ANTICANCER LEADS FROM MARINE MACROORGANISMS AND THEIR ASSOCIATED MICROORGANISMS

海洋微生物及其相关微生物的抗癌作用

基本信息

批准号：
6237147
负责人：
BRADLEY S DAVIDSON
金额：
$ 8.08万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 1998-08-31
项目状态：
已结题

项目摘要

While effective therapeutic agents for the treatment of leukemias and lymphomas are available, little progress has been made in the development of new drugs that are useful for the treatment of clinically important tumors, such as breast, colon, lung, ovarian, and prostate. The lack of success in this area can be traced to the absence of effective assay models or screening technologies for the discovery of such agents. However, recent advances in our knowledge of cancer biology have catalyzed the development of innovative new methods.for the detection of compounds that affect biochemical targets such as oncogene products, tumor suppressor gene products, proteins involved in various signal transduction pathways, and proteins involved in apoptosis. We believe that compounds which have a mechanism of action involving one of these areas will be active against the important solid tumors listed above. To fully exploit the arsenal of new screens provided by Sandoz Pharmaceuticals, we will endeavor to provide compounds and extracts resulting from the widest possible diversity of biosynthetic pathways. Therefore, we will not only investigate marine sponges and ascidians, which are well proven sources of an array of unique secondary metabolites, we will also access the microbial fauna (i.e., bacteria and actinomycetes) present on the surfaces or within the tissues of these invertebrates. In this way we will maximize our resources and utilize the research specimens to their fullest potential. The overall goal of this segment of the NCNPDDG proposal is the discovery of new compounds produce by marine invertebrates, particularly sponges and ascidians, or their-associated microorganisms that will serve as new anticancer chemotherapeutic leads. To succeed in satisfying this goal, we propose to do the following: (a) obtain marine sponges and ascidians to serve both as a pool of biologically active compounds as well as a unique nutrient-rich source of microorganisms; (b) culture marine bacteria and actinomycetes from the surfaces and interior spaces of the collected invertebrates; (c) employ mechanism-based assays to uncover extracts containing new chemical agents which act on important biochemical targets; (d) optimize fermentation conditions for those marine isolates which produce active metabolites; (e) efficiently isolate active metabolites, guided by rapid primary biochemical assays; (f) elucidate the chemical structures of active compounds using spectrochemical methods; (g) initiate recollection or scale-up fermentation and re-isolation of those compounds selected for further pharmacological study or preclinical investigation; (h) prepare semi- synthetic analogs of active compounds for investigation of structure- activity relationships; and (i) obtain patent coverage for promising antitumor natural products and their derivatives.

虽然是治疗白血病的有效治疗剂淋巴瘤已经存在，但发展进展甚微可用于治疗临床上重要疾病的新药肿瘤，如乳腺癌、结肠癌、肺癌、卵巢癌和前列腺癌。缺乏该领域的成功可以追溯到缺乏有效的分析用于发现此类药物的模型或筛选技术。然而，我们癌症生物学知识的最新进展已经促进了创新性新方法的开发，用于检测影响生化目标的化合物，例如癌基因产物，抑癌基因产物、参与各种信号的蛋白质转导途径和参与细胞凋亡的蛋白质。我们相信具有涉及其中之一的作用机制的化合物领域将积极对抗上面列出的重要实体瘤。充分利用山德士提供的新屏幕库制药，我们将努力提供化合物和提取物来自尽可能广泛的生物合成途径多样性。因此，我们不仅要研究海洋海绵和海鞘，这些都是经过充分证明的一系列独特的二次元的来源代谢物，我们还将接触微生物区系（即细菌和放线菌）存在于这些表面或组织内无脊椎动物。通过这种方式，我们将最大限度地利用我们的资源并利用充分发挥研究标本的潜力。 NCNPDDG 提案这一部分的总体目标是发现海洋无脊椎动物，特别是海绵产生的新化合物和海鞘，或它们相关的微生物，将成为新的抗癌化疗药物。为了成功实现这一目标，我们建议采取以下行动： (a) 获取海绵和海鞘既可以作为生物活性化合物库，也可以作为独特的营养丰富的微生物来源； (b) 海洋养殖来自物体表面和内部空间的细菌和放线菌收集的无脊椎动物； (c) 采用基于机制的分析来发现含有作用于重要物质的新化学剂的提取物生化目标； (d) 优化发酵条件产生活性代谢物的海洋分离物； (e) 有效隔离活性代谢物，以快速初级生化测定为指导；（六）使用阐明活性化合物的化学结构光谱化学方法； (g) 启动回忆或扩大规模发酵并重新分离那些选择用于进一步的化合物药理学研究或临床前研究； (h) 准备半用于结构研究的活性化合物的合成类似物活动关系； (i) 获得有前途的专利覆盖率抗肿瘤天然产物及其衍生物。