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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Roles of DNA topoisomerase Ⅱ isozymes in chemotherapy and secondary malignancies
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Roles of DNA topoisomerase Ⅱ isozymes in chemotherapy and secondary malignancies

机译：DNA拓扑异构酶Ⅱ同工酶在化疗和继发性恶性肿瘤中的作用

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摘要

Drugs that target DNA topoisomerase Ⅱ (Top2), including etopo-side (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute my-eloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the β rather than the α isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2β~+ than in skin-specific top2β-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2β-dependent and preventable by cotreatment with a protea-some inhibitor, suggesting the importance of proteasomal degradation of the Top2β-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2α-dependent. These results point to the importance of developing Top2α-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.
机译：靶向DNA拓扑异构酶Ⅱ（Top2）的药物包括依托泊苷（VP-16），阿霉素和米托蒽醌，是临床上最有效的抗癌药物。但是，基于Top2的化学疗法与继发性恶性肿瘤的发生率较高相关，特别是在接受VP-16治疗的患者中发生急性骨髓性白血病。这种联系暗示了致癌作用与Top2介导的DNA损伤之间的联系。我们在这里显示VP-16诱导的癌变主要涉及Top2的β而不是α同工酶。在小鼠皮肤癌变模型中，经VP7诱导的黑色素瘤在7,12-二甲基苯并[a]蒽处理的小鼠皮肤中的发生率在TOP2β〜+中显着高于皮肤特异性top2β敲除老鼠。此外，发现VP-16诱导的DNA序列重排和双链断裂（DSB）是Top2β依赖性的，并且可以通过与蛋白酶体抑制剂共同处理来预防，这表明蛋白酶体降解Top2β-DNA裂解复合物的重要性。 VP-16诱导的DNA序列重排。然而，发现表达两种Top2同工酶的转化细胞中的VP-16细胞毒性主要是Top2α依赖性的。这些结果表明开发有效治疗的Top2α特异性抗癌药物而不引起与治疗相关的继发性恶性肿瘤的重要性。

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