Topoisomerase I inhibitors and drug resistance

Abstract

DNA topoisomerase I is a nuclear enzyme which catalyzes the conversion of the DNA topology by introducing single-strand breaks into the DNA molecule. This enzyme represents a novel and distinct molecule target for cancer therapy by antitopoisomerase drugs belonging to the campthotecin series of antineoplastics. As many tumors can acquire resistance to drug treatment and become refractary to the chemotherapy it is very important to investigate the mechanisms involved in such a drug resistance for circumventing the phenomenon.This article describes the role of topoisomerase I in cell functions and the methods used to assess its in vitro catalytic activity. It reviews the mechanisms of cytotoxicity of the most specific antitopoisomerase I drugs by considering also the phenomenon of drug resistance. Some factors useful to drive the future perspectives in the development of new topoisomerase I inhibitors are also evidenced and discussed.

Bn80927

“…It is well known that the clinical efficacy of anticancer agents, including some topoisomerase inhibitors, is limited by drug resistance mechanisms (38,39). This resistance can be due to a decrease in the levels and/or activities of topoisomerase, to a decrease of intracellular drug accumulation (MDR phenotype; Ref.…”

High sensitivity of human epidermal keratinocytes (HaCaT) to topoisomerase inhibitors

“…Eukaryotic topoisomerase I is a nuclear enzyme capable of introducing transient breaks in one strand of doubled‐strand DNA (Wang 1985). This enzyme is involved in many DNA functions such as replication, transcription and recombination mechanisms (Parchment & Pessina 1998) and has been shown to be the target of antineoplastic drugs of the Camptothecin group (Hsiang et al. 1985), which act by stabilizing the covalent complex between the single‐strand DNA break and the topoisomerase I molecule.…”