DNA repair protein MGMT protects against N-methyl-N-nitrosourea-induced conversion of benign into malignant tumors.

Abstract

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 O(6)-methylguanine-DNA methyltransferase (MGMT) protects against N-methyl-N-nitrosourea (MNU)-induced tumor initiation without affecting tumor promotion. This indicated that O(6)-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 O(6)-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.

• Authors: Klaus Becker, Cornelia Gregel, Christa Fricke, Dymitr Komitowski, Jörg Dosch, Bernd Kaina
• Journal: Carcinogenesis (Carcinogenesis) Vol. 24 Issue 3 Pg. 541-6 (Mar 2003) ISSN: 0143-3334 [Print] England
• PMID: 12663516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Methylnitrosourea
• O(6)-Methylguanine-DNA Methyltransferase

Topics

• Animals
• Carcinogens (toxicity)
• DNA Repair
• Methylnitrosourea (toxicity)
• Mice
• Mice, Transgenic
• O(6)-Methylguanine-DNA Methyltransferase (metabolism)
• Papilloma (genetics, pathology)
• Skin Neoplasms (genetics, pathology)