NOVEL TREATMENT OF BRAIN TUMORS

描述：（申请人摘要）对于大多数恶性脑肿瘤患者， 肿瘤常规放化疗是高毒性的， 生存数月。 迫切需要更有效和 毒性较小的治疗。 这导致了过度乐观 人类基因治疗的环境。 这种乐观情绪 掩盖了弥合关于对环境的影响的知识方面的重大差距的必要性。 肿瘤生理学和克服障碍，发展适当的交付 系统. 本应用程序的目标是解决这些被忽视的 问题. 申请人的实验室已经开发并开始测试有效的 抗癌构建体。 这些是复制缺陷型腺病毒 其能够使myc家族癌基因拮抗剂异位过表达（Mad， Mxil，和RepMax，一种含有Mxil抑制结构域的嵌合体， 与MAX连接的MYC拮抗剂）和细胞周期蛋白依赖性激酶抑制剂 （CDKIs）p21 WAFI/CIPI和p27 KIPI）。 选择这些基因是因为它们 都是抗增殖的，并且在生物化学上得到了很好的研究， 细胞水平。 假设是异位过度表达 这些基因将抑制手术后显微镜下残留物的增殖 不损害邻近正常的恶性人脑肿瘤细胞 不分裂的有丝分裂后的大脑 目的是通过以下方式来检验这一假设： 研究这些试剂对正常人生理学的影响， 脑和恶性脑肿瘤的动物模型。 这些体外 研究是最重要的，因为在细胞培养中发生的事件 不一定反映体内发生的情况。 的组成部分 目的是优化腺病毒载体递送系统。 这 将通过以下方式实现：1）通过以下方式改进腺病毒系统： 四环素阻遏型启动子系统的掺入， 免疫原性，以及添加神经胶质肿瘤特异性启动子元件， 2)确定这些基因的异位过表达对 正常脑，和3）确定异位过表达的影响， 这些基因对脑肿瘤生理学的影响 在免疫缺陷和免疫活性动物中的肿瘤异种移植物。

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.