Sinha B K
Biochemical and Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Drugs. 1995 Jan;49(1):11-9. doi: 10.2165/00003495-199549010-00002.
The nuclear enzymes topoisomerase I and II are critical for DNA function and cell survival, and recent studies have identified these enzymes as cellular targets for several clinically active anticancer drugs. Topoisomerase II inhibitors (anthracyclines, epipodophyllotoxins, etc.) are active against several types of tumours. However, treatment with these drugs often results in the development of the multi-drug resistance. Because topoisomerase II-active drugs have several different modes of action, different mechanisms of resistance, including decreased activation and increased detoxification by glutathione-dependent enzymes, have also been implicated. Unlike topoisomerase II, topoisomerase I is not a cell cycle-dependent enzyme and, therefore, it is a more desirable cellular target for anticancer drug development. Topoisomerase I inhibitors, such as camptothecin and its derivatives, have shown significant activity against a broad range of tumours and, in general, are not substrates for either the multi-drug-resistance P-170 glycoprotein or the multi-drug-resistance-associated protein. Because of manageable toxicity and encouraging activity against solid tumours, topoisomerase I-active drugs offer promise in the clinical management of human tumours.
核酶拓扑异构酶I和II对DNA功能及细胞存活至关重要，近期研究已将这些酶确定为几种临床活性抗癌药物的细胞靶点。拓扑异构酶II抑制剂（蒽环类、表鬼臼毒素等）对多种类型肿瘤具有活性。然而，使用这些药物治疗常常导致多药耐药性的产生。由于拓扑异构酶II活性药物有几种不同的作用模式，不同的耐药机制，包括谷胱甘肽依赖性酶导致的活化降低和解毒增加，也被牵涉其中。与拓扑异构酶II不同，拓扑异构酶I不是细胞周期依赖性酶，因此，它是抗癌药物开发中更理想的细胞靶点。拓扑异构酶I抑制剂，如喜树碱及其衍生物，已显示出对多种肿瘤具有显著活性，并且一般而言，它们既不是多药耐药P - 170糖蛋白的底物，也不是多药耐药相关蛋白的底物。由于毒性可控且对实体瘤具有令人鼓舞的活性，拓扑异构酶I活性药物在人类肿瘤的临床治疗中展现出前景。
