DNA topoisomerase II as the target for the anticancer drug TOP-53: Mechanistic basis for drug action
DNA topoisomerase II as the target for the anticancer drug TOP-53: Mechanistic basis for drug action
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DOI：
10.1021/bi0021838
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发表时间：
2001-01-23
期刊：
影响因子：
2.9
通讯作者：
Osheroff, N
中科院分区：
文献类型：
--
作者：
Byl, JAW;Cline, SD;Osheroff, N
TOP-53是一种很有前途的抗癌剂，在动物肿瘤模型中显示出对非小细胞肺癌的高活性[Utsugi，T.，et al.(1996)癌症研究56,2809-2814]。与其母体化合物依托泊苷相比，TOP-53对非小细胞肺癌细胞的毒性要大得多，在产生染色体断裂方面更活跃，并在动物肺组织中表现出改善的细胞摄取和药代动力学。尽管TOP-53在临床前取得了成功，但关于其细胞毒性机制仍有几个问题。因此，本研究表征了药物作用的基础。结果表明，拓扑异构酶II是TOP-53的主要细胞毒性靶点。此外，这种药物通过充当拓扑异构酶II毒药来杀死细胞。Top-53显示出与依托泊苷相同的DNA切割位点特异性。像它的母体化合物一样，这种药物通过干扰酶的DNA宗教活动来增加酶介导的DNA断裂的数量。在促进拓扑异构酶II介导的DNA切割方面，Top-53比依托泊苷更有效，并且在体外和培养细胞中显示出对人拓扑异构酶IIα和IIβ的高活性。因此，至少在一定程度上，TOP-53的细胞毒活性的增强可以归因于对拓扑异构酶II的活性的增强。最后，TOP-53对对依托泊苷高度耐药的突变酵母II型酶显示出接近野生型的活性。这一发现表明，TOP-53可以保持对依托泊苷产生耐药性的系统的活性，并表明依托泊苷C环上的取代基对于拓扑异构酶II与药物的相互作用是重要的。
TOP-53 is a promising anticancer agent that displays high activity against non-small cell lung cancer in animal tumor models [Utsugi, T., et al. (1996) Cancer Res. 56, 2809-2814]. Compared to its parent compound, etoposide, TOP-53 is considerably more toxic to non-small cell lung cancer cells, is more active at generating chromosomal breaks, and displays improved cellular uptake and pharmacokinetics in animal lung tissues. Despite the preclinical success of TOP-53, several questions remain regarding its cytotoxic mechanism. Therefore, this study characterized the basis for drug action. Results indicate that topoisomerase II is the primary cytotoxic target for TOP-53. Furthermore, the drug kills cells by acting as a topoisomerase II poison. TOP-53 exhibits a DNA cleavage site specificity that is identical to that of etoposide. Like its parent compound, the drug increases the number of enzyme-mediated DNA breaks by interfering with the DNA religation activity of the enzyme. TOP-53 is considerably more efficient than etoposide at enhancing topoisomerase II-mediated DNA cleavage and exhibits high activity against human topoisomerase II alpha and II beta in vitro and in cultured cells. Therefore, at least in part, the enhanced cytotoxic activity of TOP-53 can be attributed to an enhanced activity against topoisomerase II. Finally, TOP-53 displays nearly wild-type activity against a mutant yeast type II enzyme that is highly resistant to etoposide, This finding suggests that TOP-53 can retain activity against systems that have developed resistance to etoposide, and indicates that substituents on the etoposide C-ring are important for topoisomerase II-drug interactions.