Antitumor-Antibiotics from Marine Microorganisms

这是一个有竞争力的更新申请，以继续探索海洋微生物作为新的 抗肿瘤抗生素的来源。拟议的项目将继续作为化学家之间的合作 加利福尼亚州拉霍亚斯克里普斯海洋研究所的微生物学家。和癌症生物学家 百时美施贵宝制药研究所（Bristol-Myers Squibb Pharmaceutical Research Institute）位于新泽西州普林斯顿。拟议延长的研究报告 期间包括： - 不同生境海洋微生物的分离、培养和生物学评价。的 更新申请的重点将是7个新的专性海洋放线菌群（盐孢菌属， Marinomyces和MAR 3-7群）。 - 总的来说，继续分离和描述新的分子，这些分子显示了新的作用机制， 癌症相关的、基于机制的筛选显示了NCI 60细胞系中的体外组织类型选择性， BMS ODCA组，并随后研究其体内功效。 - 将筛选工作集中在新的癌症相关靶点IGF-1生长因子，DMA甲基 转移酶-1（DNMT-1）、辅活化剂相关精氨酸甲基转移酶（CARM-1）和神经酰胺酶， 以及酵母选择性DNA修复和细胞检查点靶点。这些目标还将在 SIO与几种专注于感染性疾病的检测方法（针对耐药病原体进行筛查， 对于两种选择的细菌外排泵的抑制剂）。 - 为了继续推进先前的发现（Salinosporamide A，Halimide，Sargassamide A和几个 其他分子）用于在BMS P388和L1210白血病和鼠实体瘤中进行体内评价 型号M109、Mam 16/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.