ENHANCEMENT OF HSV-TK GENE THERAPY IN CANCER

增强 HSV-TK 基因治疗癌症

• 批准号: 2631506
• 负责人: Douglas Yee
• 金额: $ 14.48万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2631506
• 关键词: Adenoviridae; Alphaherpesvirinae; MCF7 cell; athymic mouse; carcinoembryonal antigen; combination cancer therapy; cytotoxicity; dosage; drug metabolism; drug resistance; estrogens; ganciclovir; gene expression; gene mutation; gene therapy; genetic manipulation; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; polymerase chain reaction; prodrugs; thymidine kinase; transfection /expression vector; tumor promoters; virus genetics

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.

描述：缺乏目标特异性限制了我们提供 用常规剂量治疗播散性癌症所需的剂量强度 全身性细胞毒性药物。 从理论上讲，增加剂量强度可以 通过插入一个基因来激活一个非细胞毒性的前体 转化为细胞毒性形式。 因此，这些研究人员研究了腺病毒 将单纯疱疹病毒胸苷激酶基因（HSV-tk）转移至 恶性细胞在裸鼠中作为腹水瘤生长，从而使这些 细胞代谢的核苷类似物更昔洛韦（GCV），以致死 产品 虽然这种治疗延长了生存期，但他们不能 治好动物。 尝试通过增加剂量来增加剂量强度 剂量的病毒实际上缩短了生存，由于正常的转导 通过腺病毒载体。 在本申请中，研究人员 建议通过定义启动子的作用来改进HSV-tk基因治疗 HSV-tk基因治疗的疗效。 具体目标是： (1)增加促进剂强度以增强剂量强度， HSV-tk基因治疗的疗效，（2）区分 HSV-tk/GCV治疗失败的几种可能原因（无效的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），和（3） 增强HSV-tk的肿瘤特异性表达，增加剂量强度，和 通过在控制下创建HSV-tk表达载体来降低宿主毒性 的雌激素反应元件，并通过利用腺病毒构建体， CEA和CA-15-3启动子控制下的HSV-tk。 远景目标 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。 本文提出的研究将 增强HSV-tk基因局部剂量强度方法鉴定 治疗，用于规避或克服对这种治疗的抵抗，以及 测试癌症特异性启动子改善治疗效果的能力 结果。