ADENOVIRUS BASED P53 GENE THERAPY FOR OVARIAN CANCER

基于腺病毒的 P53 基因疗法治疗卵巢癌

• 批准号: 6475842
• 负责人: J. Michael Mathis
• 金额: $ 11.45万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-08 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475842
• 关键词: Adenoviridae; alkylating agents; angiogenesis; athymic mouse; cis platinum compound; combination cancer therapy; cytotoxicity; disease /disorder model; fibroblast growth factor; gene mutation; gene therapy; human genetic material tag; immunocytochemistry; model design /development; neoplastic cell; neoplastic growth; nonhuman therapy evaluation; ovary neoplasms; p53 gene /protein; thrombospondins; transfection /expression vector; tumor suppressor genes; vascular endothelial growth factors

DESCRIPTION: (Applicant's Abstract) The goal of this application is to develop a preclinical therapeutic model of ovarian cancer involving an adenovirus-based vector encoding the human p53 tumor suppressor gene. This application involves the introduction of a gene that has direct tumor cytotoxicity or indirect tumor growth inhibitory function (through a phenomenon termed the "bystander effect"), or potentially both. The applicant has demonstrated the efficacy of gene therapy in vivo using an adenovirus vector for the transfer of biologically active p53 into ovarian cancer cells. The goal of this project is to further define the following five aspects of adenovirus-based p53 gene therapy in the treatment of ovarian cancer. First, while p53 gene therapy has shown efficacy in a microscopic disease model, the applicant plans to determine whether this treatment will be effective in the presence of larger tumor volumes that more closely model human ovarian cancer. Second, because mutant p53 protein can inhibit wild type p53 function, he plans to investigate the role of specific endogenous p53 mutations on the response to adenovirus-based p53 gene therapy. These results may allow him to predict patient response to p53 gene therapy. Third, he will determine the mechanisms by which p53 acts to inhibit tumor growth in G2. It is well documented that introduction of cancer cell lines with wild-type p53 results in a G1 arrest. However, he has recently observed that certain cells arrest at the G2/M checkpoint. The arrest of cells during DNA synthesis and replication after DNA damage is thought to provide the cell with sufficient time to repair the damage before progression through the cell cycle. Fourth, because p53 has been shown to re-sensitize chemo- resistant cells to alkylating agents, he plans to determine the effectiveness of adenovirus-based p53 gene therapy alone or in combination with cisplatin therapy. Finally, some data suggest that wild-type p53 regulates a balance of potent angiogenic and anti- angiogenic factors. Thus, he plans to investigate the bystander effect of adenovirus-based p53 gene therapy on tumor angiogenesis. In this application, he intends to take the first steps toward the translation of promising preliminary data on an adenovirus-based cancer gene therapeutic model system into practical and scientifically based human trials.

描述：（申请人摘要） 本申请的目标是开发一种临床前治疗药物 涉及基于腺病毒的载体编码的卵巢癌模型 人类p53肿瘤抑制基因。该应用程序涉及 引入具有直接或间接肿瘤细胞毒性的基因 肿瘤生长抑制功能（通过一种称为“ “旁观者效应”），或两者都有可能。申请人已证明 使用腺病毒载体进行体内基因治疗的功效 将具有生物活性的 p53 转移到卵巢癌细胞中。目标 本项目的主要内容是进一步明确以下五个方面 基于腺病毒的 p53 基因疗法治疗卵巢癌。 首先，虽然 p53 基因疗法已在显微镜下显示出疗效 疾病模型，申请人计划确定这种治疗是否 在存在较大肿瘤体积的情况下将有效 密切模拟人类卵巢癌。其次，因为突变的p53蛋白 可以抑制野生型p53功能，他计划研究其作用 特定内源性 p53 突变对腺病毒反应的影响 p53基因治疗。这些结果可以让他预测患者 对 p53 基因治疗的反应。第三，他将确定机制 p53 通过 p53 发挥作用，抑制 G2 期肿瘤生长。这是有据可查的 引入具有野生型 p53 的癌细胞系会导致 G1逮捕。然而，他最近观察到某些细胞停滞 在G2/M检查站。 DNA合成过程中细胞的停滞 DNA 损伤后的复制被认为可以为细胞提供 在细胞进展之前有足够的时间修复损伤 循环。第四，因为 p53 已被证明可以使化疗重新变得敏感。 对烷化剂产生耐药性的细胞，他计划确定 基于腺病毒的 p53 基因治疗单独或联合治疗的有效性 与顺铂联合治疗。最后，一些数据表明 野生型 p53 调节有效血管生成和抗血管生成的平衡 血管生成因子。因此，他计划研究旁观者效应 基于腺病毒的 p53 基因治疗对肿瘤血管生成的影响。在这个 申请后，他打算迈出翻译的第一步 基于腺病毒的癌症基因的有希望的初步数据 将治疗模型系统转化为实用且有科学依据的人类 试验。