Cellular resistance to topoisomerase-targeted drugs: from drug uptake to cell death.
DNA topoisomerase inhibitors are important antineoplastic agents used in the treatment of both leukemias and solid tumors, such as breast, lung and colon cancers. Their clinical usefulness is limited by both natural and acquired tumor cell resistance, which almost always is multifactorial in nature. The resistance can be due to pretarget events, such as drug accumulation, metabolism and intracellular drug distribution, or due to reduced drug-target interaction. More recently, post-target events, such as macromolecular synthesis, cell cycle progression, DNA repair/recombination and regulation of cell death, have been shown to play an important role in the sensitivity toward topoisomerase inhibitors. The different mechanisms involved in the cellular resistance toward clinically used topoisomerase inhibitors will be reviewed in this article with particular emphasis on post-target events.
Larsen
A K
AK
Laboratory of Biology and Pharmacology of DNA Topoisomerases, CNRS UMR 1772, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. aklarsen@igr.fr
Skladanowski
A
A
D000970:Antineoplastic Agents / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D004351:Drug Resistance / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000628:therapy; D011995:Recombination, Genetic / Q000235:genetics; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I