Topoisomerase I interactive agents.

Abstract

Elucidation of the crystal structure of topoisomerase I will enhance the rational development of topoisomerase I interactive agents. Although the first topoisomerase I interactive agents were camptothecin derivatives, future drugs may be designed to take advantage of the knowledge of the mechanism of interaction with topoisomerase I to increase the therapeutic index. Preclinical studies designed to determine the precise mechanism by which the topoisomerase I interactive agents lead to cell death will be essential. Future clinical trials must rationally utilize the results of preclinical studies in the design of combination regimens, both with other cytotoxics and with the newer cytostatics. Moreover, the optimum schedule of administration for irinotecan and topotecan are not known, although results of preclinical studies clearly point to protracted dosing of these S-phase-specific agents. Future clinical trials should evaluate these schedules in an effort to optimize the currently available agents, prior to introducing new analogs, which may not provide any therapeutic benefit over the current agents properly dosed. Finally, many investigators are trying to better understand the mechanism(s) of the dose-limiting toxicities observed with the currently available topoisomerase I interactive agents (e.g., glucuronidation for irinotecan diarrhea). The results of these studies may also enable the maximal dosing of the currently available agents. Even though the first priority must be to determine the therapeutic potential of the currently available agents, it is reassuring to know that many topoisomerase I interactive agents are currently under development. However, it is essential that these agents have the proper preclinical studies performed and that they be rationally developed.