De Isabella P, Capranico G, Palumbo M, Sissi C, Krapcho A P, Zunino F
Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Mol Pharmacol. 1993 May;43(5):715-21.
Mitoxantrone, a DNA intercalator, is an effective antitumor drug known to interfere with topoisomerase II function through stimulation of enzyme-mediated DNA cleavage. To clarify the drug structural requirements for stimulation of topoisomerase II DNA cleavage, the cytotoxic activity and molecular effects of mitoxantrone, ametantrone, and a new derivative (BBR2577), bearing a modification on one of the side chains, were examined in relation to their DNA binding affinities and modes of drug-DNA interaction. The results showed a good correlation between cytotoxicity and topoisomerase II DNA cleavage. The modification of one side chain did not influence the cytotoxic potency or the ability of the drug to stimulate DNA cleavage. In contrast, removal of the hydroxyl substituents in the planar aromatic moiety (ametantrone) markedly affected the efficacy of the drug. Ametantrone showed a markedly lower capacity, compared with the other two compounds, to induce cleavable complexes both in intact cells and in SV40 DNA, which suggests a critical role of these substituents in the formation of the ternary topoisomerase II-DNA-drug complex. The poor efficacy of ametantrone is likely due to low stability of the ternary complex. This is possibly related to a different orientation of the drug chromophore intercalated into DNA, compared with those of mitoxantrone and BBR2577. The DNA cleavage efficiencies of the tested drugs at low concentrations correlated with the DNA binding affinity. Identical DNA cleavage patterns were observed with the three compounds, which suggests that all tested drugs share a similar specificity for interaction with sites recognized by the enzyme.
米托蒽醌是一种DNA嵌入剂，是一种有效的抗肿瘤药物，已知它通过刺激酶介导的DNA切割来干扰拓扑异构酶II的功能。为了阐明刺激拓扑异构酶II DNA切割的药物结构要求，研究了米托蒽醌、氨茴蒽醌和一种在侧链之一上有修饰的新衍生物（BBR2577）的细胞毒性活性和分子效应与其DNA结合亲和力及药物-DNA相互作用模式的关系。结果表明细胞毒性与拓扑异构酶II DNA切割之间存在良好的相关性。一个侧链的修饰不影响细胞毒性效力或药物刺激DNA切割的能力。相反，平面芳香部分（氨茴蒽醌）中羟基取代基的去除显著影响了药物的疗效。与其他两种化合物相比，氨茴蒽醌在完整细胞和SV40 DNA中诱导可切割复合物的能力明显较低，这表明这些取代基在三元拓扑异构酶II-DNA-药物复合物的形成中起关键作用。氨茴蒽醌疗效不佳可能是由于三元复合物的稳定性低。这可能与与米托蒽醌和BBR2577相比，药物发色团嵌入DNA的方向不同有关。测试药物在低浓度下的DNA切割效率与DNA结合亲和力相关。三种化合物观察到相同的DNA切割模式，这表明所有测试药物与酶识别位点的相互作用具有相似的特异性。
