Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies
Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies
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DOI：
10.1073/pnas.0704002104
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发表时间：
2007-06-26
影响因子：
11.1
通讯作者：
Liu, Leroy F.
中科院分区：
文献类型：
--
作者：
Azarova, Anna M.;Lyu, Yi Lisa;Liu, Leroy F.
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，是临床使用中最有效的抗癌药物之一。然而，基于Top2的化疗与继发性恶性肿瘤的发生率较高相关，特别是VP-16治疗患者发生急性髓性白血病。这种关联提示致癌作用与Top2介导的DNA损伤之间存在联系。我们在这里表明，VP-16诱导的致癌作用主要涉及β，而不是α同工酶的Top2。在小鼠皮肤癌发生模型中，发现在7，12-二甲基苯并[a]蒽处理的小鼠皮肤中VP-16诱导的黑色素瘤的发生率在TOP 2 β（+）中显著高于皮肤特异性TOP 2 β敲除小鼠。此外，VP-16诱导的DNA序列重排和双链断裂（DSB）被发现是Top2 β依赖性的，并可通过与蛋白酶体抑制剂共处理来预防，这表明蛋白酶体降解Top2 β-DNA切割复合物在VP-16诱导的DNA序列重排中的重要性。然而，VP-16在表达两种Top2同工酶的转化细胞中的细胞毒性主要是Top2 α依赖性的。这些结果指出了开发Top2 α特异性抗癌药物用于有效化疗而不发生治疗相关继发性恶性肿瘤的重要性。
Drugs that target DNA topoisomerase II (Top2), including etoposide (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 myeloid 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 beta rather than the alpha 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 TOP2 beta(+) than in skin-specific top2 beta-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2 beta-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2 beta-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 Top2 alpha-dependent. These results point to the importance of developing Top2 alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.