Does increase in DNA repair allow "Tolerance‐to‐Insult" in chemical carcinogenesis? Skin tumor experiments with MGMT‐overexpressing mice. (1st December 2013) - Becker, Klaus
Abstract Several genotoxicity endpoints have been evaluated to define nonlinear dose‐responses for SN1 and SN2 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 O6‐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 O6‐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. Environ. Mol. Mutagen. 55:145–150, 2014. © 2013 Wiley Periodicals, Inc.