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

O^6-甲基鸟嘌呤-DNA甲基转移酶参与的选择性脑肿瘤化疗策略

基本信息

批准号：
07457304
负责人：
MINEURA Katsuyoshi
金额：
$ 4.03万
依托单位：
Akita University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457304/
关键词：
Brain tumor Chemotherapy Chloroethylnitrosourea DNA repair enzyme mRNA PCR Enzyme inhibitor

项目摘要

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

耐药性一直是氯乙基亚硝基脲（CENU）化疗治疗高级别胶质瘤临床失败的一个主要问题。 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 CENU 的抵抗中发挥关键作用。根据 MGMT 活性，CENU 应仅限于敏感神经胶质瘤。通过外源性MGMT底物O^6-烷基鸟嘌呤衍生物灭活MGMT活性是克服MGMT相关耐药性的另一种策略。我们测量了人脑肿瘤中MGMT mRNA的表达水平，并研究了MGMT mRNA水平在CENU化疗中的意义。高级别胶质瘤的MGMT mRNA水平显着低于低级别胶质瘤和非胶质瘤（P<0.05）。在接受 CENU 化疗的 11 名患者中，有 3 名患者出现部分缓解。所有三名应答者的 MGMT mRNA 水平均较低。六名水平低于中位数的患者的肿瘤进展时间虽小，但明显长于五名水平较高的患者 (P<0.05)。作为 MGMT 灭活剂测试的 O^6-烷基鸟嘌呤衍生物为 O^6-（4-、3-和 2-氟苄基）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，4位或3位加合物的化合物表现出强的MGMT消耗活性，而2位加合物的化合物则无活性。 O^6-烷基鸟嘌呤的MGMT消耗活性与其对ACNU（CENU）的细胞毒性增强活性之间存在良好的相关性（r=-0.856，p<0.001）。这些结果表明，部分脑肿瘤具有低表达的MGMT mRNA，并且MGMT mRNA的水平是选择性CENU有效性的有用指标。化疗。苄基的位置对于 O^6-烷基鸟嘌呤衍生物与 MGMT 相互作用从而导致 MGMT 失活非常重要。有效的 MGMT 失活剂使肿瘤细胞对 CENU 化疗敏感。较少的