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: 6624687
• 负责人: J. Michael Mathis
• 金额: $ 11.8万
• 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 2004-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624687
• 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：（申请人的摘要） 该应用的目的是开发临床前治疗 涉及基于腺病毒的载体编码的卵巢癌模型 人p53肿瘤抑制基因。此应用程序涉及 引入具有直接肿瘤细胞毒性或间接的基因 肿瘤生长抑制功能（通过称为 “旁观者效应”），或可能两者兼而有之。申请人已证明 基因疗法在体内使用腺病毒载体在体内的功效 将生物活性p53转移到卵巢癌细胞中。目标 这个项目的进一步定义了以下五个方面 基于腺病毒的p53基因治疗卵巢癌。 首先，p53基因治疗在微观中显示出疗效 疾病模型，申请人计划确定该治疗方法是否 在较大的肿瘤量的情况下将有效 密切建模人类卵巢癌。其次，因为突变体p53蛋白 可以抑制野生型p53功能，他计划调查 对基于腺病毒的反应的特定内源性p53突变 p53基因治疗。这些结果可能使他可以预测病人 对p53基因疗法的反应。第三，他将确定机制 p53通过它抑制G2的肿瘤生长。它有充分的记录 引入野生型p53的癌细胞系导致 G1逮捕。但是，他最近观察到某些细胞停滞不前 在G2/M检查点。 DNA合成过程中细胞的停滞和 DNA损伤后的复制被认为为细胞提供了 足够的时间来修复通过细胞进展之前的损害 循环。第四，因为已显示p53重新敏感性化学 他计划确定 基于腺病毒的p53基因治疗的有效性 结合顺铂治疗。最后，一些数据表明 野生型p53调节有效的血管生成和抗 血管生成因子。因此，他计划调查旁观者效应 基于腺病毒的p53基因疗法的肿瘤血管生成。在这个 应用程序，他打算迈出翻译的第一步 关于基于腺病毒的癌症基因的有希望的初步数据 治疗模型系统进入实用和基于科学的人类 试验。

项目成果

The role of natural killer cells in adenovirus-mediated p53 gene therapy.

自然杀伤细胞在腺病毒介导的 p53 基因治疗中的作用。

• 发表时间: 2001
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Carroll,JL;Nielsen,LL;Pruett,SB;Mathis,JM
• 通讯作者: Mathis,JM