NOVEL TREATMENT OF BRAIN TUMORS

脑肿瘤的新疗法

• 批准号: 6137590
• 负责人: Richard B Gaynor
• 金额: $ 20.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-15 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137590
• 关键词: Adenoviridae; aneuploidy; apoptosis; astrocytes; athymic mouse; brain neoplasms; cell cycle; cell differentiation; cell proliferation; chemical hypersensitivity; cyclin dependent kinase; disease /disorder model; gene expression; histopathology; immunogenetics; laboratory rat; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; neoplastic process; oncogenes; oncoprotein p21; radiosensitizer; tissue /cell culture; transfection /expression vector; tumor promoters

DESCRIPTION: (Applicant's Abstract) For most patients with malignant brain tumors conventional chemoradiotherapy is highly toxic and only prolongs survival by months. There is an urgent need for more effective and less-toxic treatment. This has contributed to the excessive optimism surrounding human gene therapy for these neoplasms. This optimism has overshadowed the need to bridge major gaps in knowledge about effects on tumor physiology and overcome the hurdle of developing suitable delivery systems. The goal of this application is to address these overlooked issues. The applicant's laboratory has developed and begun testing potent anti-oncogenic constructs. These are replication-defective adenoviruses that enable ectopic overexpression of myc-family oncogene antagonists (Mad, Mxil, and RepMax, a chimera containing the repression domain of MYC-antagonists linked to MAX) and cyclin dependent kinase inhibitors (CDKIs) p21 WAFI/CIPI and p27KIPI). These genes were chosen because they are both anti-proliferative and are well studied biochemically and at the cellular level in vitro. The hypothesis is that ectopic overexpression of these genes will inhibit proliferation of post-surgical microscopic residual malignant human brain tumor cells without damaging adjacent normal nondividing post-mitotic brain. The objective is to test this hypothesis by investigating the effects of these reagents on the physiology of normal brain and of malignant brain tumors in animal models. These in vitro studies are of primary importance since events that occur in cell culture do not necessarily reflect what happens in vivo. An integral part of this objective will be to optimize the adenoviral vector delivery system. This will be accomplished by: 1) refining the adenovirus system via incorporation of a tetracycline-repressible promoter system, reduction of immunogenicity, and the addition of glial tumor-specific promoter elements, 2) determining the effects of ectopic overexpression of these genes on normal brain, and 3) determining the effects of ectopic overexpression of these genes on brain tumor physiology in vivo using intracerebral brain tumor xenografts in both immunodeficient and immunocompetent animals.

描述：（申请人摘要）对于大多数患有恶性脑病的患者 肿瘤传统放化疗具有剧毒且只能延长治疗时间 存活数月。 迫切需要更加有效和 毒性较小的治疗。 这导致了过度乐观 围绕这些肿瘤的人类基因治疗。 这种乐观情绪已经 掩盖了弥合关于影响的知识方面的重大差距的需要 肿瘤生理学并克服开发合适的递送的障碍 系统。 该应用程序的目标是解决这些被忽视的问题 问题。 申请人的实验室已开发并开始测试有效的 抗癌结构。 这些是复制缺陷型腺病毒 使 myc 家族癌基因拮抗剂异位过度表达（Mad、 Mxil 和 RepMax，一种包含抑制结构域的嵌合体 与 MAX 相关的 MYC 拮抗剂和细胞周期蛋白依赖性激酶抑制剂 (CDKI) p21 WAFI/CIPI 和 p27KIPI）。 选择这些基因是因为它们 两者都具有抗增殖作用，并在生化方面得到了充分研究 体外细胞水平。 假设是异位过度表达 这些基因将抑制术后微观残留物的增殖 恶性人脑肿瘤细胞不损害邻近正常细胞 不可分裂的有丝分裂后脑。 目的是通过以下方式检验该假设 研究这些试剂对正常生理机能的影响 动物模型中的大脑和恶性脑肿瘤。 这些在体外 研究至关重要，因为细胞培养中发生的事件确实 不一定反映体内发生的情况。 这其中不可或缺的一部分 目标是优化腺病毒载体传递系统。 这 将通过以下方式完成：1）通过以下方式完善腺病毒系统 掺入四环素抑制型启动子系统，减少 免疫原性，以及添加神经胶质瘤特异性启动子元件， 2) 确定这些基因的异位过度表达对 正常大脑，以及 3) 确定异位过度表达的影响 使用大脑内的体内这些基因对脑肿瘤生理学的影响 免疫缺陷和免疫功能正常动物的肿瘤异种移植物。