Discovery of Anticancer Agents of Diverse Natural Orgin

描述（由申请人提供）：此申请代表了基于先前提交的审稿人意见的实质性修订计划。同样，该项目申请团队由俄亥俄州立大学（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、结构阐明和生物学评估方面的丰富合作经验，完成了一个整合的，高度整合的程序，用于发现不同来源的新型抗癌药物，以发展为有效的癌症化疗药物。在NAPRALERT数据库的帮助下，位于热带国家的成熟植物学家将收集植物材料，蓝藻和丝状真菌也将被访问。获得的生物体将在OSU、UIC、RTI和B-MS（项目1-3，核心a和C）开展的各种相关机制、细胞和肿瘤生长相关分析中进行提取和评估。已知活性化合物的复制将在OSU， UIC和RTI使用计算机文献调查和LC-MS耦合生物测定完成。将采用生物测定定向分离（OSU， UIC， RTI；分别为项目1-3）来阐明活性原理。通过合成化学和药物化学主导活性天然产物的开发将在俄勒冈州立大学进行（核心B）。由此发现的新型活性化合物将在生物统计学（核心D）的支持下，在体外和体内生物测定（项目1和3，核心A和C）小组中进一步评估。小组将就进一步开发潜在的抗癌药物作出决定。生物和毒理学测试的更高级状态，以及大量先导化合物的采购将由B-MS （Core C）赞助。实验数据的管理将通过NAPIS数据库（Core D）进行集中。该联盟将在NCI项目主任的参与下开展工作，并计划定期召开关键科学人员（包括我们的外部顾问小组）会议，以加强沟通和决策过程（核心D）。为这个拟议项目的所有技术和行政方面提供了优良的设施。

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.