title: The DNA repair protein O6-methylguanine-DNA methyltransferase protects against skin tumor formation induced by antineoplastic chloroethylnitrosourea.
abstract: 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.
authors.affiliation: DNA Repair Group, Institute of Plant Genetics and Crop Plant Research, Gatersleben, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Becker
authors.forename: C M
authors.initials: CM
authors.lastname: Gregel
authors.forename: B
authors.initials: B
authors.lastname: Kaina
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D004252:DNA Mutational Analysis; D011905:Genes, ras / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008780:Methyltransferases / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D015376:Nimustine / Q000009:adverse effects*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D017354:Point Mutation; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate
chemical_list: D018906:Antineoplastic Agents, Alkylating; D015376:Nimustine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013755:Tetradecanoylphorbol Acetate