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Does increase in DNA repair allow "Tolerance-to-Insult" in chemical carcinogenesis? Skin tumor experiments with MGMT-overexpressing mice

Becker, Klaus; Thomas, Adam D.; Kaina, Bernd

Authors

Klaus Becker

Adam Thomas Adam7.Thomas@uwe.ac.uk
Senior Lecturer in Human Genetics and Genomics

Bernd Kaina



Abstract

Several genotoxicity endpoints have been evaluated to define nonlinear dose-responses for S N 1 and S N 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. Environ. Mol. Mutagen. 55:145-150, 2014. © 2013 Wiley Periodicals, Inc.

Citation

Becker, K., Thomas, A. D., & Kaina, B. (2014). Does increase in DNA repair allow "Tolerance-to-Insult" in chemical carcinogenesis? Skin tumor experiments with MGMT-overexpressing mice. Environmental and Molecular Mutagenesis, 55(2), 145-150. https://doi.org/10.1002/em.21834

Journal Article Type Article
Acceptance Date Sep 5, 2013
Online Publication Date Dec 1, 2013
Publication Date Mar 1, 2014
Journal Environmental and Molecular Mutagenesis
Print ISSN 0893-6692
Electronic ISSN 1098-2280
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 55
Issue 2
Pages 145-150
DOI https://doi.org/10.1002/em.21834
Public URL https://uwe-repository.worktribe.com/output/933411
Publisher URL https://doi.org/10.1002/em.21834