Discovery of Anticancer Agents of Diverse Natural Orgin

描述（由申请人提供）：本申请代表了根据先前提交的评审员意见进行的大幅修订的程序。同样，该计划项目申请组由俄亥俄州州立大学（OSU），伊利诺伊大学芝加哥分校（UIC），三角研究所（RTI）和百时美施贵宝（B-MS）代表，他们结合了他们在天然产物的分离，结构解析和生物评价方面的丰富合作经验，完善了一个综合，该项目是一个高度整合的项目，用于发现不同来源的新型抗癌剂，以开发为有效的癌症化疗剂。在NAPRALERT数据库的帮助下，热带国家的植物学家将收集植物材料，还将访问蓝细菌和丝状真菌。将在目前在OSU、UIC、RTI和B-MS（项目1-3;核心A和C）运行的基于相关机制、基于细胞和肿瘤生长相关测定的各种组合中提取和评价获得的微生物。将在OSU、UIC和RTI使用计算机化文献调查和LC-MS结合生物测定完成已知活性化合物的去复制。将采用生物测定定向分级分离（分别为OSU、UIC、RTI;项目1-3）来阐明活性成分。将在OSU（核心B）通过合成和药物化学进行活性天然产物的先导开发。由此发现的新型活性化合物将在我们的体外和体内生物测定组（项目1和3，核心A和C）中进一步评估，并得到生物统计学（核心D）的支持。将就进一步开发可能用作抗癌药物的药物做出小组决定。B-MS（核心C）将赞助更先进的生物学和毒理学试验以及采购更大量的先导化合物。实验数据的管理将通过NAPIS数据库（核心D）集中管理。该联盟将与NCI项目主任一起参与发现过程，并计划定期举行关键科学人员会议（包括我们的外部咨询小组），以加强沟通和决策过程（核心D）。本拟议项目的所有技术和行政方面都有优良的设施。

DESCRIPTION (provided by applicant): This application represents a substantially revised program based on the comments of reviewers in the prior submission. Again, this program project applicant group is represented by The Ohio State University (OSU), the University of Illinois at Chicago (UIC), Research Triangle Institute (RTI), and Bristol-Myers Squibb (B-MS) who have combined their vast collaborative experience in the isolation, structure elucidation, and biological evaluation of natural products, to consummate a consolidated, highly integrated program for the discovery of novel anticancer agents of diverse origin for development as effective cancer chemotherapeutic agents. Plant materials will be collected by established botanists located in tropical countries with the assistance of the NAPRALERT database, and cyanobacteria and filamentous fungi will also be accessed. Organisms acquired will be extracted and evaluated in a diverse battery of relevant mechanism-based, cell based, and tumor-growth related assays currently operational at OSU, UIC, RTI, and B-MS (Projects 1-3; Cores A and C). Dereplication of known active compounds will be accomplished at OSU, UIC, and RTI using computerized literature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed (OSU, UIC, RTI; Projects 1-3, respectively) for the elucidation of active principles. Lead development of active natural products via synthetic and medicinal chemistry will be conducted at OSU (Core B). Novel, active compounds thus discovered will be further evaluated in our panel of in vitro and in vivo bioassays (Projects 1 and 3, Cores A and C), supported by biostatistics (Core D). Group decisions will be made regarding the further development of agents for potential use as anticancer agents. The more advanced states of biological and toxicological testing, as well as the procurement of larger quantities of lead compounds will be sponsored by B-MS (Core C). Management of experimental data will be centralized through the NAPIS database (Core D). The Consortium will work with the involvement of the NCI Program Director in the discovery process, and plans to hold regular meetings of key scientific personnel (inclusive of our External Advisory Panel) to enhance communication and decision-making processes (Core D). Excellent facilities for all technical and administrative aspects of this proposed project are available.