COMBINED SUICIDE GENE THERAPY/RADIOTHERAPY FOR CANCER

癌症自杀基因疗法/放射疗法的联合治疗

• 批准号: 2386972
• 负责人: SVEND O FREYTAG
• 金额: $ 22.81万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2386972
• 关键词: Alphaherpesvirinae; Escherichia coli; aminohydrolases; combination cancer therapy; fusion gene; gene expression; gene therapy; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; prodrugs; recombinant virus; thymidine kinase; tumor suppressor genes

Two impediments which limit the effectiveness of conventional cancer treatment are the lack of a significant differential response between normal and tumor tissue and the development of biochemical resistance to commonly used therapies. Recent evidence suggests that the latter limitation is determined, in part, by the genetic makeup of the tumor cell. This research proposal will examine the general hypothesis that the therapeutic index of cancer radiotherapy can be enhanced by employed suicide gene therapy as an adjuvant therapy and by manipulating the p53 status of the tumor cell. Recombinant retroviruses encoding a novel E. Coli cytosine deaminase (CD)/Herpes Simplex Virus thymidine kinase (HSV-1TK) fusion gene have been generated and used to express the CD/HSV-1 TK fusion protein in tumor cells. We will test hypothesis that these two suicide gene systems, when combined, function synergistically to kill tumor cells in vivo. Based on our previous observations that each suicide gene system independently can radiosensitize tumor cells in vitro, we will test the hypothesis that expression of the CD/HSV-1 TK fusion protein will result in tumor radiosensitization in vivo. Because recent studies have indicated that the efficacy of chemotherapy and radiotherapy is dependent on tumor p53 status, we will test the hypothesis that co-expression of wild-type p53 will increase the effectiveness of the combined suicide gene therapy/radiotherapy approach. Recombinant adenoviruses will be used to deliver the CD/HSV-1 TK fusion and p53 genes to tumor cells I vivo. We will test the hypothesis that this multifaceted approach will be more efficacious at tumor control than either suicide gene therapy or radiotherapy alone. As improvements in locoregional control of tumor could translate into better survival outcomes, this research may provide the rationale upon which future clinical trials using this multifaceted approach will be based.

限制常规武器有效性的两个障碍 癌症治疗缺乏显著的差异反应， 正常组织和肿瘤组织之间的关系， 对常用疗法的生化抗性。 最近 有证据表明，后一种限制在一定程度上， 由肿瘤细胞的基因组成。 本研究提案 将检查一般假设，即治疗指数 应用自杀基因可增强肿瘤的放射治疗 治疗作为辅助治疗，并通过操纵p53状态 肿瘤细胞。 重组逆转录病毒编码一种新的E. 大肠杆菌胞嘧啶脱氨酶（CD）/单纯疱疹病毒胸苷 已经产生了HSV-1 TK融合基因， 在肿瘤细胞中表达CD/HSV-1 TK融合蛋白。 我们将 测试假设，这两个自杀基因系统，当 组合，协同作用以在体内杀死肿瘤细胞。 基于我们之前的观察每个自杀基因系统 可以独立地在体外放射增敏肿瘤细胞，我们将测试 CD/HSV-1 TK融合蛋白的表达 将导致体内肿瘤放射增敏。 因为最近 研究表明，化疗的疗效和 放疗依赖于肿瘤p53状态，我们将检测 假设野生型p53共表达将增加 联合自杀基因治疗/放疗的疗效 approach. 重组腺病毒将用于递送 CD/HSV-1 TK融合和p53基因与体内肿瘤细胞的融合。 我们 将检验这一假设，即这种多方面的方法将 在肿瘤控制方面比自杀基因疗法 或单独放疗。 作为局部控制的改进 可以转化为更好的生存结果， 研究可以提供未来临床 将以采用这种多方面办法的审判为基础。