COMBINED SUICIDE GENE THERAPY/RADIOTHERAPY FOR CANCER

限制常规措施有效性的两个障碍 癌症的治疗缺乏明显的差异反应 正常组织和肿瘤组织之间的关系以及肿瘤的发展 对常用疗法产生生化抗性。近期 证据表明，后一种限制在一定程度上是确定的， 由肿瘤细胞的基因组成。这项研究建议 将检验这样一个普遍假设，即治疗指数 使用自杀基因可加强癌症放射治疗 作为辅助治疗的治疗和通过操纵P53状态 肿瘤细胞的。重组逆转录病毒编码一种新型E. 大肠埃希菌胞嘧啶脱氨酶/单纯疱疹病毒胸苷 已构建了HSV-1TK融合基因，并用于 在肿瘤细胞中表达CD/HSV-1 TK融合蛋白。我们会 测试假设这两个自杀基因系统，当 两者结合，协同作用可在体内杀死肿瘤细胞。 根据我们之前的观察，每个自杀基因系统 在体外可以独立地使肿瘤细胞放射增敏，我们将测试 CD/HSV-1 TK融合蛋白表达的假说 会导致体内肿瘤的放射增敏。因为最近 研究表明，化疗和化疗的疗效 放射治疗依赖于肿瘤的P53状态，我们将测试 假设野生型P53的共同表达将增加 自杀基因治疗联合放射治疗的疗效观察 接近。重组腺病毒将用于传递 CD/HSV-1TK融合基因和p53基因在体内对肿瘤细胞的作用。我们 将检验这样一种假设，即这种多方面的方法将是 在控制肿瘤方面比自杀基因疗法更有效 或者只接受放射治疗。随着局部区域控制的改进 肿瘤的发生可以转化为更好的生存结果，这 研究可能为未来的临床提供理论基础 使用这种多方面方法的试验将基于。

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.