Osheroff N, Corbett A H, Elsea S H, Westergaard M
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146.
Cancer Chemother Pharmacol. 1994;34 Suppl:S19-25. doi: 10.1007/BF00684859.
Topoisomerase II is the primary cellular target for a variety of antineoplastic drugs that are active against human cancers. These drugs exert their cytotoxic effects by stabilizing covalent topoisomerase II-cleaved DNA complexes that are fleeting intermediates in the catalytic cycle of the enzyme. Despite this common feature of drug action, a number of mechanistic differences between drug classes have been described. These mechanistic differences (including effects on DNA cleavage/religation, DNA strand passage, and adenosine triphosphate hydrolysis) were used as the basis for a series of competition experiments to determine whether different compounds share a common site of action on topoisomerase II or interact at distinct sites. Results of the present study strongly suggest that at least four structurally disparate antineoplastic drugs, etoposide, amsacrine, genistein, and the quinolone CP-115,953, share an overlapping interaction domain on the enzyme.
拓扑异构酶II是多种对人类癌症有效的抗肿瘤药物的主要细胞靶点。这些药物通过稳定共价拓扑异构酶II切割的DNA复合物发挥其细胞毒性作用，这些复合物是该酶催化循环中的短暂中间体。尽管药物作用有这一共同特征，但已描述了不同药物类别之间的一些机制差异。这些机制差异（包括对DNA切割/重新连接、DNA链通过和三磷酸腺苷水解的影响）被用作一系列竞争实验的基础，以确定不同化合物是否在拓扑异构酶II上共享一个共同的作用位点或在不同位点相互作用。本研究结果强烈表明，至少四种结构不同的抗肿瘤药物，依托泊苷、安吖啶、染料木黄酮和喹诺酮CP-115,953，在该酶上共享一个重叠的相互作用结构域。
