DNA repair protein MGMT protects against N-methyl-N-nitrosourea-induced conversion of benign into malignant tumors.
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.
Becker
Klaus
K
DNA Repair Group, Institute of Plant Genetics, Corrensstrasse 3, D-06466 Gatersleben, Germany.
Gregel
Cornelia
C
Fricke
Christa
C
Komitowski
Dymitr
D
Dosch
Jörg
J
Kaina
Bernd
B
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004260:DNA Repair; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D010212:Papilloma / Q000235:genetics / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*
D002273:Carcinogens; D008770:Methylnitrosourea; D019853:O(6)-Methylguanine-DNA Methyltransferase