Regional AGT Depeltion of CNS and Leptomeningeal Tumors

描述：（由申请人提供）中枢神经系统（CNS）肿瘤 它要么出现在大脑中，要么从神经外原发灶转移 是所有传统疗法都难以治愈的高度恶性肿瘤。 同样，几乎任何肿瘤（例如， 黑色素瘤、肉瘤或乳腺癌的治疗效果较差，平均生存期如下 软脑膜扩散以月为单位。成功的主要障碍 治疗是从头开始或获得对化疗的耐药性。替莫唑胺是一种 咪唑四嗪酮与达卡巴嗪相似，需要转换为 活性甲基化剂MTIC。甲基化剂，包括替莫唑胺， 由于错配修复的致命循环而产生细胞毒性 O(6)-甲基鸟嘌呤的细胞错误识别。最近的临床前和临床 研究证实了替莫索胺在治疗中的活性 恶性胶质瘤。不幸的是，大多数患者最终表现出 替莫唑胺耐药。两种主要的耐药机制 替莫唑胺和其他烷化剂是 O(6)-烷基鸟嘌呤-DNA 酶 烷基转移酶 (AGT) 和 DNA 错配修复途径缺陷。的 通过这两种机制，AGT 在替莫唑胺耐药中发挥主要作用 实际上，从鸟嘌呤的 O(6) 位去除烷基 逆转替莫唑胺的细胞毒性损伤。肿瘤细胞的敏感性 替莫唑胺和烷化剂 BCNU 的品系可与 AGT 相关 水平。中枢神经系统实质或软脑膜肿瘤的区域治疗 分别瘤内或鞘内给药，提供了潜力 增强对目标肿瘤的递送同时最大限度地减少递送的好处 从而对全身器官产生毒性。我们之前已经演示过 鞘内注射替莫唑胺治疗以下疾病的活性和适度毒性 携带蛛网膜下腔 AGT 人类恶性神经胶质细胞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 脑内微量输注治疗恶性胶质瘤 无胸腺裸鼠颅内。本提案的具体目标是：1. 确定瘤内 O(6)-BG 和其他 AGT 抑制剂在 增强恶性神经胶质瘤的全身或肿瘤内替莫唑胺治疗； 2. 确定鞘内 AGT 抑制剂在增强系统或 鞘内注射替莫唑胺治疗肿瘤性脑膜炎。

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.