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Prevention of Lethal and Renal Toxicity of cis-Diamminedichloroplatinum(II) by Induction of Metallothionein Synthesis without Compromising Its Antitumor Activity in Mice¹

Department of Public Health, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 108, Japan

The participation of renal metallothionein (MT) in the toxicity and antitumor activity of cis-diamminedichloroplatinum(II) (cis-DDP) in male mice was examined. Preinduction of MT in the kidney by the s.c. administration of bismuth compounds decreased the lethality and renal and gastrointestinal toxicity caused by a single s.c. injection of cis-DDP. In the present study a correlation between the protective effect of pretreatment with bismuth nitrate against cis-DDP toxicity and the preinduced MT levels in the kidney was observed. Bismuth nitrate pretreatment showed no effect on the antitumor activity of cis-DDP against several transplantable tumors, probably because it induces MT in the kidney but not in tumor tissues. The fact that p.o. preadministration of bismuth subnitrate, an antidiarrheal drug, also depressed the lethal toxicity of cis-DDP is promising for its prompt application in medical attention. Thus, bismuth pretreatment allows higher doses of cis-DDP with no apparent toxicity, resulting in more efficient utilization of this anticancner drug.

¹ Supported by Grant-in-Aid for Special Project Research, Cancer-Bioscience, from the Ministry of Education, Science, and Culture, Japan (No. 60218031) and in part by a grant from Nippon Kayaku Co., Ltd., Tokyo, Japan.

² To whom requests for reprints should be addressed.

Received 7/11/85. Revised 8/ 1/86. Accepted 10/30/86.

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