甲基化抗肿瘤药物治疗中的DNA修复:治疗效果与健康结局

在甲基化抗肿瘤药物治疗中，DNA修复是决定治疗效果与不良生物效应（如突变、癌变和致畸）的一个关键机制。本文主要对甲基化抗肿瘤药物在DNA修复过程的作用进行综述。尽管这些抗肿瘤药物无选择性地靶向作用于癌细胞和正常细胞的DNA，但因其削弱了癌细胞内某些特异的DNA修复活动，从而更多地杀死癌细胞。单功能的烷化剂显示出甲基化改变特性（丙卡巴肼、达卡巴嗪、链脲佐菌素、替莫唑胺），或者氯乙基化形成单加合物并在下一步反应中引起DNA链内交联（洛莫司汀、尼莫地平、卡莫司汀、福莫司汀）。癌细胞对抗肿瘤药物的一个主要机制是通过自杀酶O⁶-甲基鸟嘌呤-DNA甲基转移酶（MGMT）直接逆转DNA损伤，形成O⁶-甲基鸟嘌呤和O⁶-氯化鸟嘌呤。由于MGMT对恶性肿瘤治疗的结局有显著影响，它被认为是一个耐药的重要标志，特别是在高级恶性胶质瘤。MGMT也被认为是甲基化抗肿瘤药物有效性的预测标志，许多临床试验正在分析MGMT抑制对治疗效果的影响。其他涉及甲基化抗肿瘤药物耐药的DNA修复因素包括错配修复、通过同源重组和DNA双链断裂（DSB）信号启动的相关修复。碱基切除修复和alkB同源蛋白（如ABH2）也可能与烷化类药物耐药有关，该现象在高表达MGMT的细胞株异常明显。对于这些机制的进一步了解，将有助于设计更为有效的治疗方案，同时减少副作用。

DNA repair in cancer therapy with methylating anticancer drugs: improving therapeutic efficacy and reducing side effects

For patients who are treated with anti-cancer drugs,DNA repair is often a critical mechanism,which determines therapeutic efficacy and/or adverse biological consequences such as mutagenesis,carcinogenesis and teratogenesis. This brief review is focused onto DNA repair activities on damage resulting from exposure to methylating anticancer drugs. Although these drugs unselectively target DNA from cancer and normal cells,the cancer-specific killing effect is likely due to downregulation of specific DNA repair activities,thereby killing more cancer than normal cells. The monofunctional alkylating agents exhibit methylating properties (procarbazine,dacarbazine,streptozotocine, temozolomide) or they chloroethylate the DNA forming monoadducts and,in a second step,DNA interstrand crosslinks (lomustine,nimustine,carmustine,fotemustine). A major mechanism of defense of cancer cells to these drugs is direct reversal of the critical DNA damage,O⁶-methylguanine as well as O⁶-chloroethylguanine,by the suicide enzyme O⁶-methylguanine-DNA methyltransferase (MGMT),which represents an important drug resistance marker especially in high-grade malignant gliomas. Since MGMT has a significant impact on the outcome of anti-cancer therapy,it is a predictive marker of the effectiveness of methylating anticancer drugs,and clinical trials are underway analyzing the influence of MGMT inhibition on the therapeutic success. Other DNA repair factors involved in methylating drug resistance are mismatch repair,DNA double-strand break (DSB) repair by homologous recombination and DSB signaling. Base excision repair and alkB homologous proteins (such as ABH2) might also contribute to alkylating drug resistance notably in cells expressing a high amount of MGMT. Better understanding of these mechanisms will be helpful in designing more effective therapies that have less adverse outcomes.