Carcinogenicity of Antitumorcis-Platinum(ll) Coordination Complexes in the Mouse and Rat1

Severalcis-platinum coordination complexesweretested for their carcinogenic and mutagenic potencies in view of the known electrophilic reactivities of antitumor platinum complexes toward cellular nucleophiles and the mutagen icities of some of these complexes. cis-Dichlorodiammineplatinum(Il) (total dose, 32.5 mg/kg) administered i.p. over 10 to 19 weeks increased the lung adenoma multiplicity in A/Jax mice from the control level of 0.5 to 0.8 adenoma/mouse to 10 to 16 adenomas/ mouse at 8 months. Injection i.p. of cis-dichlorobis (cyclopentylamine)phatmnum(ll) (total dose, 189 mg/kg) caused an average of 2.7 adenomas/mouse. Repeated i.p. doses of cis-dichlorodiammineplatinum(Il) (total dose, 25.9 mg/kg) and concurrent and subsequent topical applications of croton oil induced skin papillomas in female CD-i mice. At 41 weeks, 50% of the mice had papillomas with an average of 3.2 papillomas/mouse. Mice treated only with the platinum complex or only with croton oil developed no papillomas. Sarcomas developed in 35 and 25%, respectively, of male Fischer rats that received multiple s.c. injections of cis d ichhorobis(cyclopentylammne)platinum(Il) and cis-dichlo robis(pyrrohidmne)platinum(ll) (total doses, 18 and 15 mg/rat, respectively). cis-Dichlorod iammineplatinum(II), cis-dichlomobis(cyclo pentylammne)platmnum(ll), and cis-dichlomobis(pyrrolidmne) platinum(Il) were each directly mutagenic for Salmonella typhimurium TA100. Treatment of patients with platinum antitumor complexes may impose a risk of induction of second tumors in long term survivors.