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The DNA Repair Protein O⁶-Methylguanine-DNA Methyltransferase Protects against Skin Tumor Formation Induced by Antineoplastic Chloroethylnitrosourea¹

DNA Repair Group, Institute of Plant Genetics and Crop Plant Research, D-06466 Gatersleben [K. B., C. M. G.], and Division of Applied Toxicology, Institute of Toxicology, Medical Faculty, University of Mainz, D-55131 Mainz [B. K.], Germany

Chloroethylnitrosoureas (CNUs) are being used in the therapy of various neoplastic diseases, including skin cancer. Because secondary tumor formation is a serious threat in chemotherapy with these drugs, we explored whether and to what extent the DNA repair protein DNA-O⁶-methylguanine:protein-L-cysteine S-methyltransferase (MGMT) protects against CNU-induced tumors. We made use of transgenic mice overexpressing human MGMT in their skin and the initiation-promotion protocol on treatment with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine) that is representative of CNUs. ACNU applied topically as a single low dose to the dorsal skin was highly effective in tumor induction in nontransgenic mice, whereas in cytokeratin MGMT transgenic mice, tumor formation was remarkably reduced. ACNU-induced skin tumors harbored mutations in the c-Ha-ras gene in both groups of mice. The results provide clear evidence that MGMT exerts protection against CNU-induced cancer. Our data also indicate that O⁶-chloroethylguanine, which is repaired by MGMT, is a main precarcinogenic CNU-induced DNA lesion.

¹ Supported by Research Grants Be 1484/1-2 (to K. B.) and Ka 724/4-2 (to B. K.) from the Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed, at DNA Repair Group, Institute of Plant Genetics and Crop Plant Research, Corrensstr. 3, D-06466 Gatersleben, Germany.

Received 4/23/97. Accepted 7/ 1/97.

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