以DNA拓扑异构酶Ⅱ为靶点的抗癌药物

Anticancer drugs targeting DNA topoisomerase Ⅱ

DNA拓扑异构酶Ⅱ (TopoisomeraseⅡ ,TOPOⅡ )是一种真核生物生存所必需的泛酶 ,在几乎所有DNA代谢过程中发挥重要作用。TOPOⅡ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TOPOⅡ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TOPOⅡ为靶点的药物按作用方式可分为 2类 :一类通过稳定TOPOⅡ介导的可切割复合物而杀死肿瘤细胞 ,称为TOPOⅡ毒剂 (TOPOⅡpoison) ;另一类通过抑制TOPOⅡ的催化活性而达到抑制肿瘤的作用 ,称为TOPOⅡ催化抑制剂 (TOPOⅡinhibi tor)。近年来 ,对TOPOⅡ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TOPOⅡ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TOPOⅡ为靶点的抗癌药物的作用机制及其发展现状。

DNA topoisomerase Ⅱ(TOPO Ⅱ) is a ubiquitous enzyme that is essential for survival of the eukaryotic organisms,playing an important role in most processes of the DNA mechanisms.The enzyme unknots or decatenates DNA by passing an intact helix through a transient double stranded break. In addition to its critical cellular functions, TOPO Ⅱ is an important target for a number of the most active and widely prescribed anticancer drugs.Despite the fact that they share the same target,drugs targeting TOPO Ⅱ have different modes of action:TOPO Ⅱ poisons kill cell by stabilizing the DNA TOPO Ⅱ cleavable complex;while TOPO Ⅱ catalytic inhibitors act by blocking overall catalytic activity.Over the past several years,great progress has been made in the catalytic mechanisms of TOPO Ⅱ and the mechanism of action of drugs targeting this enzyme.These advances have provided novel insight into the physiological functions of TOPO Ⅱ and have led to the development of more efficacious chemotherapeutic regimens and new anticancer drugs.The anti cancer mechanism of TOPO Ⅱ inhibitors and the status of development are introduced in this review.