Swann P F, Waters T R, Moulton D C, Xu Y Z, Zheng Q, Edwards M, Mace R
Cancer Research Campaign Nitrosamine-Induced Cancer Group, Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, UK.
Science. 1996 Aug 23;273(5278):1109-11. doi: 10.1126/science.273.5278.1109.
It is proposed here that the delayed cytotoxicity of thioguanine involves the postreplicative DNA mismatch repair system. After incorporation into DNA, the thioguanine is chemically methylated by S-adenosylmethionine to form S6-methylthioguanine. During DNA replication, the S6-methylthioguanine directs incorporation of either thymine or cytosine into the growing DNA strand, and the resultant S6-methylthioguanine-thymine pairs are recognized by the postreplicative mismatch repair system. Azathioprine, an immunosuppressant used in organ transplantation, is partly converted to thioguanine. Because the carcinogenicity of N-nitrosamines depends on formation of O6-alkylguanine in DNA, the formation of the analog S6-methylthioguanine during azathioprine treatment may partly explain the high incidence of cancer after transplantation.
本文提出，硫鸟嘌呤的延迟细胞毒性涉及复制后DNA错配修复系统。硫鸟嘌呤掺入DNA后，会被S-腺苷甲硫氨酸化学甲基化形成S6-甲基硫鸟嘌呤。在DNA复制过程中，S6-甲基硫鸟嘌呤会引导胸腺嘧啶或胞嘧啶掺入正在生长的DNA链中，由此产生的S6-甲基硫鸟嘌呤-胸腺嘧啶碱基对会被复制后错配修复系统识别。硫唑嘌呤是一种用于器官移植的免疫抑制剂，部分会转化为硫鸟嘌呤。由于N-亚硝胺的致癌性取决于DNA中O6-烷基鸟嘌呤的形成，因此在硫唑嘌呤治疗过程中形成类似物S6-甲基硫鸟嘌呤可能部分解释了移植后癌症的高发病率。
