以DNA拓扑异构酶II为靶点抗癌药物 2002.pdfVIP

Chinese Journal of New Drugs 2002, Vol. 11 No. 2002 11 DNA Ò , , ( 中国科学院上海药物研究所肿瘤药理实验室, 上海200031) [ ] DNA 拓扑异构酶Ò(Topoisomerase Ò, T OPO Ò) 是 一种真核生物生存所必 的泛酶, 在几乎所有 DNA 代谢过程中发挥重要作用T OPO Ò使 一条完整的DNA 双链穿过 一个移过性的双链断口, 从而导致DNA 解 结或解旋因为T OPO Ò具有重要的生理功能, 它已成为抗癌药物的重要作用靶点以T OPO Ò为靶点的药物按 作用方式可分为2 类: 一类通过稳定T OPO Ò介导的可切割复合物而杀死肿瘤细胞, 称为T OPO Ò毒剂(T OPO Ò poison) ; 另 一类通过抑制T OPO Ò的催化活性而达到抑制肿瘤的作用, 称为T OPO Ò催化抑制剂(T OPO Ò inhibi- tor) 近年来, 对T OPO Ò催化机制和药物作用方式的研究取得了很大进展, 这些发现有助于进 一步了解T OPO Ò的生理功能, 进而研究出更有效的治疗方案和新的抗癌药本文介绍了以T OPO Ò为靶点的抗癌药物的作用机 制及其发展现状 [ ] 抗癌药物; 拓扑异构酶Ò; 肿瘤 [ ] R 73 [ ] A [ ] 1003- 3734( 2002) 0 - 0675- 0 Anticancer drugs targeting DNA topoisomerase Ò MENG Ling-hua, ZHANG Yong-wei, DING Jian (Div ision of A ntitumor Pharmacology , Shanghai I nstitute of Materia M edica, Chinese A cademy of Sciences , Shanghai 200031, China) [Abstract] DNA topoisomerase Ò(T OPO Ò) is a ubiquitous enzyme that is essential for sur- vival of the eukaryotic organisms, playing an important role in most processes of the DNA mechanisms. T he enzyme unknots or decatenates DNA by passing an intact helix through a transient double-strand- ed break. In addition to its critical cellular functions, TOPO Òis an important target for a number of the most active and w idely prescribed anticancer drugs. Despite the fact that they share the same tar- get, drugs targeting TOPO Òhave different modes of action: TOPO Òpoisons kill cell by stabilizing the DNA-TOPO Òcleavable complex ; w hile TOPO Òcatalytic inhibitors act by blocking overall cata- lytic activity . Over the past several years, great progress has been made in the catalytic mechanisms of T OPO Òand the mechanism of action of