The DNA repair protein O6-methylguanine-DNA methyltransferase protects against skin tumor formation induced by antineoplastic chloroethylnitrosourea.

Abstract

Chloroethylnitrosoureas (CNUs) are being used in the therapy of various neoplastic diseases, including skin cancer. Because secondary tumor formation is a serious threat in chemotherapy with these drugs, we explored whether and to what extent the DNA repair protein DNA-O6-methylguanine:protein-L-cysteine S-methyltransferase (MGMT) protects against CNU-induced tumors. We made use of transgenic mice overexpressing human MGMT in their skin and the initiation-promotion protocol on treatment with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine) that is representative of CNUs. ACNU applied topically as a single low dose to the dorsal skin was highly effective in tumor induction in nontransgenic mice, whereas in cytokeratin MGMT transgenic mice, tumor formation was remarkably reduced. ACNU-induced skin tumors harbored mutations in the c-Ha-ras gene in both groups of mice. The results provide clear evidence that MGMT exerts protection against CNU-induced cancer. Our data also indicate that O6-chloroethylguanine, which is repaired by MGMT, is a main precarcinogenic CNU-induced DNA lesion.

• Authors: K Becker, C M Gregel, B Kaina
• Journal: Cancer research (Cancer Res) Vol. 57 Issue 16 Pg. 3335-8 (Aug 15 1997) ISSN: 0008-5472 [Print] United States
• PMID: 9269990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Nimustine
• Methyltransferases
• O(6)-Methylguanine-DNA Methyltransferase
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Antineoplastic Agents, Alkylating (adverse effects)
• DNA Mutational Analysis
• Genes, ras (drug effects, genetics)
• Humans
• Methyltransferases (physiology)
• Mice
• Mice, Transgenic
• Neoplasms, Experimental (chemically induced, enzymology, genetics, prevention & control)
• Nimustine (adverse effects)
• O(6)-Methylguanine-DNA Methyltransferase
• Papilloma (chemically induced, enzymology, genetics, prevention & control)
• Point Mutation
• Skin Neoplasms (chemically induced, enzymology, genetics, prevention & control)
• Tetradecanoylphorbol Acetate