Mechanisms of resistance to topoisomerase i-targeting drugs

ABSTRACT DNA topoisomerases are a class of enzymes that alter the topology of DNA and are targets of several anticancer drugs. Camptothecins (CPTs) are a relatively new family of compounds

that specifically target topoisomerase I (Top1). These compounds ‘poison’ Top1 by binding to the Top1–DNA complex in a manner that prevents the religation of DNA. Topotecan and irinotecan

are two CPTs that are approved for the treatment of a variety of malignancies, including colorectal, ovarian, and small cell lung cancers, as well as myeloid malignancies. Although CPTs have

proven to be effective anticancer drugs, resistance is still a critical clinical problem. The mechanisms underlying _de novo_ and acquired clinical resistance to CPTs and the newer classes

of Top1 poisons are unclear. However, based on preclinical studies, it is likely that clinical resistance to these drugs is the result of: (1) inadequate accumulation of drug in the tumor,

(2) resistance-conferring alterations in Top1, or (3) alterations in the cellular response to the Top1–CPT interaction. This review will focus on the current knowledge regarding mechanisms

of resistance to CPTs and other Top1-targeting drugs. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ICRF193 POTENTIATES THE GENOTOXICITY OF ETOPOSIDE Article Open access 04 June

2025 DIANHYDROGALACTITOL SYNERGIZES WITH TOPOISOMERASE POISONS TO OVERCOME DNA REPAIR ACTIVITY IN TUMOR CELLS Article Open access 24 July 2020 ATM INHIBITOR KU60019 SYNERGISTICALLY

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AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Molecular and Cellular Pharmacology, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, 195 Little

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Springer Nature SharedIt content-sharing initiative KEYWORDS * topoisomerase I * camptothecin * topotecan * irinotecan * drug resistance