SEQUENCE-DEPENDENT CYTOTOXIC EFFECTS DUE TO COMBINATIONS OF CISPLATIN AND THE ANTIMICROTUBULE AGENTS TAXOL AND VINCRISTINE

The antineoplastic activity that taxol has demonstrated in advanced ovarian cancer and other neoplasms in which the platinum analogues are among the most active agents has been the impetus for the development of taxol/platinum combination regimens. Since both classes of agents are known to induce cell-cycle-dependent effects and to delay cell-cycle traverse in specific phases of the cycle, an evaluation of drug sequence dependence was incorporated into initial clinical studies of the drug combination. To complement clinical studies, sequence-dependent interactions were assessed in vitro using L1210 leukemia. Cytotoxicity resulting from the combination of taxol and cisplatin was significantly increased over that achieved with cisplatin alone only when cisplatin was administered after taxol. This sequence was significantly superior to both the reverse sequence and to simultaneous drug treatment. Results achieved with sequence iterations of vincristine and cisplatin were nearly identical. In addition, alkaline-elution studies, using the optimal sequence of cisplatin and either taxol or vincristine, demonstrated that these antimicrotubule agents do not increase the formation of cisplatin-induced DNA interstrand and DNA-protein crosslinking over that produced by cisplatin alone. Although the mechanisms for the sequence-dependent cytotoxic interactions between cisplatin and the antimicrotubule agents have not been determined, it is likely that antagonistic interactions occur with the suboptimal sequences, probably because of cell-cycle-dependent phenomena.