Induction of Renal Metallothionein Allows Increasing Dose of an Extensively Used Antitumor Drug, cis-Diamminedichloroplatinum

Abstract

The effect of preadministration of bismuth, a specific potent inducer of renal metallothionein (MT), on the lethal and renal toxicity of cis-DDP, an extensively used antitumor drug containing heavy metal platinum, in mice was investigated. Pretreatment of mice with two s.c. doses of bismuth nitrate (BN; 30μmol/kg/day) at 24-hr interval prevented the lethal toxicity, the increase in BUN value and the occurrence of diarrhea caused by cis-DDP (35μmol/kg, s.c.). This protective effect of BN-pretreatment was signifincantly correlated with increased MT levels in the kidney. The pretreatment of tumor-bearing mice with BN also depressed the lethal and renal toxicity of cis-DDP without compromising its antitumor activity, and allowed the administration of relatively high dose of cis-DDP. Daily five consecutive p.o. preadministration of bismuth subnitrate (BSN), one of the bismuth compounds being in use as a protectant of the gastrointestinal lining, was also effective to depress the lethal toxicity of cis-DDP. Since the effective dose of BSN is not far from that commonly used for men, this treatment will allow the increase in cis-DDP dose, promising a clinical advantage in cancer chemotherapy.