Targeting DNA Topoisomerase I with Non-Camptothecin Poisons

G.      L. Beretta; V.      Zuco; P.      Perego; N.      Zaffaroni

Abstract

DNA topoisomerase I is required for DNA relaxation during a variety of cellular functions. The identification of camptothecins as specific enzyme poisons and their clinical efficacy have stimulated extensive efforts to exploit topoisomerase I as a therapeutic target for cancer. However, several limitations of camptothecins, such as low solubility and stability, high toxicity, and the occurrence of resistance, have encouraged the development of non-camptothecin topoisomerase I inhibitors. Different natural and synthetic compounds (e.g., indolocarbazoles, dibenzonaphthyridine and indenoisoquinoline) have been extensively studied as alternatives to camptothecins and have been proved to be promising therapeutic agents. In this review, we comparatively evaluate the preclinical results obtained with the different non-camptothecin poisons proposed thus far as topoisomerase I inhibitors, with special reference to cellular pharmacology, and discuss the perspective for their use in the clinical setting.

Keywords: Cellular pharmacology, Clinical studies, Dibenzonaphthyridines, DNA topoisomerase I, Drug resistance, Indenoisoquinolines, Indolocarbazoles, Lamellarins, Topopyrones, Tumor cells