Role of Postreplicative DNA Mismatch Repair in the Cytotoxic Action of Thioguanine

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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 S 6 -methylthioguanine. During DNA replication, the S 6 -methylthioguanine directs incorporation of either thymine or cytosine into the growing DNA strand, and the resultant S 6 -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 O 6 -alkylguanine in DNA, the formation of the analog S 6 -methylthioguanine during azathioprine treatment may partly explain the high incidence of cancer after transplantation.