Guano F, Pourquier P, Tinelli S, Binaschi M, Bigioni M, Animati F, Manzini S, Zunino F, Kohlhagen G, Pommier Y, Capranico G
Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Mol Pharmacol. 1999 Jul;56(1):77-84. doi: 10.1124/mol.56.1.77.
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 IIalpha and IIbeta. 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 IIalpha and IIbeta. 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.
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。这些药物是众所周知的拓扑异构酶II毒药；然而，最近一些蒽环类类似物已被证明可毒害拓扑异构酶I。在本研究中，我们检测了新型二糖类似物和母体药物伊达比星对人类拓扑异构酶I以及拓扑异构酶IIα和IIβ的毒害作用。通过体外DNA切割试验和酵母系统对药物进行评估，以测试这些药物是否能够在体内毒害这些酶。我们发现测试药物是拓扑异构酶IIα和IIβ的强效毒药。新型二糖类似物中第二个糖相对于第一个糖的轴向取向被证明是中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低水平刺激拓扑异构酶I介导的DNA切割。正如预期的那样，药物的细胞毒性水平受拓扑异构酶II含量的高度影响；然而，测试药物具有酵母细胞杀伤活性，该活性也微弱地依赖于细胞拓扑异构酶I的含量。这些结果对于全面理解抗癌药物对拓扑异构酶中毒的分子机制具有重要意义，并且它们确定了蒽环类药物的结构决定因素，这可能有助于合理设计针对拓扑异构酶I的新化合物。
