BRAIN TUMORS--UNDERSTANDING AND CONTROL OF GROWTH

恶性脑肿瘤是侵袭性的，快速生长的肿瘤， 对手术、放疗和化疗无效， 非弹性受限空间中不受控制的局部生长。 肿瘤 肿瘤发生、对生长至关重要的代谢途径以及 细胞外基质在肿瘤浸润和扩散中的作用较差 恶性脑肿瘤的发病机制 需要新的治疗选择。 在本RFA中，我们将探讨中枢神经系统肿瘤的发展， 生长模式，并检查戊糖磷酸途径，以了解 恶性细胞生长 在神经胶质瘤组织培养中，我们将进一步 研究卤代嘧啶类药物敏感性并试图阐明其 机制和开始临床试验卤嘧啶作为 化疗增敏剂，希望能改善治疗效果。 在项目1中，我们将探讨神经胶质肿瘤的DNA甲基化状态 假设低甲基化对它们的发生很重要。 我们 将探索甲基转移酶基因的活性，以了解其机制 并将甲基化状态与存活率相关联。 项目2将研究神经胶质瘤细胞中的酶系统， 保护免受H2O2氧化损伤。 戊糖磷酸途径特异性 酶抑制剂将被用来系统地研究的作用， 胶质瘤组织中抗氧化系统的体外和体内研究及其在胶质瘤中的作用 H2O2的解毒作用。 髓母细胞瘤（项目3），一种儿科CNS 肿瘤将在3个细胞系中检查其与 细胞外基质蛋白，其基质蛋白受体和 这些蛋白质的合成，以了解肿瘤的迁移倾向， 在CNS内外。 在项目4中，我们将量化并建立 BrdUrd对BCNU和CisPt化疗敏感性增加的机制 在人类神经胶质瘤细胞中取代的DNA。 我们还将评估 BrdUrd取代对BCNU抗性发展的影响和在BCNU中的作用 抗性细胞 在项目5中，我们将开始I期剂量递增 14天连续动脉内颈动脉灌注后3天研究 然后动脉内注射BCNU 第一阶段研究完成后，我们会 开始BrdUrd化疗增敏的II期研究，以确定反应 启动后的缓解率、缓解持续时间和生存率 疗法 总之，我们希望通过增加脑肿瘤的治疗， 了解发展、传播、增长和控制扩散 原发性中枢神经系统肿瘤

Malignant brain tumors are aggressive, rapidly growing tumors that are refractory to surgery, radiation and chemotherapy and most often kill by uncontrolled local growth in an inelastic confined space. Tumor oncogenesis, metabolic pathways critical for growth and the role of extracellular matrix in infiltration and spread of tumor are poorly understood in malignant brain tumors. New treatment options are needed. In this RFA we will explore central nervous system tumor development and growth patterns, and examine the pentose phosphate pathways to understand malignant cell growth. In glioma tissue cultures, we will further investigate halopyrimidine chemosensitivity and attempt to elucidate its mechanisms and begin clinical trials with halopyrimidines as chemosensitizers with the hope of improving treatment. In Project 1 we will explore the DNA methylation state of glial neoplasms with the hypothesis that hypomethylation is important to their genesis. We will explore methyltransferase gene activity to understand the mechanisms of methylation state change and correlate methylation state with survival. Project 2 will examine the enzymatic systems in glioma cells which provide protection from H2O2 oxidant injury. Pentose phosphate pathway specific enzyme inhibitors will be used to systematically investigate the role of antioxidant systems in vitro and in vivo in glioma tissue and their role in the detoxification of H2O2. Medulloblastoma (Project 3), a pediatric CNS neoplasm, will be examined in 3 cell lines for its interaction with extracellular matrix proteins, its matrix protein receptors and the synthesis of these proteins to understand the tumors propensity to migrate within and outside the CNS. In Project 4, we will quantitate and establish the mechanisms of increased chemosensitivity to BCNU and CisPt in BrdUrd substituted DNA in human glioma cells. We also will evaluate the effect of BrdUrd substitution on the development of BCNU resistance and in BCNU resistant cells. In Project 5, we will begin a phase I dose escalation study of 14 day continuous intra-arterial carotid infusion followed 3 days later by intra-arterial BCNU. When the phase I study is complete, we will begin a phase II study of BrdUrd chemosensitization to determine response rate, duration of response and survival following initiation of this therapy. In summary, we hope to improve brain tumor therapy by increasing understanding of development, spread, growth and control of proliferation of primary central nervous system tumors.