Burden D A, Osheroff N
Department of Biochemistry, 654 Medical Research Building I, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):139-54. doi: 10.1016/s0167-4781(98)00132-8.
Topoisomerase II is a ubiquitous enzyme that is essential for the survival of all eukaryotic organisms and plays critical roles in virtually every aspect of DNA metabolism. The enzyme unknots and untangles DNA by passing an intact helix through a transient double-stranded break that it generates in a separate helix. Beyond its physiological functions, topoisomerase II is the target for some of the most active and widely prescribed anticancer drugs currently utilized for the treatment of human cancers. These drugs act in an insidious fashion and kill cells by increasing levels of covalent topoisomerase II-cleaved DNA complexes that are normally fleeting intermediates in the catalytic cycle of the enzyme. Over the past several years, we have made considerable strides in our understanding of the catalytic mechanism of topoisomerase II and the mechanism of action of drugs targeted to this enzyme. These advances have provided novel insights into the physiological functions of topoisomerase II and have led to the development of more efficacious chemotherapeutic regimens and novel anticancer drugs. Considering the importance of topoisomerase II to the eukaryotic cell and to cancer chemotherapy, it is essential to understand its enzymatic function and pharmacological properties. Therefore, this review will discuss the mechanism of action of eukaryotic topoisomerase II and topoisomerase II-targeted drugs.
拓扑异构酶II是一种普遍存在的酶，对所有真核生物的生存至关重要，并且在DNA代谢的几乎每个方面都发挥着关键作用。该酶通过使完整的螺旋穿过其在另一条螺旋中产生的瞬时双链断裂来解开和理顺DNA。除了其生理功能外，拓扑异构酶II还是目前用于治疗人类癌症的一些最活跃且处方广泛的抗癌药物的靶点。这些药物以一种隐匿的方式起作用，通过增加共价拓扑异构酶II切割的DNA复合物的水平来杀死细胞，这些复合物通常是该酶催化循环中的短暂中间体。在过去几年中，我们在理解拓扑异构酶II的催化机制以及靶向该酶的药物的作用机制方面取得了长足的进展。这些进展为拓扑异构酶II的生理功能提供了新的见解，并导致了更有效的化疗方案和新型抗癌药物的开发。鉴于拓扑异构酶II对真核细胞和癌症化疗的重要性，了解其酶功能和药理特性至关重要。因此，本综述将讨论真核拓扑异构酶II和靶向拓扑异构酶II的药物的作用机制。
