Baldwin E L, Osheroff N
Department of Biochemistry, 654 Robinson Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Curr Med Chem Anticancer Agents. 2005 Jul;5(4):363-72. doi: 10.2174/1568011054222364.
Etoposide is an important chemotherapeutic agent that is used to treat a wide spectrum of human cancers. It has been in clinical use for more than two decades and remains one of the most highly prescribed anticancer drugs in the world. The primary cytotoxic target for etoposide is topoisomerase II. This ubiquitous enzyme regulates DNA under- and overwinding, and removes knots and tangles from the genome by generating transient double-stranded breaks in the double helix. Etoposide kills cells by stabilizing a covalent enzyme-cleaved DNA complex (known as the cleavage complex) that is a transient intermediate in the catalytic cycle of topoisomerase II. The accumulation of cleavage complexes in treated cells leads to the generation of permanent DNA strand breaks, which trigger recombination/repair pathways, mutagenesis, and chromosomal translocations. If these breaks overwhelm the cell, they can initiate death pathways. Thus, etoposide converts topoisomerase II from an essential enzyme to a potent cellular toxin that fragments the genome. Although the topoisomerase II-DNA cleavage complex is an important target for cancer chemotherapy, there also is evidence that topoisomerase II-mediated DNA strand breaks induced by etoposide and other agents can trigger chromosomal translocations that lead to specific types of leukemia. Given the central role of topoisomerase II in both the cure and initiation of human cancers, it is imperative to further understand the mechanism by which the enzyme cleaves and rejoins the double helix and the process by which etoposide and other anticancer drugs alter topoisomerase II function.
依托泊苷是一种重要的化疗药物，用于治疗多种人类癌症。它已在临床使用二十多年，至今仍是世界上处方量最高的抗癌药物之一。依托泊苷的主要细胞毒性靶点是拓扑异构酶II。这种普遍存在的酶调节DNA的解旋和超螺旋，并通过在双螺旋中产生瞬时双链断裂来消除基因组中的结和缠结。依托泊苷通过稳定一种共价酶切割的DNA复合物（称为切割复合物）来杀死细胞，这种复合物是拓扑异构酶II催化循环中的瞬时中间体。经处理的细胞中切割复合物的积累会导致永久性DNA链断裂的产生，从而触发重组/修复途径、诱变和染色体易位。如果这些断裂超过细胞的承受能力，就会引发死亡途径。因此，依托泊苷将拓扑异构酶II从一种必需酶转化为一种能使基因组断裂的强效细胞毒素。尽管拓扑异构酶II-DNA切割复合物是癌症化疗的重要靶点，但也有证据表明，依托泊苷和其他药物诱导的拓扑异构酶II介导的DNA链断裂可引发导致特定类型白血病的染色体易位。鉴于拓扑异构酶II在人类癌症的治疗和引发中都起着核心作用，进一步了解该酶切割和重新连接双螺旋的机制以及依托泊苷和其他抗癌药物改变拓扑异构酶II功能的过程势在必行。
