Activity of O(6)-methylguanine-DNA methyltransferase in relation to p53 status and therapeutic response in ovarian cancer
| Autor: | Rolf Meinert, Jan G. Hengstler, Berno Tanner, Bernd Kaina, Lars Möller |
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| Rok vydání: | 1999 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Methyltransferase Time Factors Cyclophosphamide medicine.medical_treatment Biology Disease-Free Survival chemistry.chemical_compound O(6)-Methylguanine-DNA Methyltransferase Predictive Value of Tests medicine Humans neoplasms Neoplasm Staging Retrospective Studies Ovarian Neoplasms Chemotherapy L-Lactate Dehydrogenase Cancer medicine.disease Genes p53 Immunohistochemistry Survival Analysis digestive system diseases Nitrogen mustard Carboplatin Oncology chemistry Cancer research Female Tumor Suppressor Protein p53 Ovarian cancer medicine.drug Alkyltransferase Follow-Up Studies |
| Zdroj: | International journal of cancer. 84(4) |
| ISSN: | 0020-7136 |
| Popis: | 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 ( |
| Databáze: | OpenAIRE |
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