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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6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O-甲基鸟嘌呤-DNA甲基转移酶(MGMT)直接逆转6 6DNA损伤,形成O-甲基鸟嘌呤和O-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alk B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。
In methylation antitumor drug therapy, DNA repair is a key mechanism that determines the effects of treatment and adverse biological effects such as mutation, carcinogenesis and teratogenicity. This article reviews the role of methylated antitumor drugs in DNA repair. Although these antitumor drugs selectively target DNA that acts on cancer cells and normal cells, they kill more cancer cells by impairing certain specific DNA repair activities in cancer cells. Monofunctional alkylating agents exhibit methylation-changing properties (procarbazine, dacarbazine, streptozotocin, temozolomide) or are chloroethylated to form a monoadduct and cause a DNA strand within the next reaction Cross-linking (lomustine, nimodipine 6, carmustine, fotemustine). One of the major mechanisms by which cancer cells counteract antineoplastic drugs is the direct reversal of 6 6 DNA damage by the suicide enzyme O-methylguanine-DNA methyltransferase (MGMT), forming O-methylguanine and O-chlorinated guanine. Because MGMT has a significant effect on the outcome of cancer treatment, it is considered as an important marker of resistance, especially in advanced glioblastomas. MGMT is also considered a predictive marker of the effectiveness of methylated antitumor drugs and many clinical trials are analyzing the effect of MGMT inhibition on the efficacy of the treatment. Other DNA repair factors involved in drug resistance to methylated antitumor drugs include mismatch repair, related repair initiated by homologous recombination and DNA double strand break (DSB) signaling. Base excision repair and alk B homologous protein (such as ABH2) may also be related to alkylating drug resistance, the phenomenon of cell lines highly expressed MGMT abnormal obvious. A better understanding of these mechanisms will help design more effective treatment options with fewer side effects.