Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.
Intercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II.
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DOI：
10.1016/s0021-9258(17)47282-6
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发表时间：
1984
期刊：
影响因子：
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通讯作者：
K. M. Tewey;G. L. Chen;E. Nelson;L. Liu
中科院分区：
文献类型：
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作者：
K. M. Tewey;G. L. Chen;E. Nelson;L. Liu
许多嵌入性抗肿瘤药物已被证明在培养的哺乳动物细胞中诱导可逆的蛋白质连接的DNA断裂。利用纯化的哺乳动物DNA拓扑异构酶II，我们证明了抗肿瘤药物椭圆藤碱和2-甲基-9-羟基椭圆藤碱（2-Me-9-OH-E+）在体外能产生可逆的蛋白质连接的DNA断裂。2-Me-9-OH-E+对L1210细胞的细胞毒性和对实验性肿瘤的活性比椭圆藤碱更强，在体外刺激DNA切割也更有效。类似于4 '-（9-吖啶氨基）-甲磺酰-间-茴香胺（m-AMSA）在体外对拓扑异构酶II的作用，椭圆藤碱诱导DNA断裂的机制最可能是由于拓扑异构酶II与DNA之间形成的可裂解复合物的药物稳定性。可切割复合物的蛋白质变性剂处理导致DNA断裂和一个拓扑异构酶II亚基与切割的DNA的每个5 '端的共价连接。通过椭圆树碱或2-Me-9-OH-E+处理产生的pBR 322 DNA上的切割位点定位在相同位置。然而，这些切割位点中的许多与由也靶向拓扑异构酶II的抗肿瘤药物m-AMSA产生的那些明显不同。因此，我们的研究结果表明，虽然哺乳动物DNA拓扑异构酶II可能是这些抗肿瘤药物的共同目标，药物DNA拓扑异构酶的相互作用，不同的抗肿瘤药物可能是不同的。
Many intercalative antitumor drugs have been shown to induce reversible protein-linked DNA breaks in cultured mammalian cells. Using purified mammalian DNA topoisomerase II, we have demonstrated that the antitumor drugs ellipticine and 2-methyl-9-hydroxyellipticine (2-Me-9-OH-E+) can produce reversible protein-linked DNA breaks in vitro. 2-Me-9-OH-E+ which is more cytotoxic toward L1210 cells and more active against experimental tumors than ellipticine is also more effective in stimulating DNA cleavage in vitro. Similar to the effect of 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) on topoisomerase II in vitro, the mechanism of DNA breakage induced by ellipticines is most likely due to the drug stabilization of a cleavable complex formed between topoisomerase II and DNA. Protein denaturant treatment of the cleavable complex results in DNA breakage and covalent linking of one topoisomerase II subunit to each 5'-end of the cleaved DNA. Cleavage sites on pBR322 DNA produced by ellipticine or 2-Me-9-OH-E+ treatment mapped at the same positions. However, many of these cleavage sites are distinctly different from those produced by the antitumor drug m-AMSA which also targets at topoisomerase II. Our results thus suggest that although mammalian DNA topoisomerase II may be a common target of these antitumor drugs, drug-DNA-topoisomerase interactions for different antitumor drugs may be different.