Base excision repair of reactive oxygen species-initiated 7,8-dihydro-8-oxo-2'-deoxyguanosine inhibits the cytotoxicity of platinum anticancer drugs.
Base excision repair of reactive oxygen species-initiated 7,8-dihydro-8-oxo-2'-deoxyguanosine inhibits the cytotoxicity of platinum anticancer drugs.
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DOI：
10.1158/1535-7163.mct-08-0929
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发表时间：
2009-07
影响因子：
5.7
通讯作者：
Wells PG
中科院分区：
文献类型：
--
作者：
Preston TJ;Henderson JT;McCallum GP;Wells PG
顺铂和奥沙利铂的抗癌治疗受到毒性和肿瘤耐药性发作的限制。两种药物均形成铂-DNA交联加合物，顺铂引起氧化性DNA损伤，包括7，8-二氢-8-氧代-2 ′-脱氧鸟苷（8-oxodG）损伤。为了评估氧化性DNA损伤作为顺铂和奥沙利铂细胞毒性的机制，通过FLAG标记的人氧鸟嘌呤糖基化酶1（α-OGG 1）或其功能同源物E.大肠杆菌甲酰氨基嘧啶糖基化酶（fpg）。两种药物均增加活性氧（ROS）和8-oxodG水平，抗氧化剂预处理降低细胞毒性。细胞克隆中α-OGG 1或fpg的异位表达增加了核和线粒体8-oxodG修复，并减少了ROS引发剂（H2 O2，甲萘醌）和两种铂类药物引起的死亡。暴露于奥沙利铂比暴露于顺铂引起更显著和持续的细胞增殖阻滞。我们的结论是8-oxodG病变是细胞毒性的，BER可能是风险的决定因素。奥沙利铂的抗肿瘤疗效更高，似乎与氧化性DNA损伤无关，这提示了一种改善癌症治疗治疗指数的新策略。
Anticancer therapy with cisplatin and oxaliplatin is limited by toxicity and onset of tumor resistance. Both drugs form platinum-DNA crosslinked adducts, and cisplatin causes oxidative DNA damage including the 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxodG) lesion. To assess oxidative DNA damage as a mechanism of cisplatin and oxaliplatin cytotoxicity, 8-oxodG-directed base excision repair (BER) was stably enhanced in human embryonic kidney cells by FLAG-tagged expression of human oxoguanine glycosylase 1 (α-OGG1) or its functional homolog, E. coli formamidopyrimidine glycosylase (fpg). Both drugs increased reactive oxygen species (ROS) and 8-oxodG levels, and cytotoxicity was decreased by antioxidant pretreatment. Ectopic expression of α-OGG1 or fpg in cell clones increased nuclear and mitochondrial 8-oxodG repair, and reduced death by ROS initiators (H2O2, menadione) and both platinum drugs. Exposure to oxaliplatin caused a more marked and sustained block of cell proliferation than exposure to cisplatin. We conclude that the 8-oxodG lesion is cytotoxic, and BER a likely determinant of risk. The greater antitumor efficacy of oxaliplatin appears unrelated to oxidative DNA damage, suggesting a novel strategy for improving the therapeutic index in cancer therapy.