Strategy for Selective Brain Tumor Chemotherapy Involved in O^6-Methylguanine-DNA Methyltransferase

耐药一直是氯乙基亚硝脲(CENUS)治疗高级别胶质瘤临床失败的主要问题。O^6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)通过接受CENU形成的致死加合物，在细胞对CENU的抗性中起关键作用。根据MGMT的活性，中心应仅限于敏感的胶质瘤。利用MGMT的底物O^6-烷基鸟嘌呤类化合物灭活MGMT活性是克服MGMT相关耐药的另一种策略。高级别胶质瘤MGMT基因表达水平显著低于低级别胶质瘤和非胶质瘤(P&lt；0.05)。在接受CENU化疗的11名患者中，有3名有部分反应。所有三名应答者的mgmtmRNA水平都很低。低于中位数的6名患者的肿瘤进展时间很短，但有显著意义…被测试为MGMT失活剂的O^6-烷基鸟嘌呤衍生物是O^6-(4-，3-和2-氟苯基)鸟嘌呤，O^6-(4，3-和2-三氟甲基)鸟嘌呤，和O^6-(4-，3-和2-吡啶甲基)鸟嘌呤。其中，4位或3位加合物的化合物表现出较强的MGMT耗竭活性，而2位加合物的化合物表现出较低的MGMT耗竭活性。O^6-烷基鸟嘌呤的MGMT耗竭活性与其增强ACNU细胞毒活性之间存在良好的相关性(r=-0.856，p&lt；0.001)。结果表明，部分脑肿瘤MGMT基因低表达，MGMT基因表达水平可作为临床选择性化疗疗效的指标。O^6-烷基鸟嘌呤类化合物与MGMT相互作用导致MGMT失活的关键是苄基的位置。潜在的MGMT失活剂使肿瘤细胞对CENU化疗敏感。较少

Drug resistance has been a major problem in the clinical failure of chemotherapeutic chloroethylnitrosoureas (CENUs) for high-grade gliomas. O^6-Methylguanine-DNA methyltransferase (MGMT) plays a key role in cellular resistance to CENUs by accepting CENU-forming fatal adducts. CENUs should be limited to sensitive gliomas on the basis of MGMT activity. Inactivation of MGMT activity by exogenous O^6-alkylguanine derivatives, substrates of MGMT,is another strategy to overcome MGMT-related resistance.We measured the levels of MGMT mRNA expression in human brain tumors, and studied the significance of MGMT mRNA levels in CENU chemotherapy. High-grade gliomas had significantly lower levels of MGMT mRNA than did low-grade gliomas and non-glial tumors (P<0.05). Out of 11 patients who received CENU chemotherapy, three had a partial response. All three responders had a low level of MGMT mRNA.The time to tumor progression for six patients with a level lower than the median was small but significa … More ntly longer than that for five patients with a higher level (P<0.05).O^6-Alkylguanine derivatives tested as an MGMT inactivator were O^6- (4-, 3-, and 2-fluorobenzyl) guanines, O^6- (4,3-, and 2-trifluoromethylbenzyl) guanines, and O^6- (4-, 3-, and 2-pyridylmethyl) guanines. Among these, compounds with an adduct at 4- or 3-position showed a strong MGMT depletion activity, whereas compounds with an adduct at 2-position were inactive. There was a good relationship (r=-0.856, p<0.001) between the MGMT depletion activity of O^6-alkylguanines and their potentiation activity of cytotoxicity of ACNU,a CENU.These results indicate that a fraction of brain tumors have a low expression of MGMT mRNA,and that the level of MGMT mRNA is a useful indicator of effectiveness in selective CENU chemotherapy. The position of benzyl groups is important for the interaction of O^6-alkylguanine derivatives with MGMT to result in the inactivation of MGMT.Potent MGMT inactivators sensitize tumor cells to CENU chemotherapy. Less