DNA-based drug interactions of cisplatin.

Abstract

The interactions of cisplatin with other anti-cancer agents on the DNA level have been studied extensively in pre-clinical experiments. In general, combination of cisplatin with an antimetabolite, taxane, or topoisomerase inhibitor, can result in a modulation of platinum pharmacology on the DNA, for example, enhanced retention of the platinum-DNA adducts. These interactions are mostly sequence and cell type dependent. In cell line models, antimetabolites can enhance the number of platinum-DNA adducts, probably by inhibition of DNA repair pathways. However, in clinical trials, the opposite effect has been observed, with a reduction of these adducts upon combined treatment. For the taxanes it has been shown that they can inhibit the formation of platinum-DNA adducts, whereas topoisomerase I inhibitors increase the number of adducts, resulting in strong synergistic cytotoxicity. For this last interaction a mechanistic model has recently been proposed, in which the topoisomerase I enzyme directly binds to the platinum-DNA adduct. Thereafter, the topoisomerase I inhibitor binds to this complex, which yields large stabilised lesions to the DNA that are probably difficult to repair. Ongoing studies will proceed to elucidate the exact mechanism underlying the interactions between cisplatin and other anti-neoplastic agents on the DNA level. Such increased understanding might help in designing new and more effective treatment regimens for cancer. In this paper, we review the pre-clinical and clinical studies investigating the observed interactions between cisplatin, the antimetabolites, taxanes, and topoisomerase inhibitors on the DNA level.