ANTITUMOR AGENTS FROM MARINE MICROORGANISMS AND INVERTEBRATES

来自海洋微生物和无脊椎动物的抗肿瘤剂

• 批准号: 6203184
• 负责人: FRANCIS J SCHMITZ
• 金额: $ 10.92万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-17 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203184
• 关键词: Dinoflagellates; Fungi; Invertebrata; Porifera; Tunicata; anaerobic bacteria; antineoplastics; aquatic organism; bioassay; biological products; biological signal transduction; clone cells; cooperative study; cytotoxicity; drug discovery /isolation; inhibitor /antagonist; neoplasm /cancer pharmacology; oncogenes; saltwater environment; spectrometry; transcription factor

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.

这项研究的长期目标是发现天然产品 将在癌症化疗中有用，但会通过 机制与当前使用的药物不同。实现 我们建议筛选海洋无脊椎动物，细菌提取物 和真菌针对一组生化和细胞测定 潜在的药物并使用这些测定来指导纯活动的隔离 化合物。一些测定方法是为了检测信号的拮抗剂 转导，转录因子和肿瘤阻遏蛋白是 定义的肿瘤细胞系的癌基产品。另一个测定系统将 检查可以将肿瘤细胞转变回非 - 的化合物 恶性表型。蛋白质Bcl-2和Bcl-X的拮抗剂 还将测试调节凋亡的活性化合物 在细胞测定中确认抑制细胞生长的功效，然后 在动物模型中。纯化合物将使用现代化合物隔离 色谱方法和结构使用 光谱技术。 用于此药物发现工作的天然产品池 将由文化专业和兼职的提取物组成 卤素或卤代厌氧菌，海洋真菌和一些 海洋无脊椎动物，主要是海绵和海沿岸。微生物 将从海洋沉积物，陆盐水沉积物中孤立 作为盐平原和海洋无脊椎动物组织。 该项目与发现的NCNPDDG目标直接相关 有效的化学疗法具有自然作用的新作用机制 资源和该项目的独特贡献将是 来自未经忽视的资源的天然产品，海洋真菌和 兼性和专性海洋细菌。我们的药物合作伙伴， Sandoz将提供新颖的初级和次要生物测定 会影响阳性和 阴性对照机制参与细胞增殖。这 生化目标与当前的目标不同 可用毒品法。