Dual topoisomerase I/II inhibitors

Abstract

Topoisomerase (topo) I and II are nuclear enzymes, which play a major role in the topological rearrangement of DNA during replication and transcription processes. In the course of years, many different agents have been found which can inhibit the topos and thereby exploit cytotoxicity, also against tumour cells. Selective inhibition of the topo I enzyme can, however, induce a reactive increase in topo II levels, and vice versa. This mechanism is associated with the development of drug resistance. Dual inhibition of both topo I and II may, theoretically, overcome this resistance problem. In this review, the most important and promising dual topo I/II inhibitors designed as anticancer agents will be discussed. Thus far, only the indolyl quinoline derivative TAS-103, the 7 H-benzo [ e] pyrido [4,3- b] indole derivative intoplicine, and the acridine derivative PZA have been shown to be dual topo inhibitors with high cytotoxicity.