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: 2746455
• 负责人: J. Michael Mathis
• 金额: $ 10.46万
• 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/2746455
• 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， 涉及腺病毒载体的卵巢癌模型 人类p53肿瘤抑制基因。此应用程序涉及 导入具有直接肿瘤细胞毒性或间接肿瘤细胞毒性的基因 肿瘤生长抑制功能（通过称为 “旁观者效应”），或潜在地两者。本申请人已经证明 使用腺病毒载体进行体内基因治疗的功效 转移生物活性p53到卵巢癌细胞。目标 本项目的主要目标是进一步明确以下五个方面， 腺病毒介导的p53基因治疗卵巢癌 首先，虽然p53基因治疗在微观上显示出有效性， 疾病模型，申请人计划确定这种治疗是否 在肿瘤体积较大的情况下， 人类卵巢癌的模型。其次，由于突变型p53蛋白 可以抑制野生型p53功能，他计划研究 特异性内源性p53突变对基于腺病毒的 p53基因治疗这些结果可能使他能够预测患者 对p53基因治疗的反应。第三，他将确定机制， p53通过其抑制G2中的肿瘤生长。有据可查 引入野生型p53的癌细胞系导致 G1级心跳骤停。然而，他最近观察到，某些细胞 在G2/M检查站细胞在DNA合成过程中的停滞， DNA损伤后的复制被认为为细胞提供了 有足够的时间在细胞内修复损伤 周期第四，由于p53已被证明可以重新敏化化疗， 他计划确定细胞对烷化剂的抗性， 基于腺病毒的p53基因治疗单独或联合 联合顺铂治疗。最后，一些数据表明， 野生型p53调节有效的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 腺病毒介导的p53基因治疗对肿瘤血管生成的影响。在这 应用程序，他打算采取的第一步，对翻译 关于一种基于腺病毒的癌症基因的有希望的初步数据， 治疗模型系统，以实际和科学为基础的人类 审判