Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT)
Acquired resistance to 6-thioguanine in melanoma cells involves the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT)
复制标题
DOI：
10.4161/cbt.9.1.10285
复制
发表时间：
2010-01-01
影响因子：
3.6
通讯作者：
Gopas, Jacob
中科院分区：
文献类型：
--
作者：
Gefen, Nir;Brkic, Gordana;Gopas, Jacob
O-6-甲基鸟嘌呤-DNa甲基转移酶（MGMT）是一种识别O-6-烷基化鸟嘌呤的DNa修复酶，O-6-烷基化鸟嘌呤是一种用烷化剂处理产生的碱基类似物。O-6-6-硫代鸟嘌呤（6-TG）在临床上用于治疗恶性疾病以及炎性疾病。尽管MGMT参与了对烷化剂的抗性，但尚未显示其参与肿瘤对6-TG的抗性。在这项研究中，我们使用了人类黑色素瘤细胞系（Ga）和其选定的6-TG耐药变异（Ga-6-TG），以调查是否MGMT发挥作用，在确定Ga-6-TG细胞的耐药表型。我们发现Ga-6-TG抗性细胞表达的MGMT蛋白和mRNa比Ga细胞多约三倍。用6-TG处理后，两种细胞系中MGMT的量均显著减少，耐药细胞中MGMT的量增加与MGMT基因编码区的高甲基化一致。用MGMT抑制剂O-6苄基鸟嘌呤预处理细胞，导致Ga-6-TG细胞对6-TG的敏化。总之，我们的数据表明MGMT与6-TG耐药相关。与用烷化剂治疗的患者类似，具有含有增加的MGMT量的肿瘤的患者可能对6-TG更具抗性，因此可能受益于用MGMT抑制剂治疗。
O-6-methyguanine-DNa methyltransferase (MGMT), is a DNa repair enzyme that recognizes O-6-alkylated guanine, a base analog resulting from treatment with alkylating agents. O-6-6-thioguanine (6-TG) is used clinically to treat malignant as well as inflammatory diseases. although MGMT participates in resistance to alkylating agents, it has not been shown to be involved in resistance of tumors to 6-TG. In this study we used a human melanoma cell line (Ga) and its selected 6-TG drug resistant variant (Ga-6-TG) to investigate whether MGMT plays a role in determining the drug resistant phenotype of Ga-6-TG cells. We showed that Ga-6-TG resistant cells express about three fold more MGMT protein and mRNa than Ga cells. Treatment with 6-TG diminishes significantly MGMT amounts in both cell lines.Increased amounts of MGMT in resistant cells, are consistent with hypermethylation of the MGMT gene coding-region. pretreatment of cells with the MGMT inhibitor O-6 benzyl guanine, resulted in sensitization of Ga-6-TG cells to 6-TG. Taken together, our data suggests that MGMT is associated with 6-TG drug resistance. In analogy to patients treated with alkylating agents, patients with tumors containing increased MGMT amounts, may be more resistant to 6-TG and therefore may benefit from treatment with MGMT inhibitors.