PHASE I TRIAL OF O6-BENZYLGUANINE PLUS BCNU IN GLIOMA

描述：恶性人脑胶质瘤构成了一组高度致命的 肿瘤。氯乙基亚硝脲(CENUS)对 成人神经胶质瘤的治疗。它们通过烷基产生细胞毒性 DNA鸟嘌呤残基的取代，随后形成DNA 链内交叉连接。可以从O6中除去烷基 DNA修复蛋白O6-烷基鸟嘌呤-DNA烷基转移酶的定位 (Agat)，恢复完整的鸟嘌呤。阻力和 对亚硝脲和甲基化药物的敏感性，如 Proarbazine可由该蛋白介导，该蛋白在 到目前为止研究的大多数肿瘤，包括那些发生在 中枢神经系统。AGAT耗竭的观察 烷基鸟嘌呤或甲基化试剂使细胞对细胞毒敏感 Cenus的行为为组合词的使用提供了机会 旨在恢复对耐药肿瘤细胞的敏感性的疗法 头孢卡莫司汀(BCNU)。最近的研究表明， 髓母细胞瘤和胶质母细胞瘤中亚硝脲活性的研究 异种皮下和脑内生长的多形性移植 O6-苄基鸟嘌呤介导的AGAT耗竭裸鼠模型。这个 本项目的假设是：1)高级别胶质瘤AGAT水平 和细胞分布决定了对亚硝脲的反应和 2)O6-苄基鸟嘌呤对AGAT活性的抑制作用可逆转 无不可接受的高级别胶质瘤对亚硝脲的耐药性 毒性增加。该项目的具体目标是：1) 确定O6-苄基鸟嘌呤和BCNU的最佳组合剂量 在治疗复发间变性患者中的作用 星形细胞瘤或多形性胶质母细胞瘤和2)定义活动性 O6-苄基鸟嘌呤与BCNU联合应用的疗效观察 复发性间变性星形细胞瘤或胶质母细胞瘤患者 多种多样的。

DESCRIPTION: Malignant human gliomas constitute a group of highly lethal neoplasms. Chloroethylnitrosoureas (CENUs) are moderately effective in the treatment of gliomas in adults. They produce cytotoxicity by alkyl substitution of DNA guanine residues, with subsequent formation of DNA intrastrand cross-links. The alkyl group can be removed from the O6 position by a DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGAT), with restoration of an intact guanine. Resistance and susceptibility to nitrosoureas and methylating agents such as procarbazine can be mediated by this protein, which is expressed in the majority of tumors studied to date, including those arising in the central nervous system. The observation that depletion of AGAT with alkylguanines or methylating agents sensitizes cells to the cytotoxic action of CENUs provides the opportunity for the use of combination therapy designed to restore sensitivity to tumor cells resistant to the CENU carmustine (BCNU). Recent studies have demonstrated enhancement of nitrosourea activity in human medulloblastoma and glioblastoma multiforme xenografts growing subcutaneously and intracranially in athymic nude mice by O6-benzylguanine-mediated depletion of AGAT. The hypotheses of this project are: 1) High grade glioma AGAT levels and cellular distribution determine response to nitrosoureas and 2) inhibition of AGAT activity by O6- benzylguanine can reverse nitrosourea resistance in high grade gliomas without an unacceptable increase in toxicity. The specific aims of the project are: 1) To define the optimal doses of the combination of O6-benzylguanine and BCNU in the treatment of patients with recurrent anaplastic astrocytoma or glioblastoma multiforme and 2) To define the activity of the combination of O6-benzylguanine and BCNU in the treatment of patients with recurrent anaplastic astrocytoma or glioblastoma multiforme.