NOVEL TREATMENT OF BRAIN TUMORS

描述：(申请者摘要)适用于大多数恶性脑部疾病患者 肿瘤常规放化疗毒性大，只能延长 几个月的存活时间。迫切需要更有效和更有效的 毒性较低的治疗。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 掩盖了弥合有关影响的主要知识差距的必要性 肿瘤生理学和克服发展适宜分娩的障碍 系统。本应用程序的目标是解决这些被忽视的问题 问题。申请人的实验室已经开发出并开始测试有效的 抗致癌构造物。这些是复制缺陷型腺病毒。 使myc家族癌基因拮抗剂(Mad， Mxil和RepMax，这是一个包含Mxil抑制域的嵌合体 MYC-与MAX连锁的拮抗剂)和细胞周期蛋白依赖性激酶抑制剂 (CDKI)p21WAFI/CIPI和p27KIPI)。之所以选择这些基因是因为它们 都是抗增殖的，并且在生物化学和 体外细胞水平。假设是异位过度表达 这些基因将抑制手术后微小残留物的增殖 恶性人脑肿瘤细胞不损害邻近正常组织 无分裂的有丝分裂后大脑。我们的目标是通过以下方式来检验这一假设 探讨这些试剂对正常人生理的影响 在动物模型中观察脑部和恶性脑瘤的变化。这些是体外培养的 研究是最重要的，因为细胞培养中发生的事件 并不一定反映体内发生的情况。这是其中不可或缺的一部分 目的对腺病毒载体递送系统进行优化。这 将通过以下方式完成：1)通过以下方式提炼腺病毒系统 掺入四环素可抑制的启动子系统，还原 免疫原性，以及胶质瘤特异性启动子元件的添加， 2)确定这些基因的异位过表达对 正常大脑，以及3)确定异位过表达的影响 这些基因对脑肿瘤生理学的活体脑内研究 免疫缺陷和免疫活性动物的肿瘤异种移植。

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.