SELECTIVE KILLING OF 0RAL CANCER CELLS

选择性杀死 0RAL 癌细胞

• 批准号: 2631565
• 负责人: EDWARD J. SHILLITOE
• 金额: $ 5.3万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2631565
• 关键词: Papillomavirus; athymic mouse; cytomegalovirus; cytotoxicity; ganciclovir; gene expression; gene mutation; genetic enhancer element; genetic markers; genetic promoter element; herpes simplex virus 1; linkage mapping; molecular cloning; multidrug resistance; neoplasm /cancer genetics; neoplastic cell; oral pharyngeal neoplasm; plasmids; reporter genes; thymidine kinase; tissue /cell culture; transfection /expression vector; tumor suppressor genes

DESCRIPTION: (from applicant's abstract). Oral cancer affects around 30,000 persons/year in the USA and leads to around 15,000 deaths, yet no new forms of treatment have been introduced for many decades. One form of gene therapy for oral cancer could consist of introducing the HSV gene for TK into the tumor, followed by administration of the prodrug ganciclovir. Unfortunately there are no ways of limiting the expression of any such gene to the tumor cells. The applicant proposes to develop ways of maximizing the expression of the TK gene in oral cancer cells, while minimizing expression in non-cancer cells. This will be done by developing new gene promoter/enhancer elements that will be preferentially active in oral cancer cells. In Specific Aim 1, new gene promoters will be developed which show higher activity in oral cancer cells than in other cells. This will be done by linking a promoter which shows some of the desired qualities to a selectable marker gene - the constructs will the undergo random mutations in oral cancer cells and the improved promoters will be recovered from the surviving cells. In Specific Aim 2, the new promoters will be compared to known promoters for strength, specificity and spectrum of action. This will be done by linking the promoters to reporter genes and introducing them into a large panel of cell lines. In Specific Aim 3, the applicant will use the promoters with the most specific activity and broadest spectrum of action to induce expression of the TK gene in cells, so as to obtain selective killing of oral cancer cells by ganciclovir. If the project succeeds in obtaining selective killing of oral cancer cells it will be extended in the future to more extensive experiments in animal models, and possibly to trials in human patients.

描述：（来自申请人的摘要）。 口腔癌影响周围 美国每年有30，000人，导致约15，000人死亡，但没有新的 几十年来一直采用各种治疗形式。 一种形式的基因 口腔癌的治疗可以包括引入用于TK的HSV基因 进入肿瘤，然后给予前药更昔洛韦。 不幸的是，没有办法限制任何这样的基因的表达 to the tumor肿瘤cells细胞. 申请人建议制定最大限度地 TK基因在口腔癌细胞中的表达，同时最小化 在非癌细胞中的表达。 这将通过开发新的基因 在口腔癌中优先起作用的启动子/增强子元件 细胞 在具体目标1中，将开发新的基因启动子，其显示 口腔癌细胞中的活性高于其他细胞。 为此将 通过将显示某些所需品质的启动子连接到 选择性标记基因-构建体将经历随机突变， 口腔癌细胞和改进的启动子将从 存活的细胞 在具体目标2中，新的推动者将与 已知的启动子的强度、特异性和作用谱。 这将 通过将启动子连接到报告基因并将它们引入到 一大组细胞系。 在具体目标3中，申请人将使用 具有最特异活性和最广谱作用的启动子， 诱导TK基因在细胞中的表达，从而获得选择性杀伤 口腔癌细胞的生长。 如果项目成功获得 选择性杀死口腔癌细胞，它将在未来扩展到 在动物模型中进行更广泛的实验，并可能进行人体试验 患者