Mutagenicity, Tumorigenicity, and Electrophilic Reactivity of the Stereoisomeric Platinum(ll) Complexes of 1,2-Diaminocyclohexane1

Without external activation, c/'sand frans-dichlorodiammineplatinum(ll) (DDP) and the c/s, frans(-), and frans(+) forms of dichloro-1,2-diaminocyclohexaneplatinum(ll) (DDCP) and sulfato-1,2-diaminocyclohexaneplatinum(ll) (SHP) showed a 400-fold range of mutagenicity for Salmonella typhimurium TA100 and TA98; they were 2 to 10 times more mutagenic for strain TA100 than for strain TA98. With strain TA100, fransDDP was less than 0.5% as mutagenic as the c/s isomer, which produced 180 revertants/nmol. For the diaminocyclohexane complexes, mutagenic activity was strongly dependent on the stereoisomer of the diaminocyclohexane in the complex. Thus, with strain TA100, the frans(+) forms of DDCP and SHP produced 220 and 66 revertants/nmol, respectively, while the c/s and fransi-) isomers induced only 10 and 5% as many revertants as the fransi+) forms. The SHP complexes were the most reactive toward DNA and produced a greater reduction in the transforming activity of Bacillus subtilis DNA after 3-hr reaction times than did the DDP or DDCP complexes. With 20-hr reaction times, all of the platinum complexes showed similar extents of reaction with DNA and caused approximately equal losses of transforming activity. The Stereoisomeric form of the diaminocyclohexane ligand of the DDCP or SHP complexes did not affect either the reactivity of the complex with DNA or its ability to reduce the transforming activity of DNA. Significant increases in the number of lung adenomas in A/ J mice were induced by multiple i.p. injections of c/s-DDP and each of the DDCP and SHP complexes (total doses, 21 to 108 jumol/kg body weight). Similar treatments with c/s-DDP caused a significant increase in the number of skin papillomas in female CD-1 mice given promoting treatments with croton oil; the DDCP and SHP complexes had little or no activity in this system. At these levels, frans-DDP was not active for the induction of either lung adenomas or skin tumors. With the systems used for this study, the mutagenicities and tumorigenicities of the platinum(ll) complexes did not correlate with their reported antitumor activities. Further studies appear warranted to determine whether there may be effective antitumor platinum(ll) complexes that are not strongly mutagenic or carcinogenic.