Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.
Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.
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DOI：
10.1016/s0021-9258(18)90729-5
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发表时间：
1984-11
期刊：
影响因子：
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通讯作者：
G. L. Chen;L. Yang;T. Rowe;B. Halligan;K. M. Tewey;L. Liu
中科院分区：
文献类型：
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作者：
G. L. Chen;L. Yang;T. Rowe;B. Halligan;K. M. Tewey;L. Liu
许多嵌入性抗肿瘤药物已经显示通过它们对哺乳动物DNA拓扑异构酶II和DNA之间形成的可裂解复合物的稳定化的特异性作用而间接裂解DNA（纳尔逊，E.M.，Tewey，K.M.，和Liu，L.F.等人（1984）Proc. Acad. Sci. U.S.A.81，1361-1365）。不嵌入DNA的抗肿瘤表鬼臼毒素（VP-16和VM-26）可以类似地诱导培养的哺乳动物细胞中蛋白质连接的DNA断裂。使用纯化的哺乳动物DNA拓扑异构酶II的体外研究表明，表鬼白毒素通过稳定可切割的复合物干扰哺乳动物DNA拓扑异构酶II的断裂-团聚反应。用蛋白质变性剂处理这种稳定的可切割复合物导致DNA链断裂和拓扑异构酶亚基与断裂DNA的5 '端共价连接。此外，表鬼臼毒素还抑制哺乳动物DNA拓扑异构酶II的链通过活性，推测是药物-酶相互作用的结果。体内和体外研究之间的协议表明，哺乳动物DNA拓扑异构酶II是体内的药物靶点。表鬼臼毒素对哺乳动物DNA拓扑异构酶II的作用与萘啶酸对大肠杆菌DNA促旋酶的作用之间的相似性表明，表鬼臼毒素的细胞毒性作用可能类似于萘啶酸的杀菌作用。
Many intercalative antitumor drugs have been shown to cleave DNA indirectly through their specific effect on the stabilization of a cleavable complex formed between mammalian DNA topoisomerase II and DNA (Nelson, E.M., Tewey, K.M., and Liu, L.F. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 1361-1365). Antitumor epipodophyllotoxins (VP-16 and VM-26) which do not intercalate DNA can similarly induce protein-linked DNA breaks in cultured mammalian cells. In vitro studies using purified mammalian DNA topoisomerase II show that epipodophyllotoxins interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II by stabilizing a cleavable complex. Treatment of this stabilized cleavable complex with protein denaturants results in DNA strand breaks and the covalent linking of a topoisomerase subunit to the 5'-end of the broken DNA. Furthermore, epipodophyllotoxins also inhibit the strand-passing activity of mammalian DNA topoisomerase II, presumably as a result of drug-enzyme interaction. The agreement between the in vivo and in vitro studies suggests that mammalian DNA topoisomerase II is a drug target in vivo. The similarity between the effect of epipodophyllotoxins on mammalian DNA topoisomerase II and the effect of nalidixic acid on Escherichia coli DNA gyrase suggests that the cytotoxic action of epipodophyllotoxins may be analogous to the bactericidal action of nalidixic acid.