Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine
Mechanisms of carcinogenicity/chemotherapy by O6-methylguanine
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DOI：
10.1093/mutage/17.6.483
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发表时间：
2002-11-01
期刊：
影响因子：
2.7
通讯作者：
Povey, AC
中科院分区：
文献类型：
--
作者：
Margison, GP;Koref, MFS;Povey, AC
烷基化剂是一组结构多样的化合物，可引起广泛的生物效应，包括细胞死亡、突变和癌症。被这些试剂破坏的DNA含有12种烷基化嘌呤/嘧啶和两种磷酸三酯异构体。生物效应似乎主要是通过攻击鸟嘌呤的O-6位点介导的。从各种正常人体组织中提取的DNA含有可检测水平的o -6-烷基鸟嘌呤，其来源尚未确定。鉴于，在DNA复制之后，这种病变不仅产生点突变，而且还可以启动错配修复介导的DNA重组和细胞死亡，似乎值得考虑这些事件和细胞杀伤对人类癌症病因学的可能贡献。越来越多的证据表明，点突变并不是烷基化剂恶性转化的唯一机制。一些癌症化疗药物利用了o -6-烷基鸟嘌呤的细胞毒性作用，对这种病变过程的理解使人们能够开发出提高这些药物有效性的策略。
Alkylating agents are a structurally diverse group of compounds that cause a wide range of biological effects, including cell death, mutation and cancer. DNA damaged by these agents contains widely different amounts of 12 alkylated purines/pyrimidines and two phosphotriester isomers. The biological effects appear to be mediated predominantly by attack at the O-6 position of guanine. DNA extracted from various normal human tissues contains detectable levels of O-6-alkylguanine, the source of which has not been defined. Given that, following DNA replication, this lesion cannot only generate point mutations but can also initiate mismatch repair-mediated DNA recombination and cell death, it seems worthwhile to consider the possible contribution of these events and cell killing to the aetiology of human cancer. There is increasing evidence that point mutations are not the only mechanism involved in malignant transformation by alkylating agents. Some cancer chemotherapeutic agents exploit the cytotoxic effects of O-6-alkylguanine and an understanding of the processing of this lesion has allowed strategies to be developed that should increase the effectiveness of such agents.