Activity of O(6)-methylguanine-DNA methyltransferase in relation to p53 status and therapeutic response in ovarian cancer.
The DNA-repair protein O(6)-methylguanine-DNA methyltransferase (alkyltransferase; MGMT) is a major determinant of resistance of cells to various alkylating cytostatic drugs. Its expression in tissues is highly variable, indicating complex regulatory mechanisms involved. Transfection-mediated expression of wild-type p53 has been shown to negatively regulate basal promoter activity of MGMT in vitro. To elucidate whether p53 is involved in regulation of MGMT in tumor tissue, we examined MGMT expression and the p53 status of 140 primary ovarian carcinomas and analyzed the data as to the correlation between MGMT and p53, as well as the survival response of the patients after chemotherapy. We show that MGMT expression is highly variable in ovarian carcinomas, ranging from zero level up to 2500 fmol/mg protein. MGMT activity was significantly lower in tumors with wild-type p53 (p53wt) than in tumors with mutant p53 (p53mt) (p = 0.045). As expected, the percentage of tumors with p53mt increased with increasing histologic grade of the tumors. Thus, p53mt was observed in 4, 45 and 64% of grades 1, 2 and 3 tumors, respectively (p = 0.001). Increase in p53mt was accompanied by an increase in MGMT activity, which was, on average, 460 +/- 66, 624 +/- 63 and 662 +/- 60 fmol/mg protein in grades 1, 2 and 3 tumors, respectively (p = 0.047). In addition, MGMT activity as well as p53mt were associated with the FIGO stage of the tumors. Mean MGMT activity was 472 +/- 48 fmol/mg for patients with FIGO stages I and II, as compared with 675 +/- 50 fmol/mg for patients with FIGO stages III and IV, (p = 0.0179). The percentage of p53mt was 27% and 54% in ovarian tumors with FIGO stages I/II and FIGO stages III/IV, respectively (p = 0.004). Thus, progression of ovarian tumors was clearly associated with increase of both MGMT activity and the percentage of p53mt. In tumors expressing low MGMT (<100 fmol/mg), p53mt was very rarely found. No significant association was observed between MGMT level in ovarian carcinomas and the survival of patients treated with cyclophosphamide and carboplatin. On the other hand, a clear correlation was found between histological type, grading, residual tumor mass and p53wt expression and duration of the patient's survival. The finding that p53wt expression was associated with low MGMT level in primary ovarian cancer supports the view that down-regulation of basal MGMT promoter activity by p53wt is also relevant in tumor cells in vivo. Int. J. Cancer (Pred. Oncol.) 84:388-395, 1999.
Institute of Toxicology, University of Mainz, Mainz, Germany.
J G
JG
Hengstler
B
B
Tanner
L
L
Möller
R
R
Meinert
B
B
Kaina
D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D016158:Genes, p53; D006801:Humans; D007150:Immunohistochemistry; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D009367:Neoplasm Staging; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000032:analysis / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology* / Q000601:surgery*; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D016159:Tumor Suppressor Protein p53; D007770:L-Lactate Dehydrogenase; D019853:O(6)-Methylguanine-DNA Methyltransferase