ENHANCEMENT OF HSV-TK GENE THERAPY IN CANCER

描述：缺乏靶标特异性限制了我们提供 常规药物治疗播散性癌症所需的剂量-强度 全身性细胞毒剂。从理论上讲，剂量强度的增加可能是 通过插入一种基因来激活一种非细胞毒性前体 变成了一种细胞毒性形式。因此，这些研究人员研究了腺病毒 单纯疱疹病毒胸苷激酶基因(HSV-tk)的转移 恶性细胞在裸鼠体内以腹水肿瘤的形式生长，从而使这些 细胞代谢核苷类似物更昔洛韦(GCV)至致死 产品。虽然这种治疗延长了存活时间，但他们不能 治愈动物。试图通过增加剂量强度来增加剂量强度 剂量的病毒实际上缩短了生存时间，因为转导正常 通过腺病毒载体进行器官移植。在本申请中，调查人员 建议通过明确启动子的作用来改进HSV-tk的基因治疗 在HSV-tk基因治疗中的疗效。具体目标是： (1)加大促进剂强度，提高剂量强度和 单纯疱疹病毒tk基因治疗的疗效，(2)鉴别 HSV-tk/GCV治疗失败的几种可能原因(无效HSV-tk 肿瘤细胞转导、HSV-tk基因突变或基因缺失 在肿瘤细胞中的表达，或改变GCV的宿主代谢)，以及(3) 增强HSV-tk的肿瘤特异性表达，增加剂量强度，并 控制下构建HSV-tk表达载体降低宿主毒性 通过利用带有雌激素反应元件的腺病毒载体 CEA和CA-15-3启动子控制下的HSV-tk。长期目标 是将基因治疗策略从临床前模型系统转移到 癌症患者的治疗。这里提出的研究将 寻找提高HSV-tk基因局部剂量强度的方法 治疗，用于规避或克服对这种治疗的抵抗力，并 检测癌症特异性启动子提高治疗效果的能力 结果。

DESCRIPTION: Lack of target specificity limits our ability to provide the dose-intensity required to cure disseminated cancer with conventional systemic cytotoxic agents. In theory, increased dose-intensity could be achieved by inserting a gene that would activate a non-cytotoxic precursor to a cytotoxic form. These investigators have therefore studied adenoviral transfer of the herpes simplex virus thymidine kinase gene (HSV-tk) to malignant cells growing as ascites tumors in nude mice, thus enabling these cells to metabolize the nucleoside analog ganciclovir (GCV) to a lethal product. While this treatment prolonged survival, they were not able to cure the animals. Attempts to increase the dose intensity by increasing the dose of virus actually shortened survival, due to transduction of normal organs by the adenoviral vector. In this application, the investigators propose to improve HSV-tk gene therapy by defining the role of the promoter in the therapeutic efficacy of HSV-tk gene therapy. The Specific Aims are: (1) to increase promoter strength to enhance the dose intensity and therapeutic efficacy of HSV-tk gene therapy, (2) to distinguish among several possible causes of HSV-tk/GCV treatment failure (ineffective HSV-tk transduction of tumor cells, mutation of HSV-tk gene or loss of gene expression in tumor cells, or altered host metabolism of GCV), and (3) to enhance tumor specific expression of HSV-tk, increase dose intensity, and reduce host-toxicity by creating HSV-tk expression vectors under the control of the estrogen-response element and by utilizing adenoviral constructs with HSV-tk under the control of CEA and CA-15-3 promoters. The long-term goal is to transfer gene therapy strategies from pre-clinical model systems to the treatment of patients with cancer. The studies proposed here will identify approaches for enhancing local dose-intensity of HSV-tk gene therapy, for circumventing or overcoming resistance to this therapy, and to test the ability of cancer-specific promoters to improve therapeutic outcome.