Pommier Yves, Leo Elisabetta, Zhang HongLiang, Marchand Christophe
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Chem Biol. 2010 May 28;17(5):421-33. doi: 10.1016/j.chembiol.2010.04.012.
DNA topoisomerases are the targets of important anticancer and antibacterial drugs. Camptothecins and novel noncamptothecins in clinical development (indenoisoquinolines and ARC-111) target eukaryotic type IB topoisomerases (Top1), whereas human type IIA topoisomerases (Top2alpha and Top2beta) are the targets of the widely used anticancer agents etoposide, anthracyclines (doxorubicin, daunorubicin), and mitoxantrone. Bacterial type II topoisomerases (gyrase and Topo IV) are the targets of quinolones and aminocoumarin antibiotics. This review focuses on the molecular and biochemical characteristics of topoisomerases and their inhibitors. We also discuss the common mechanism of action of topoisomerase poisons by interfacial inhibition and trapping of topoisomerase cleavage complexes.
DNA拓扑异构酶是重要的抗癌和抗菌药物的作用靶点。喜树碱以及正在临床开发中的新型非喜树碱类药物（茚并异喹啉和ARC - 111）作用于真核生物IB型拓扑异构酶（Top1），而人类IIA型拓扑异构酶（Top2α和Top2β）是广泛使用的抗癌药物依托泊苷、蒽环类药物（多柔比星、柔红霉素）和米托蒽醌的作用靶点。细菌II型拓扑异构酶（回旋酶和拓扑异构酶IV）是喹诺酮类和氨基香豆素类抗生素的作用靶点。本综述重点关注拓扑异构酶及其抑制剂的分子和生化特性。我们还讨论了拓扑异构酶毒物通过界面抑制和捕获拓扑异构酶切割复合物的共同作用机制。
