Murakami Jun, Lee You-Jin, Kokeguchi Susumu, Tsujigiwa Hidetsugu, Asaumi Jun-Ichi, Nagatsuka Hitoshi, Fukui Kazuhiro, Kuroda Masahiro, Tanaka Noriaki, Matsubara Nagahide
Department of Oral and Maxillofacial Radiology, Field of Tumor Biology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Oncol Rep. 2007 Jun;17(6):1461-7.
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose expression is controlled by its promoter methylation. A cell that expresses a low amount of MGMT is known to be more sensitive to the antiproliferative effects of alkylating agents. We have previously shown that the colorectal cancer patients treated with 5-fluorouracil (5-FU) as adjuvant chemotherapy had a better prognosis when the tumor revealed hypermethylation in its MGMT promoter. Therefore, we sought to investigate the relationship between the expression levels of MGMT and the anti-tumor effect of 5-FU in vitro by using two colon adenocarcinoma and four oral cancer cell lines with a variety of MGMT expression. We also investigated the effects of MGMT depletion by O6-benzylguanine (O6-BG), a potent inhibitor of MGMT. The 5-FU treatment uniformly depleted protein and mRNA expression of MGMT in all cell lines examined. Cell lines expressing low levels of MGMT were sensitive to 5-FU. On the other hand, cells expressing high levels of MGMT were less sensitive to 5-FU. The 5-FU treatment exhibited a better antiproliferative effect on the cells expressing high levels of MGMT by the pretreatment of O6-BG. Depletion of MGMT by O6-BG enhanced the anti-tumor effect of 5-FU. Assessment of the levels of MGMT expression in cancer cells and the control of its expression could contribute to the effective chemotherapy by 5-FU especially in patients who previously were considered as low-responsive individuals whose tumors have high levels of MGMT.
O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）是一种DNA修复酶，其表达受启动子甲基化调控。已知表达低水平MGMT的细胞对烷化剂的抗增殖作用更敏感。我们之前已经表明，接受5-氟尿嘧啶（5-FU）辅助化疗的结直肠癌患者，当肿瘤的MGMT启动子呈现高甲基化时，预后较好。因此，我们试图通过使用两种具有不同MGMT表达水平的结肠腺癌和四种口腔癌细胞系，来研究体外MGMT表达水平与5-FU抗肿瘤作用之间的关系。我们还研究了MGMT的强效抑制剂O6-苄基鸟嘌呤（O6-BG）对MGMT的耗竭作用。5-FU处理均使所有检测细胞系中的MGMT蛋白和mRNA表达降低。表达低水平MGMT的细胞系对5-FU敏感。另一方面，表达高水平MGMT的细胞对5-FU不太敏感。通过O6-BG预处理，5-FU处理对表达高水平MGMT的细胞表现出更好的抗增殖作用。O6-BG对MGMT的耗竭增强了5-FU的抗肿瘤作用。评估癌细胞中MGMT的表达水平并对其表达进行调控，可能有助于5-FU的有效化疗，特别是对于那些之前被认为是低反应个体且其肿瘤具有高水平MGMT的患者。
