PHASE I TRIAL OF O6-BENZYLGUANINE PLUS BCNU IN GLIOMA

描述：恶性人类神经胶质瘤构成了一组高度致命的 肿瘤。氯乙基亚硝基脲（CENUs）在以下方面具有中等效果： 成人神经胶质瘤的治疗它们通过烷基化产生细胞毒性 取代DNA鸟嘌呤残基，随后形成DNA 链内交联。烷基可以从O6上除去， 通过DNA修复蛋白，O6-烷基鸟嘌呤-DNA烷基转移酶 （AGAT），恢复完整的鸟嘌呤。电阻和 对亚硝基脲和甲基化剂的敏感性， 甲基苄肼可以通过这种蛋白质介导，这种蛋白质在细胞中表达。 迄今为止，大多数研究的肿瘤，包括那些发生在 中枢神经系统观察到AGAT的消耗与 烷基鸟嘌呤或甲基化剂使细胞对细胞毒性的 CENUs的行动提供了使用组合的机会 治疗旨在恢复对肿瘤细胞的敏感性， CENU卡莫司汀（BCNU）。 最近的研究表明， 人髓母细胞瘤和胶质母细胞瘤中亚硝基脲活性的研究 皮下和颅内生长的多形性异种移植物， 通过O6-苄基鸟嘌呤介导的AGAT耗竭的无胸腺裸鼠。的 本项目假设：1）高级别胶质瘤AGAT水平 和细胞分布决定对亚硝基脲的反应， 2)AGAT活性抑制 通过O6-苄基鸟嘌呤可以逆转 高级别胶质瘤中的亚硝基脲耐药， 毒性增加。 该项目的具体目标是：1） 确定O6-苄基鸟嘌呤和BCNU联合用药的最佳剂量 在治疗复发性间变性的患者中， 星形细胞瘤或多形性胶质母细胞瘤，以及2）定义活性 O6-苄基鸟嘌呤和BCNU联合治疗 复发性间变性星形细胞瘤或胶质母细胞瘤患者 多形。

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.