Regional AGT Depeltion of CNS and Leptomeningeal Tumors

中枢神经系统和软脑膜肿瘤的区域 AGT 清除

• 批准号: 6621379
• 负责人: HENRY S. FRIEDMAN
• 金额: $ 30.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621379
• 关键词: antineoplastics; combination chemotherapy; enzyme activity; enzyme inhibitors; glioma; laboratory rat; meningitis; methylguanine DNA methyltransferase; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; temozolomide

DESCRIPTION: (provided by applicant) Central nervous system (CNS) neoplasms which either arise in the brain or metastasize from an extraneural primary site, are highly malignant tumors refractory to all conventional therapy. Similarly, patients with neoplastic meningitis from virtually any tumor such as melanoma, sarcoma or breast carcinoma do poorly, with mean survival following leptomeningeal spread measured in months. The major impediment to successful treatment is de novo or acquired resistance to chemotherapy. Temozolomide is an imidazole tetrazinone similar to dacarbazine, requiring conversion to the active methylating agent MTIC. Methylating agents, including temozolomide, produce cytotoxicity due to a lethal cycle of mismatch repair following cellular misrecognition of O(6)-methylguanine. Recent preclinical and clinical studies have confirmed the activity of temoxolomide in the treatment of malignant glioma. Unfortunately, the majority of patients ultimately display resistance to temozolomide. The two primary mechanisms of resistance to temozolomide and other alkylating agents are the enzyme O(6)-alkylguanine-DNA alkyltransferase (AGT) and a deficiency in the DNA mismatch repair pathway. Of these two mechanisms, AGT plays a primary role in resistance to temozolomide by removing the alkyl groups from the O(6) position of guanine, in effect reversing the cytotoxic lesion of temozolomide. The sensitivity of tumor cell lines to temozolomide and the alkylating agent BCNU can be correlated with AGT levels. Regional therapy of CNS parenchymal or leptomeningeal neoplasms with intratumoral or intrathecal administration respectively, offers the potential benefit of enhancing delivery to the target neoplasm while minimizing delivery and hence toxicity to systemic organs. We have previously demonstrated the activity and modest toxicity of intrathecal temozolomide in the treatment of athymic rats bearing subarachnoid AGT-human malignant gliom xenografts. We have extended these results and demonstrated the activity and safety of temozolomide delivered by intracerebral microinfusion in the treatment of malignant gliomas intracranially in athymic nude rats. The specific aims of this proposal are: 1. To define the role of intratumoral O(6)-BG and other AGT inhibitors in enhancing systemic or intratumoral temozolomide therapy of malignant glioma; 2. To define the role of intrathecal AGT inhibitors in enhancing system or intrathecal temozolomide therapy of neoplastic meningitis.

描述：（由申请方提供）中枢神经系统（CNS）肿瘤 这些肿瘤要么发生在脑内，要么从原发性神经瘤转移而来。 是所有常规疗法都难以治愈的高度恶性肿瘤。 同样，几乎任何肿瘤引起的肿瘤性脑膜炎患者， 黑色素瘤、肉瘤或乳腺癌的效果较差， 以月为单位测量的软脑膜扩散。成功的主要障碍 治疗是从头或获得性耐药性化疗。替莫唑胺是一种 咪唑四嗪酮类似于达卡巴嗪，需要转化为 活性甲基化剂MTIC。甲基化剂，包括替莫唑胺， 由于错配修复的致死循环， 细胞对O（6）-甲基鸟嘌呤的错误识别。近期临床前和临床 研究已经证实了替莫索胺在治疗 恶性神经胶质瘤不幸的是，大多数患者最终显示 对替莫唑胺耐药。两种主要的耐药机制 替莫唑胺和其它烷化剂是酶O（6）-烷基鸟嘌呤-DNA 烷基转移酶（AGT）和DNA错配修复途径中的缺陷。的 在这两种机制中，AGT在替莫唑胺耐药中发挥主要作用， 从鸟嘌呤的O（6）位除去烷基， 逆转替莫唑胺的细胞毒性损伤。肿瘤细胞的敏感性 对替莫唑胺和烷化剂BCNU的敏感性与AGT相关 程度.中枢神经系统实质或软脑膜肿瘤的区域治疗， 肿瘤内或鞘内给药，提供了潜在的 在最大限度减少递送的同时增强靶向肿瘤递送的益处 从而对全身器官产生毒性。我们之前已经证明了 替莫唑胺鞘内注射治疗慢性阻塞性肺疾病 携带蛛网膜下AGT-人恶性神经胶质瘤异种移植物的无胸腺大鼠。我们有 扩展了这些结果，并证明了替莫唑胺的活性和安全性 脑内微灌注治疗恶性胶质瘤 在无胸腺裸大鼠中颅内注射。该提案的具体目标是：1. 为了确定肿瘤内O（6）-BG和其他AGT抑制剂在 增强恶性胶质瘤的全身或瘤内替莫唑胺治疗; 2. 明确鞘内AGT抑制剂在增强系统或 替莫唑胺鞘内注射治疗肿瘤性脑膜炎