ANTITUMOR AGENTS FROM MARINE MICROORGANISMS AND INVERTEBRATES

这项研究的长期目标是发现 将在癌症化疗中有用，但它将通过 作用机制与目前使用的药物不同。要实现 我们的目标是筛选海洋无脊椎动物、细菌的提取物 和真菌对一组生化和细胞检测 潜在药物，并使用这些检测方法直接分离纯活性物质 化合物。已经设计了一些检测信号拮抗剂的方法 转导、转录因子和肿瘤抑制蛋白 已确定的肿瘤细胞系的癌基因产物。另一种化验系统将 检查是否有化合物可以将肿瘤细胞转化为非 恶性表型。Bcl2和Bclx蛋白的拮抗剂 还将寻求调节细胞凋亡的活性化合物将进行测试 在细胞测试中确认抑制细胞生长的有效性，然后 在动物模型中。纯净的化合物将使用现代 使用一组 光谱技术。 用于这一药物发现工作的天然产品池 将由培养的专性和兼性的提取物组成 嗜盐或耐盐厌氧细菌、海洋真菌和一些 海洋无脊椎动物，主要是海绵和海鞘动物。微生物 将从海洋沉积物中分离出来，陆地盐分沉积物 盐碱地和海洋无脊椎动物组织。 该项目与NCNPDDG的发现目标直接相关 从天然物质中获得新作用机制的有效化疗药物 来源&该项目的独特贡献将是 未被开发的资源的天然产品，海洋真菌和 兼性和专性海洋细菌。我们的医药合作伙伴， Sandoz将提供新的一次和二次生物检测方法来检测 会影响正极中选定元素的化合物和 参与细胞增殖的负性调控机制。这个 生化指标不同于目前 可获得的药物起作用。

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.