ANTITUMOR AGENTS FROM MARINE MICROORGANISMS AND INVERTEBRATES

这项研究的长期目标是发现天然产品， 在癌症化疗中是有用的， 与目前使用的药物不同。实现 这个目标，我们建议筛选海洋无脊椎动物，细菌， 和真菌对一组生化和细胞测定，以检测 并使用这些测定来直接分离纯活性物质 化合物.已经设计了一些测定来检测信号的拮抗剂， 转导、转录因子和肿瘤阻遏蛋白， 确定的肿瘤细胞系的癌基因产物。另一种测定系统将 检查可以将肿瘤细胞转化为非肿瘤细胞的化合物。 恶性表型蛋白Bcl-2和Bcl-x的拮抗剂， 还将寻找调节细胞凋亡的活性化合物 在细胞测定中以确认抑制细胞生长的功效，然后 在动物模型中。纯化合物将被分离使用现代 色谱方法和使用一系列的 光谱技术 用于药物发现的天然产物库 将由培养的专性和兼性 嗜盐或耐盐厌氧菌，海洋真菌，和一些 海洋无脊椎动物，主要是海绵和海鞘。微生物 将从海洋沉积物、陆地盐沉积物中分离出来， 作为盐平原和海洋无脊椎动物组织。 该项目与NCNPDDG的目标直接相关， 具有新的作用机制的有效化学疗法 来源&这个项目的独特贡献将是输入 来自未开发资源的天然产品，海洋真菌， 兼性和专性海洋细菌。我们的医药合作伙伴， 山德士，将提供新的主要和次要的生物测定，以检测 化合物，将影响选定的元素，在积极的和 阴性对照机制参与细胞增殖。的 生物化学目标与目前的生物化学目标不同， 可获得药物法

The long term goal of this research is to discover natural products that will be useful in cancer chemotherapy but which will operate by mechanisms different from those of the currently used drugs. To achieve this goal we propose to screen extracts of marine invertebrates, bacteria and fungi against a group of biochemical and cellular assays to detect potential drugs and use these assays to direct isolation of pure active compounds. Some assays have been designed to detect antagonists of signal transduction, transcription factor and tumor repressor proteins that are oncogene products of defined tumor cell line. Another assay system will check for compounds which can transform tumor cells back to a non- malignant phenotype. Antagonists to the proteins Bcl-2 and Bcl-x which modulate apoptosis will also be sought Active compounds will be tested in cellular assays to confirm efficacy in inhibiting cell growth and then in animal models. Pure compounds will be isolated using modern chromatographic methods and Structures determined using an array of spectroscopic techniques. The pool of natural products to be used for this drug discovery effort will be comprised of extracts of cultured obligate and facultative halophilic or halotolerant anaerobic bacteria, marine fungi, and some marine invertebrates, primarily sponges and ascidians. Microorganisms will be isolated from marine sediments, terrestrial saline sediments such as salt plains, and marine invertebrate tissues. This project is directly related to the NCNPDDG objectives of discovering effective chemotherapies having new mechanisms of action from natural source& The unique contribution of this project will be the input of natural products from an underexplored resource, marine fungi and facultative and obligate marine bacteria. Our pharmaceutical partner, Sandoz, will provide novel primary and secondary bioassays to detect compounds which will affect selected elements in the positive and negative control machinery involved in cell proliferation. The biochemical targets are different from those on which the currently available drugs act.