TEMODAR RESISTANCE IN CENTRAL NERVOUS SYSTEM

恶性胶质瘤患者的预后仍然很差，传统的手术、放疗和以烷基亚硝基源为基础的化疗不能治愈所有多形性胶质母细胞瘤患者和大部分间变性星形细胞瘤患者。对恶性胶质瘤治疗临床试验的回顾表明，进一步进展的主要障碍是耐药肿瘤细胞的出现。甲基化剂是治疗恶性胶质瘤的两个“金”标准之一（另一个是亚硝基源）。替莫达（替莫唑胺）是一种咪唑四氮酮，其作用机制与达卡巴嗪相似，特别是通过代谢转化为一种常见的活性中间体，甲基化剂MTIC。临床试验表明，替莫达在治疗新诊断和复发的高级别胶质瘤患者中具有活性。然而，很明显，一组患有这种肿瘤的患者将无法使用替莫达。针对非中枢神经系统肿瘤进行的一系列研究表明，至少有两种耐药机制在介导对Temodar的耐药中起作用，即o6 -烷基鸟嘌呤-DNA烷基转移酶（AGT）和DNA错配修复缺陷。该提议的假设是：涉及DNA碱基切除修复和细胞信号改变的机制（与AGT或DNA错配修复缺陷无关）介导了恶性胶质瘤和成神经管细胞瘤的替莫达耐药。该提案的具体目的是：1)通过定量AGT、AGT突变和DNA错配修复缺陷的作用，定义在人类胶质瘤和髓母细胞瘤细胞系、异种移植物和临床肿瘤样本中对替莫达耐药的新机制的相对重要性（根据specific aims 2和3）；2)明确加合管修复在介导人胶质瘤和髓母细胞瘤细胞系、异种移植物和临床肿瘤样本对替莫达耐药中的作用；3)确定替莫达诱导DNA甲基化后细胞信号传导改变在介导人胶质瘤和髓母细胞瘤细胞系、异种移植细胞和临床肿瘤样本对替莫达耐药中的作用；4)替莫达联合DNA修复抑制剂在恶性胶质瘤和成神经管细胞瘤患者中的1期和2期试验。

The prognosis of patients with malignant glioma remains dismal, with conventional treatment with surgery, radiotherapy and alkylnitrosourea-based chemotherapy failing to cure all patients with glioblastoma multiforme and the majority of patients with anaplastic astrocytoma. Review of clinical trials for treatment of malignant glioma indicate that a major impediment to further progress is the emergence of drug-resistant tumor cells. Methylating agents are one of the two "gold" standards (the other being nitrosoureas) for the treatment of malignant glioma. Temodar (temozolomide) is an imidazole tetrazinone whose mechanism of action is similar to that of dacarbazine, specifically via metabolic conversion to a common active intermediate, the methylating agent MTIC. Clinical trials suggest that Temodar has activity in the treatment of patients with newly diagnosed and recurrent high-grade glioma. Nevertheless, it is clear that a cohort of patients with this tumor will fail Temodar. A series of studies conducted predominantly, but not exclusively, for non-CNS tumors has demonstrated that at least two mechanisms of resistance appear to be operational in mediating resistance to Temodar, O6-alkylguanine-DNA alkyltransferase (AGT) and DNA mismatch repair deficiency. The hypothesis of this proposal is that: mechanisms (discrete from AGT or DNA mismatch repair deficiency) involving DNA base excision repair and alterations in cell signaling mediate Temodar resistance in malignant glioma and medulloblastoma. The specific aims of this proposal are: 1) to define the relative importance of novel mechanisms (per Specific Aims 2 & 3) of resistance to Temodar in human glioma and medulloblastoma cell lines, xenografts and clinical tumor samples by quantitating the role of AGT, AGT mutations, and DNA mismatch repair deficiency; 2) to define the role of adduct repair in mediating resistance to Temodar in human glioma and medulloblastoma cell lines, xenografts and clinical tumor samples; 3) to define the role of alterations in cell signaling following Temodar induced DNA methylation in mediating resistance to Temodar in human glioma and medulloblastoma cell lines, xenografls and clinical tumor samples; 4) to conduct Phase 1 and 2 trials of Temodar in combination with inhibitors of DNA repair in patients with malignant glioma and medulloblastoma.