BRAIN TUMORS: UNDERSTANDING AND CONTROL OF GROWTH

脑肿瘤：了解和控制生长

• 批准号: 3100846
• 负责人: HARRY S GREENBERG
• 金额: $ 37.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3100846
• 关键词: brain neoplasms; cell growth regulation

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.

恶性脑肿瘤是一种侵袭性、快速生长的肿瘤， 对手术、放疗和化疗难以治愈，最常被死亡 在无弹性的有限空间中不受控制的局部生长。 瘤 肿瘤发生、对生长至关重要的代谢途径以及 细胞外基质对肿瘤的浸润和扩散能力较差 在恶性脑肿瘤中被理解。 需要新的治疗方案。 在本次 RFA 中，我们将探讨中枢神经系统肿瘤的发展和 生长模式，并检查磷酸戊糖途径以了解 恶性细胞生长。 在神经胶质瘤组织培养中，我们将进一步 研究卤代嘧啶的化学敏感性并试图阐明其 机制并开始使用卤代嘧啶作为临床试验 化学增敏剂有望改善治疗。 在项目 1 中，我们将探索神经胶质肿瘤的 DNA 甲基化状态 假设低甲基化对其起源很重要。 我们 将探索甲基转移酶基因活性以了解其机制 甲基化状态变化并将甲基化状态与生存相关联。 项目 2 将检查神经胶质瘤细胞中的酶系统，该系统提供 防止 H2O2 氧化损伤。 磷酸戊糖途径特异性 酶抑制剂将用于系统地研究其作用 神经胶质瘤组织中体外和体内的抗氧化系统及其在 H2O2 的解毒作用。 髓母细胞瘤（项目 3），一种儿科中枢神经系统 肿瘤，将在 3 种细胞系中检查其与 细胞外基质蛋白、其基质蛋白受体和 合成这些蛋白质以了解肿瘤的迁移倾向 CNS 内部和外部。 在项目 4 中，我们将量化并建立 BrdUrd 对 BCNU 和 CisPt 化学敏感性增加的机制 人类神经胶质瘤细胞中的 DNA 被取代。 我们还将评估效果 BrdUrd 替代对 BCNU 耐药性发展和 BCNU 的影响 耐药细胞。 在项目 5 中，我们将开始第一阶段剂量递增 14天连续动脉内颈动脉输注3天后的研究 随后通过动脉内 BCNU。 当第一阶段研究完成后，我们将 开始 BrdUrd 化疗增敏的 II 期研究以确定反应 发生率、反应持续时间和开始后的生存率 治疗。 总之，我们希望通过增加 对发展、传播、增长和扩散控制的理解 原发性中枢神经系统肿瘤。