Antitumor-Antibiotics from Marine Microorganisms

这是一个竞争性的续签申请，以继续探索海洋微生物作为一种新的 抗肿瘤药物的来源--抗生素。拟议的项目将继续作为化学家之间的合作 以及加利福尼亚州拉荷亚斯克里普斯海洋研究所的微生物学家。和癌症生物学家在 位于新泽西州普林斯顿的百时美施贵宝药物研究所。建议进行的重建研究 期间包括以下内容： -来自不同生境的海洋微生物的分离、培养和生物学评价。这个 更新申请的重点将是7个新的专性海洋放线菌群(盐生孢子菌， 海洋霉菌和3月3-7日群)在过去24个月中发现。 -总的来说，继续分离和描述显示出新的作用机制的新分子 与癌症相关的、基于机制的筛查显示NCI 60细胞系体外组织类型选择性和 BMS ODCA面板，并随后研究其在体内的效果。 -将筛查工作集中在新的癌症相关目标IGF-1生长因子，DMA甲基 转移酶-1(DNMT-1)、辅活化型精氨酸甲基转移酶(CARM-1)和神经酰胺酶， 以及酵母选择性DMA修复和细胞检查点靶标。这些目标也将在 SIO具有几种侧重于传染病的检测方法(筛选耐药病原体和 用于两个选定的细菌外排泵的抑制剂)。 -继续推进以前的发现(盐孢子胺A、哈利胺、马尾藻胺A和几个 其他分子)用于在BMS P388和L1210白血病以及小鼠实体瘤中的体内评价 型号为M109、Mam16/C和M50766。

This is a competitive renewal application to continue to explore marine microorganisms as a new source for antitumor-antibiotics. The proposed project would continue as a collaboration between chemists and microbiologists at the Scripps Institution of Oceanography in La Jolla, CA. and cancer biologists at the Bristol-Myers Squibb Pharmaceutical Research Institute in Princeton, NJ. Studies proposed for the renewal period include the following: - The isolation, cultivation and biological evaluation of marine microorganisms from diverse habitats. The focus of the renewal application will be on 7 new groups of obligate marine actinomycetes (Salinospora, Marinomyces, and the MAR 3-7 groups) discovered during the past 24 months. - Overall, to continue to isolate and describe new molecules which show novel mechanisms of action in cancer-relevant, mechanism-based screens, show in vitro tissue type selectivity in the NCI 60 cell line and BMS ODCA panels, and to subsequently investigate their in vivo efficacies. - To focus a screening effort on the new cancer relevant targets IGF-1 Growth Factor, DMA Methyl Transferase-1 (DNMT-1), CoactivatorAssociated Arginine Methyltransferase (CARM-1) and Ceramidase, and on yeast selective DMA repair and cell checkpoint targets. These goals will also be supplemented at SIO with several assays which focus on infectious diseases (screening against drug resistant pathogens and for inhibitors of two selected bacterial efflux pumps). - To continue to advance previous discoveries (Salinosporamide A, Halimide, Sargassamide A and several other molecules) for in vivo evaluation in the BMS P388 and L1210 leukemias and the murine solid tumor models M109, Mam16/C and M50766.