Hengstler J G, Tanner B, Möller L, Meinert R, Kaina B
Institute of Toxicology, University of Mainz, Mainz, Germany.
Int J Cancer. 1999 Aug 20;84(4):388-95. doi: 10.1002/(sici)1097-0215(19990820)84:4<388::aid-ijc10>3.0.co;2-3.
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.
DNA修复蛋白O(6)-甲基鸟嘌呤-DNA甲基转移酶（烷基转移酶；MGMT）是细胞对各种烷化剂类细胞抑制药物耐药性的主要决定因素。其在组织中的表达高度可变，表明涉及复杂的调控机制。体外实验表明，转染介导的野生型p53表达可负向调节MGMT的基础启动子活性。为阐明p53是否参与肿瘤组织中MGMT的调控，我们检测了140例原发性卵巢癌的MGMT表达及p53状态，并分析了MGMT与p53之间的相关性数据，以及化疗后患者的生存反应。我们发现，卵巢癌中MGMT表达高度可变，范围从零水平到2500 fmol/mg蛋白。野生型p53（p53wt）肿瘤中的MGMT活性显著低于突变型p53（p53mt）肿瘤（p = 0.045）。正如预期的那样，p53mt肿瘤的百分比随肿瘤组织学分级的增加而增加。因此，在1级、2级和3级肿瘤中，分别有4%、45%和64%观察到p53mt（p = 0.001）。p53mt的增加伴随着MGMT活性的增加，在1级、2级和3级肿瘤中，MGMT活性平均分别为460±66、624±63和662±60 fmol/mg蛋白（p = 0.047）。此外，MGMT活性以及p53mt与肿瘤的国际妇产科联盟（FIGO）分期相关。FIGO I期和II期患者的平均MGMT活性为472±48 fmol/mg，而FIGO III期和IV期患者为675±50 fmol/mg（p = 0.0179）。在FIGO I/II期和FIGO III/IV期的卵巢肿瘤中，p53mt的百分比分别为27%和54%（p = 0.004）。因此，卵巢肿瘤的进展显然与MGMT活性增加和p53mt百分比增加相关。在低MGMT表达（<100 fmol/mg）的肿瘤中，很少发现p53mt。未观察到卵巢癌中MGMT水平与接受环磷酰胺和卡铂治疗患者的生存之间存在显著关联。另一方面，发现组织学类型、分级、残留肿瘤大小和p53wt表达与患者生存持续时间之间存在明显相关性。原发性卵巢癌中p53wt表达与低MGMT水平相关这一发现支持了这样一种观点，即p53wt对基础MGMT启动子活性的下调在体内肿瘤细胞中也具有相关性。《国际癌症杂志（肿瘤预测）》84:388 - 395，1999年。
