title: Does increase in DNA repair allow "tolerance-to-insult" in chemical carcinogenesis? Skin tumor experiments with MGMT-overexpressing mice.
abstract: Several genotoxicity endpoints have been evaluated to define nonlinear dose-responses for SN 1 and SN 2 alkylating genotoxicants. Dose-response studies acknowledging the process of multistage tumorigenesis are important; however, data pertaining nonlinearity are not yet available. In this communication, the role of DNA repair in the dose-response relationship for benign papillomas was examined using the two-stage skin carcinogenesis protocol. The data obtained with O(6) -methylguanine-DNA methyltransferase (MGMT) overexpressing mice in which papillomas were induced by a single topical treatment with N-methyl-N-nitrosourea (MNU) followed by promotion with 12-O-tetradecanoylphorbol-13-acetate are reported. As MGMT efficiently protects cells from mutations by repairing O(6) -methylguanine, a miscoding lesion induced by MNU, the question whether MGMT is able to nullify carcinogenic lesions to an extent where they would be considered nonhazardous has been addressed. It is shown here that MGMT overexpression significantly protects against, but does not completely nullify, the effect of MNU in tumor initiation. The possible mechanisms involved have also been discussed.
authors: Institute of Plant Genetics and Crop Plant Research, Gatersleben, Germany.
authors: Klaus
authors: K
authors: Becker
authors: Adam D
authors: AD
authors: Thomas
authors: Bernd
authors: B
authors: Kaina
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000235:genetics; D015254:DNA Modification Methylases / Q000096:biosynthesis / Q000235:genetics*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics*; D060467:Disease Resistance / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008770:Methylnitrosourea; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; D008770:Methylnitrosourea; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D013755:Tetradecanoylphorbol Acetate
keywords: MGMT; alkyltransferase; dose-response; methylnitrosourea; threshold in carcinogenesis