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.

journal_name

Environ Mol Mutagen

authors

Becker K,Thomas AD,Kaina B

doi

10.1002/em.21834

subject

Has Abstract

pub_date

2014-03-01 00:00:00

pages

145-50

issue

2

eissn

0893-6692

issn

1098-2280

journal_volume

55

pub_type

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