound WR-2721 against induction of micronuclei and apoptotic cell death in the erythropoietic system by CDDP was shown.