Topoisomerase poisoning activity of novel disaccharide anthracyclines
Topoisomerase poisoning activity of novel disaccharide anthracyclines
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DOI：
10.1124/mol.56.1.77
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发表时间：
1999-07-01
影响因子：
3.6
通讯作者：
Capranico, G
中科院分区：
文献类型：
--
作者：
Guano, F;Pourquier, P;Capranico, G
阿霉素和伊达比星是治疗人类血液系统恶性肿瘤和实体瘤的非常有效的抗癌药物。这些药物是广为人知的拓扑异构酶II类毒物；然而，最近已有研究表明，一些蒽环类类似物对拓扑异构酶I具有毒性作用。在本工作中，我们测定了新的双糖类似物和母药伊达柔比星对人拓扑异构酶I和拓扑异构酶IIα和IIβ类药物的毒性作用，并用体外DNA切割试验和酵母系统来测试这些药物是否能够在体内毒化这些酶。我们发现受试剂是拓扑异构酶IIα和IIβ的强毒，第二糖相对于第一种新的双糖类似物的轴向方向被证明是毒活性和细胞毒性所必需的。有趣的是，伊达比星和新的类似物在体外刺激低水平的拓扑异构酶I介导的DNA裂解。正如预期的那样，该药物的细胞毒性水平受到拓扑异构酶II含量的高度影响；然而，受试剂具有酵母细胞杀伤活性，该活性也弱依赖于细胞拓扑异构酶I的含量。这些结果对于充分理解抗癌药物引起的拓扑异构酶中毒的分子机制具有重要意义，并确定了蒽环类化合物的结构决定因素，有助于合理设计针对拓扑异构酶I的新化合物。
Doxorubicin and idarubicin are very effective anticancer drugs in the treatment of human hematological malignancies and solid tumors. These agents are well known topoisomerase II poisons; however, some anthracycline analogs recently have been shown to poison topoisomerase I. In the present work, we assayed novel disaccharide analogs and the parent drug, idarubicin, for their poisoning effects of human topoisomerase I and topoisomerases II alpha and II beta Drugs were evaluated with a DNA cleavage assay in vitro and with a yeast system to test whether the agents were able to poison the enzymes in vivo. We have found that the test agents are potent poisons of both topoisomerases II alpha and II beta The axial orientation of the second sugar relative to the first one of the novel disaccharide analogs was shown to be required for poisoning activity and cytotoxicity. Interestingly, idarubicin and the new analogs stimulated topoisomerase I-mediated DNA cleavage at low levels in vitro. As expected, the cytotoxic level of the drug was highly affected by the content of topoisomerase II; nevertheless, the test agents had a yeast cell-killing activity that also was weakly dependent on cellular topoisomerase I content. The results are relevant for the full understanding of the molecular mechanism of topoisomerase poisoning by anticancer drugs, and they define structural determinants of anthracyclines that may help in the rational design of new compounds directed against topoisomerase I.