ANTICANCER LEADS FROM MARINE MACROORGANISMS AND THEIR ASSOCIATED MICROORGANISMS

虽然有效的治疗药物治疗白血病和 淋巴瘤是可以获得的，但在开发方面进展甚微 对临床重要疾病的治疗有用的新药 肿瘤，如乳腺癌、结肠癌、肺癌、卵巢癌和前列腺癌。缺乏 这方面的成功可以归因于缺乏有效的分析方法。 用于发现此类病原体的模型或筛选技术。 然而，我们对癌症生物学知识的最新进展 促进了创新的新方法的发展。用于检测 影响生物化学指标的化合物，如癌基因产物， 抑癌基因产物、蛋白质参与多种信号转导 信号转导途径和参与细胞凋亡的蛋白质。我们相信 那些具有作用机制的化合物涉及到这些 各地区将积极对抗上面列出的重要实体肿瘤。 要充分利用Sandoz提供的新屏幕武器库 制药，我们将努力提供化合物和提取物 这是由于生物合成途径的最广泛多样性造成的。 因此，我们不仅要调查海绵和海鞘， 它们是一系列独特的次要数据的可靠来源 代谢物，我们也将访问微生物区系(即细菌和 放线菌)存在于这些细菌的表面或组织内 无脊椎动物。这样，我们将最大限度地利用我们的资源并利用 对标本进行最大限度的研究。 NCNPDDG提案这一部分的总体目标是发现 海洋无脊椎动物，特别是海绵动物产生的新化合物 和海鞘类，或与它们相关的微生物，将作为新的 抗癌化疗先导。为了成功地实现这一目标， 我们建议做以下工作：(A)获取海绵和海鞘 既可以作为生物活性化合物的池，也可以作为 独特的营养丰富的微生物来源；(B)海洋养殖 表面和内部空间中的细菌和放线菌 收集到的无脊椎动物；(C)使用基于机制的分析来揭示 含有新的化学试剂的提取物，对重要的 生化指标；(D)优化发酵条件 产生活性代谢物的海洋分离株；(E)有效分离 活性代谢物，由快速初级生化分析指导；(F) 阐明活性化合物的化学结构 光谱化学方法；(G)启动回收或放大 进一步筛选出的化合物的发酵和再分离 药理研究或临床前研究；(H)制备半 用于结构研究的活性化合物的合成类似物- 活动关系；以及(I)获得承诺的专利覆盖范围 抗肿瘤天然产物及其衍生物。

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.