Harris L C, Remack J S, Houghton P J, Brent T P
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101-0318, USA.
Cancer Res. 1996 May 1;56(9):2029-32.
High-level expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) correlates with cellular resistance to the chloroethylnitrosourea (CENU) class of alkylating agents. Consequently, tumors expressing low levels of MGMT are sensitive to CENU chemotherapy, and any mechanism that can be used to reduce MGMT levels could sensitize resistant tumors. We have demonstrated that transient transfection of wild-type, but not mutant, p53 protein into a p53-null cell line, Saos-2, suppresses MGMT promoter activity in a reporter gene system. In addition, following a 24-h transduction of IMR90 fibroblasts with a wild-type p53-adenoviral vector, endogenous MGMT protein is down-regulated and is no longer detectable 5 days following infection. Because p53 is inducible by ionizing radiation, we propose that existing cancer therapy regimens that combine radiotherapy with CENU chemotherapy may be improved by altering scheduling and allowing enough time between the two therapies for the relatively stable MGMT protein to degrade.
DNA修复蛋白O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）的高水平表达与细胞对氯乙基亚硝脲（CENU）类烷化剂的抗性相关。因此，低水平表达MGMT的肿瘤对CENU化疗敏感，任何可用于降低MGMT水平的机制都可使耐药肿瘤敏感化。我们已经证明，将野生型而非突变型p53蛋白瞬时转染到p53缺失的细胞系Saos-2中，在报告基因系统中可抑制MGMT启动子活性。此外，用野生型p53腺病毒载体对IMR90成纤维细胞进行24小时转导后，内源性MGMT蛋白被下调，感染后5天不再可检测到。由于p53可被电离辐射诱导，我们提出，通过改变治疗方案并在两种治疗之间留出足够时间以使相对稳定的MGMT蛋白降解，现有的将放疗与CENU化疗相结合的癌症治疗方案可能会得到改善。
