Comparative toxicities and mutagenicities of platinum anticancer drugs

A significant liability of cancer chemotherapy is the appearance of treatment-induced second primary carcinomas. Cisplatin is an example of a widely used anticancer drug believed to be carcinogenic in humans. This report evaluates the molecular basis for the mutagenicity and toxicity of cisplatin, and describes how an understanding of these factors enables the design and evaluation of equally effective, but less mutagenic, platinum drugs. The approach described herein, although focused on cisplatin, should be broadly applicable to include any DNA-acting drug. The major DNA adducts formed by cisplatin (Figure 1B) were incorporated into single-stranded M13mp7L2 DNA to form singly modified, biologically viable genomes. The toxicity and mutagenicity of each adduct was determined in viva. Comparing the G*G* and A*G* adducts, which collectively comprise approximately 90% of all DNA adducts formed by cisplatin, the G*G* adduct was more than fourfold less mutagenic than the A*G* adduct while possessing equal or greater toxicity. The G*G* adduct, therefore, would appear to be an ideal candidate for inclusion in the DNA binding spectrum of a newly designed platinum anticancer drug since its high toxicity should ensure therapeutic effectiveness while its low mutagenicity should decrease carcinogenic potential. As an initial step toward validating this hypothesis, the genetic effects of a platinum compound, ACDP (Figure 1A) were compared with cisplatin. ACDP is the biologically active metabolite of ACDDP (Figure 1A), a platinum compound now undergoing clinical trials. ACDP is similar to cisplatin in that it forms a high level of toxic G*G* adducts. Importantly, however, it forms threefold fewer of the highly mutagenic A*G* adducts. As predicted from the results of the experiments with the singly modified genomes, DNA globally modified with ACDP experienced significantly (twofold) fewer mutations than DNA globally modified with cisplatin while retaining equal toxicity. This work demonstrates the feasibility of the separate evaluation of individual DNA adducts as an important step toward improving the safety and effectiveness of antineoplastic agents.