Apoptosis Modulation in Prodrug Activation Gene Therapy

前药激活基因治疗中的细胞凋亡调节

• 批准号: 6740380
• 负责人: TING SU
• 金额: $ 4.89万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-07 至 2007-04-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6740380
• 关键词: SCID mouse; aminohydrolases; apoptosis; combination cancer therapy; cyclophosphamide; cysteine endopeptidases; cytochrome P450; drug metabolism; ganciclovir; gene delivery system; gene therapy; glioma; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; neoplastic growth; nonhuman therapy evaluation; postdoctoral investigator; prodrugs; protease inhibitor; terminal nick end labeling; tissue /cell culture

DESCRIPTION (provided by applicant): The bystander cytotoxic effect, defined as the extension of the killing effects of an activated prodrug produced locally within a tumor to surrounding tumor cells, is a key feature of gene-directed enzyme prodrug therapy (GDEPT) for cancer, given that the limitation of current technologies for gene delivery allows for only a small percentage of tumor cells to be transduced with a therapeutic gene. Recent studies conducted in Dr. Waxman's laboratory suggest that a significantly enhanced bystander effect can be achieved for cytochrome P450-based GDEPT in combination with the anti-cancer prodrug cyclophosphamide by introduction of an anti-apoptotic factor, p35, into rat gliosarcoma 9L cells in a monolayer culture system. The major goals of this proposal are 1) to investigate the utility of a baculoviral caspase inhibitor, p35, in augmenting the bystander killing effect of the cancer chemotherapeutic drug cyclophosphamide in a preclinical model of cytochrome P450-based GDEPT, 2) to implement this gene therapy in a human tumor xenograft model using a replicating viral helper system, and 3) to determine whether the enhanced bystander activity seen with p35 in the P450 GDEPT system can be broadly applied to other GDEPT systems, such as herpes simplex virus thymidine kinase in combination with ganciclovir and E. coli cytosine deaminase in combination with 5-flurocytosine, both of which exert their tumor killing and/or bystander effect via distinct mechanisms. Findings obtained under this proposal may provide valuable information for paving the way of implementing this gene therapeutic strategy in the clinic.

描述（由申请人提供）：旁观者细胞毒性效应被定义为肿瘤内局部产生的活化前药对周围肿瘤细胞的杀伤作用的延伸，是癌症基因导向酶前药疗法（GDEPT）的一个关键特征，因为目前基因递送技术的限制仅允许一小部分肿瘤细胞被治疗基因转导。 Waxman 博士实验室最近进行的研究表明，通过将抗凋亡因子 p35 引入单层培养系统中的大鼠神经胶质肉瘤 9L 细胞中，基于细胞色素 P450 的 GDEPT 与抗癌前药环磷酰胺相结合，可以显着增强旁观者效应。 该提案的主要目标是 1) 研究杆状病毒半胱天冬酶抑制剂 p35 在基于细胞色素 P450 的 GDEPT 临床前模型中增强癌症化疗药物环磷酰胺的旁观者杀伤作用的效用，2) 使用复制病毒辅助系统在人类肿瘤异种移植模型中实施这种基因治疗，以及 3) 确定是否增强 P450 GDEPT 系统中 p35 观察到的旁观者活性可广泛应用于其他 GDEPT 系统，例如单纯疱疹病毒胸苷激酶与更昔洛韦组合以及大肠杆菌胞嘧啶脱氨酶与 5-氟胞嘧啶组合，两者都通过不同的机制发挥其肿瘤杀伤和/或旁观者效应。 根据该提案获得的研究结果可能会为在临床上实施这种基因治疗策略铺平道路提供有价值的信息。