MOLECULAR APPROACHES FOR THE TREATMENT OF OVARIAN CANCER

这项计划的赠款有其基础的小说，最近发现， 观察到肿瘤细胞将被药物更昔洛韦杀死，如果他们 与其他肿瘤细胞接触或邻接， 基因修饰含有单纯疱疹病毒胸苷激酶 基因（HSV-TK）。 杀肿瘤作用a）在体外细胞中产生， 培养或在具有已建立的腹膜内肿瘤的动物体内，B） 不是细胞类型或物种特异性的，c）被赋予活的或 辐射的基因修饰的细胞，和d）显然涉及凋亡细胞， 死亡可能是由于含有GCV的囊泡从垂死基因转移而来， 修饰为未修饰的细胞。 这些发现导致了一种 已批准的I期临床方案，以确定使用HSV- TK+肿瘤细胞用于治疗复发性腹膜内人卵巢癌 carcinoma. 拟议的研究将建立在这些发现的基础上并加以扩展 包括四个研究项目和三个核心配套设施。 主要目标是开发癌症治疗的新方法 它对不同的癌症具有广泛的适用性， 产生杀肿瘤蛋白质或增强 宿主的抗肿瘤免疫反应 四个研究项目， 密切协调和相互依存的目的应该实现 这些目标，并作为主要研究者的医生/科学家， 在基因治疗和相关领域建立了跟踪记录， 评估和开发治疗癌症的新疗法。 由卡米尔·阿布德博士和乔治·亚伯拉罕博士领导的项目1涉及 推进我们对HSV-TK+细胞凋亡细胞毒性过程的认识 细胞，并阐明细胞因子在赋予敏感性或 抗GCV治疗后的杀伤。 项目2（Scott Freeman博士） 将决定是否对肿瘤产生的细胞毒性作用， 给予HSV-TK+细胞和GCV可以通过给予HSV- 含有免疫细胞因子的TK+细胞（胃肠外或基因修饰） 细胞 詹姆斯·兹维贝尔博士领导的项目3将利用 生长肿瘤的血管生成和血管特性，并在小鼠中， 血管生成肿瘤模型将开发特异性靶向基因的方法 将修饰的内皮细胞直接转移到原发性肿瘤细胞生长的部位。 项目4由博士指导克雷格McCune将是一个第一阶段的基因治疗试验 其测试了使用HSV-TK+肿瘤细胞治疗 复发性卵巢癌 根据这些结果和 在其他项目中，类似的基因治疗方法将适用于 治疗肾癌和结肠癌。 通过仔细的交错， 项目和统一的目的朝着一个共同的目标，这个计划赠款 应该指出新的和广泛使用的癌症基因治疗方法。

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.