O6-methylguanine-DNA methyltransferase activity in breast and brain tumors.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a main determinant of resistance of tumor cells to the cytostatic activity of chemotherapeutic alkylating agents (methylating and chloroethylating nitrosoureas) and is effective in protecting normal cells against genotoxic and carcinogenic effects resulting from DNA alkylation. Therefore, the level of expression of MGMT is significance for the response of both the tumor and the non-target tissue following application of nitrosoureas in tumor therapy. To determine the expression of MGMT in tumor tissue, we have assayed MGMT activity in 68 breast carcinomas and 38 brain tumors. There was a wide variation of MGMT expression in breast carcinomas ranging from below the level of detection up to 863 fmol/mg protein. About 4% of breast tumors did not display detectable MGMT, 15% had activity lower than 100 fmol/mg protein, and 26% expressed more than 500 fmol/mg. The mean level of expression was 321 fmol/mg. In brain tumors (astrocytoma WHO grade I, II, and III, and glioblastoma WHO grade IV) the MGMT activity was generally lower than in breast tumors, ranging from below the level of detection up to 238 fmol/mg. The mean level of expression was 55 fmol/mg. Five percent of the brain tumors had no detectable MGMT activity. The MGMT repair activity correlated well with the amount of MGMT protein present in tumor samples, as shown by Western-blot analysis, indicating that loss of MGMT repair activity is due to inability of these tumor cells to synthesize the protein.