MOLECULAR APPROACHES FOR THE TREATMENT OF OVARIAN CANCER

这项计划拨款的基础是最近发现的小说 观察到，如果肿瘤细胞被药物更昔洛韦杀死， 与其他肿瘤细胞接触或毗邻 含有单纯疱疹病毒胸苷激酶的转基因 基因(HSV-TK)。所述杀瘤作用a)在体外细胞中产生- 已确诊的腹膜内肿瘤动物的培养或体内实验，b) 不是细胞类型或物种特有的，c)被授予活的或 辐射基因修饰细胞，以及d)明显涉及凋亡细胞- 死亡可能是通过转移死亡基因中含有GCV的囊泡- 修改为未修改的单元格。这些发现导致了一种 批准的第一阶段临床方案，以确定使用HSV- TK+肿瘤细胞治疗复发性人卵巢腹膜腔内瘤 癌症。拟议的研究将以这些发现为基础并加以扩展。 并由四个研究项目和三个配套核心设施组成。 主要目标是开发癌症治疗的新方法。 对不同的癌症有广泛的适用性，使用基因 修饰的肿瘤细胞，产生杀瘤蛋白或增强 宿主的抗肿瘤免疫反应。这四项研究计划分别是 密切协调和相互依存的目标应该实现 这些目标，并有作为首席研究员的医生/科学家 在基因治疗和相关领域，以及在 癌症治疗新疗法的评估和开发。 由Camille Abboud博士和George Abraham博士领导的项目1关注 提高对HSV-TK+细胞毒过程的认识 细胞，并澄清细胞因子在赋予敏感性或 GCV治疗后对杀伤的抵抗力。项目2(斯科特·弗里曼博士) 将决定对肿瘤产生的细胞毒性效应是否由 通过给予HSV-TK+细胞和GCV可以增强对HSV-TK+细胞和GCV的吸收 肠外或基因修饰的免疫细胞因子的TK+细胞 细胞。詹姆斯·兹维贝尔博士领导的项目3将利用 正在生长的肿瘤的血管生成和血管特性，以及在小鼠体内 血管生成肿瘤模型将开发特异性靶向基因的方法 直接将内皮细胞修饰到原代肿瘤细胞生长的部位。 由克雷格·麦克库恩博士指导的项目4将是一期基因治疗试验 测试使用HSV-TK+肿瘤细胞治疗慢性粒细胞白血病的疗效 复发性卵巢癌。根据研究结果和 在其他项目中，类似的基因治疗方法将被改编用于 肾癌和结肠癌的治疗。通过仔细地交错 项目和统一的目的朝着一个共同的目标，这个计划授予 应该指出广泛使用的癌症基因治疗的新方法。

This program grant has its basis in the novel, recently discovered observation that tumor cells will be killed by the drug ganciclovir if they are in contact with or contiguous to other tumor cells which have been genetically modified to contain the herpes simplex virus thymidine kinase gene (HSV-TK). The tumoricidal effect a) is produced in in vitro cell- culture or in vivo in animals with established intraperitoneal tumors, b) is not cell-type or species specific, c) is conferred with live or irradiated gene-modified cells, and d) apparently involves apoptotic cell- death presumably by transfer of vesicles containing GCV from dying gene- modified to unmodified cells. These findings lead to development of an approved Phase I clinical protocol to determine the efficacy of using HSV- TK+ tumor cells for treatment of recurrent intraperitoneal human ovarian carcinoma. The proposed studies will build upon and expand these findings and consist of four research projects and three supporting core facilities. the principal objectives are to develop new methods for cancer therapy which have wide applicability to diverse cancers, using genetically modified tumor cells which produce tumoricidal proteins or which potentiate a host's anti-tumor immune response. the four research projects which are intimately coordinated and interdependent as to purpose should fulfill these goals, and have as principal investigators physician/scientists with established track records in gene-therapy and related fields, and in the evaluation and development of new therapies for treatment of cancers. Project 1 lead by Drs. Camille Abboud and George Abraham is concerned with advancing our knowledge of the apoptotic cytotoxic process in HSV-TK+ cells, and clarifying the role(s) of cytokines in conferring sensitivity or resistance to killing after GCV treatment. Project 2 (Dr. Scott Freeman) will determine whether the cytotoxic effect on tumors produced by administering HSV-TK+ cells and GCV can be enhanced by administering HSV- TK+ cells with immune cytokines either parenterally or as gene-modified cells. Project 3 under Dr. James Zwiebel will take advantage of the angiogenic and vascular properties of growing tumors, and in a murine angiogenic tumor model will develop methods to specifically target gene modified endothelial cells directly to sites of primary tumor cell growth. Project 4 directed by Dr. Craig McCune will be a Phase I gene therapy trial which tests the efficacy of using HSV-TK+ tumor cells for treatment of recurrent ovarian cancer. Based on the results and from the findings in the other projects, similar gene-therapy methods will be adapted for treatment of renal and colon cancers. By careful interdigitation of projects and unification of purpose toward a common goal this program grant should point to new and widely used methods for gene-therapy of cancers.