Regional AGT Depeltion of CNS and Leptomeningeal Tumors

描述：(申请人提供)中枢神经系统肿瘤 要么发生在大脑中，要么转移自神经外的原发肿瘤 对于所有常规治疗方法来说，都是高度恶性的肿瘤。 同样，患有肿瘤性脑膜炎的患者几乎来自任何肿瘤，如 黑色素瘤、肉瘤或乳腺癌表现不佳，平均生存期紧随其后 软脑膜扩散以月为单位。成功的主要障碍 治疗方法是对化疗产生新的或获得性耐药。替莫唑胺是一种 咪唑四氮酮类似于达卡巴津，需要转换为 活性甲基化试剂MTIC。甲基化制剂，包括替莫唑胺， 由于随后的错配修复的致命循环而产生细胞毒性 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 已有研究证实替莫洛胺治疗慢性阻塞性肺疾病的活性。 恶性胶质瘤。不幸的是，大多数患者最终都表现出 对替莫唑胺耐药。两种主要的抗病机制 替莫唑胺和其他烷基化试剂是O(6)-烷基鸟嘌呤-DNA酶 烷基转移酶(AGT)和DNA错配修复途径的缺陷。的 通过这两种机制，AGT在替莫唑胺耐药中起主要作用 有效地从鸟嘌呤的O(6)位上去除烷基 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的品系与AGT相关 级别。局部注射治疗中枢神经系统实质或软脑膜肿瘤 分别在肿瘤内或鞘内给药，提供了潜在的 在最大限度减少递送的同时加强对目标肿瘤的递送的好处 从而对全身器官产生毒性。我们之前已经演示了 鞘内注射替莫唑胺治疗慢性阻塞性肺疾病的疗效和毒性 无瘤大鼠蛛网膜下腔移植人恶性胶质瘤。我们有 推广了这些结果，证明了替莫唑胺的活性和安全性 脑内微量注射治疗恶性脑胶质瘤 在裸鼠脑内注射。这项建议的具体目的是：1. 确定肿瘤内O(6)-BG和其他AGT抑制剂在 加强替莫唑胺全身或瘤内治疗恶性胶质瘤； 明确鞘内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.