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

耐药一直是化疗药物氯乙基亚硝基源（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）通过接受形成cenu的致命加合物在细胞对CENUs的抗性中起关键作用。基于MGMT活性，CENUs应局限于敏感胶质瘤。通过外源性O^6-烷基鸟嘌呤衍生物（MGMT的底物）使MGMT活性失活是克服MGMT相关抗性的另一种策略。我们检测了人脑肿瘤组织中MGMT mRNA的表达水平，并研究了MGMT mRNA水平在CENU化疗中的意义。恶性胶质瘤中MGMT mRNA水平明显低于恶性胶质瘤和非神经胶质瘤（P<0.05）。在接受CENU化疗的11例患者中，有3例有部分反应。三名应答者MGMT mRNA水平均较低。低于中位数的6例患者的肿瘤进展时间虽小，但显著高于中位数的5例患者（P<0.05）。作为MGMT灭活剂测试的O^6-烷基鸟嘌呤衍生物有O^6-（4-、3-和2-氟苯基）鸟嘌呤、O^6-（4-、3-和2-三氟甲基苄基）鸟嘌呤和O^6-（4-、3-和2-吡啶基甲基）鸟嘌呤。其中，在4位或3位加合物的化合物显示出很强的MGMT消耗活性，而在2位加合物的化合物则无活性。O^6-烷基鸟嘌呤的MGMT消耗活性与ACNU的细胞毒性增强活性之间存在良好的相关关系（r=-0.856, p<0.001）。这些结果表明，部分脑肿瘤具有MGMT mRNA的低表达，并且MGMT mRNA水平是选择性CENU化疗有效性的有用指标。苄基的位置对于O^6-烷基鸟嘌呤衍生物与MGMT相互作用导致MGMT失活很重要。有效的MGMT灭活剂使肿瘤细胞对CENU化疗敏感。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