title: Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine.
abstract: 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.
authors.affiliation: Cancer Research Campaign Nitrosamine-Induced Cancer Group, Department of Biochemistry and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: P F
authors.initials: PF
authors.lastname: Swann
authors.forename: T R
authors.initials: TR
authors.lastname: Waters
authors.forename: D C
authors.initials: DC
authors.lastname: Moulton
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Xu
authors.forename: Q
authors.initials: Q
authors.lastname: Zheng
authors.forename: M
authors.initials: M
authors.lastname: Edwards
authors.forename: R
authors.initials: R
authors.lastname: Mace
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001482:Base Composition; D001483:Base Sequence; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D004261:DNA Replication; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D012436:S-Adenosylmethionine / Q000378:metabolism; D013866:Thioguanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; C035366:6-methylthioguanine; D012436:S-Adenosylmethionine; D004247:DNA; D013866:Thioguanine