TEMODAR RESISTANCE IN CENTRAL NERVOUS SYSTEM

中枢神经系统的 TEMODAR 抵抗

• 批准号: 6844127
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 13.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844127
• 关键词: DNA methylation; DNA repair; adduct; athymic mouse; biological signal transduction; clinical trial phase I; clinical trial phase II; drug resistance; gene mutation; glioma; human subject; human therapy evaluation; medulloblastoma; methylguanine DNA methyltransferase; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; patient oriented research; temozolomide

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.

恶性胶质瘤患者的预后仍然令人沮丧，常规治疗包括手术、放疗和烷基亚硝基脲基化疗，未能治愈所有多形性胶质母细胞瘤患者和大多数间变性星形细胞瘤患者。恶性胶质瘤治疗的临床试验综述表明，进一步进展的主要障碍是耐药肿瘤细胞的出现。甲基化试剂是治疗恶性胶质瘤的两个“金”标准之一（另一个是亚硝基脲）。Temodar（替莫唑胺）是一种咪唑四嗪酮，其作用机制与达卡巴嗪相似，特别是通过代谢转化为常见的活性中间体，甲基化剂MTIC。临床试验表明，Temodar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Temodar。一系列主要但不完全针对非CNS肿瘤进行的研究表明，至少有两种耐药机制似乎在介导对Temodar的耐药性、O 6-烷基鸟嘌呤-DNA烷基转移酶（AGT）和DNA错配修复缺陷中起作用。这一提议的假设是：涉及DNA碱基切除修复和细胞信号转导改变的机制（与AGT或DNA错配修复缺陷不同）介导恶性胶质瘤和髓母细胞瘤的Temodar耐药。该建议的具体目标是：1）确定新机制的相对重要性（根据特定目的2和3）通过定量AGT、AGT突变和DNA错配修复缺陷的作用，在人神经胶质瘤和成神经管细胞瘤细胞系、异种移植物和临床肿瘤样品中对Temodar的耐药性; 2）确定加合物修复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品中介导对Temodar的抗性中的作用; 3）确定Temodar诱导的DNA甲基化后细胞信号传导的改变在人神经胶质瘤和成神经管细胞瘤细胞系、异种移植物和临床肿瘤样品中介导对Temodar的抗性中的作用; 4）在恶性胶质瘤和髓母细胞瘤患者中进行Temodar联合DNA修复抑制剂的I期和II期试验。