Journal Article

DNA repair protein MGMT protects against <i>N</i>-methyl-<i>N</i>-nitrosourea-induced conversion of benign into malignant tumors

Klaus Becker, Cornelia Gregel, Christa Fricke, Dymitr Komitowski, Jörg Dosch and Bernd Kaina

in Carcinogenesis

Volume 24, issue 3, pages 541-546
Published in print March 2003 | ISSN: 0143-3334
Published online March 2003 | e-ISSN: 1460-2180 | DOI:
DNA repair protein MGMT protects against N-methyl-N-nitrosourea-induced conversion of benign into malignant tumors

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Tumor formation is a multi-step process that can be divided into the stages of tumor initiation, promotion and progression. Previously, we showed that overexpression in skin of mice of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) protects against N-methyl-N-nitrosourea (MNU)-induced tumor initiation without affecting tumor promotion. This indicated that O6-methylguanine, which is specifically repaired by MGMT, is a major tumor-initiating lesion. Here we extended this transgenic approach to the study of tumor progression. Benign papillomas that arose on the skin of CkMGMT transgenic mice upon initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) expressed higher levels of MGMT than papillomas that appeared on DMBA/TPA treated non-transgenic NMRI mice. Treatment of papillomas with MNU resulted in the formation of malignant carcinomas to a significantly lower frequency in CkMGMT mice as compared with the non-transgenic control. The data provide evidence that increased DNA repair protects against the conversion of benign into malignant tumors. They show at the same time that a particular type of damage induced in DNA, namely O6-methylguanine, is decisively involved in triggering tumor progression. This supports the concept that the major cause of both tumor initiation and tumor progression is mutation. Data also indicate that alkylating anti-neoplastic drugs may provoke tumor progression in case of failure of tumor therapy, which is attenuated by DNA repair.

Keywords: DMBA, 7,12-dimethylbenz[a]anthracene; MGMT, O6-methylguanine-DNA methyltransferase; MNU, N-methyl-N-nitrosourea; SCC, squamous cell carcinomas; TPA, 12-O-tetradecanoylphorbol-13-acetate.

Journal Article.  4794 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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