Discovery of Anticancer Agents of Diverse Natural Origin

简介（由申请人提供）：在此修订后的计划项目续期申请中，申请团体代表三所主要院校。俄亥俄州立大学（OSU）、伊利诺伊大学芝加哥分校（UIC）和北卡罗来纳大学格林斯博罗分校（UNCG）。参与者将他们在天然产物的分离、结构解析和生物学评价方面的丰富经验结合起来，继续发展一个统一的、综合的项目，以发现不同来源的新型抗癌药物，并将其发展为癌症化疗药物。项目1 （OSU）中研究的植物材料将由位于热带国家的成熟植物学家在NAPRALERT数据库（项目2；UIC）的协助下收集，蓝藻（项目2）和丝状真菌（项目3 UNCG）也将被访问。获得的生物体将被提取并在各种相关的基于机制的、基于细胞的和肿瘤生长相关的试验中进行评估，这些试验目前在俄勒冈州立大学（项目1）、UIC（核心a）、哥伦比亚大学（通过项目3）和一家新的制药公司合作伙伴——马萨诸塞州安多弗的卫材公司（通过俄勒冈州立大学的核心C）进行。已知活性化合物的复制将在OSU， UIC和UNCG完成，使用计算机文献调查和LC-MS结合生物测定。项目1-3将采用生物测定定向分馏，以阐明活性原理。通过药物化学和药代动力学相关研究，活性天然产物的先导开发将在俄勒冈州立大学（核心B）进行，由俄勒冈州立大学生物统计学小组（核心C）促进。由此发现的新的活性化合物将在我们的体外和体内生物测定小组中进一步评估（项目1和3，核心A和卫材）。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阶段，以及大量先导化合物的采购将由卫材赞助（通过核心C）。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（包括我们的外部和OSU内部顾问小组）会议，以加强沟通和决策过程。该会议将由Core c组织。整体项目数据管理是可用的。

DESCRIPTION (provided by applicant): In this revised Program Project renewal application, the applicant group is representative of three primary institutions. The Ohio State University (OSU), the University of Illinois at Chicago (UIC), and the University of North Carolina at Greensboro (UNCG). The participants have combined their vast experience in the isolation, structure elucidation, and biological evaluation of natural products, to continue the development of a consolidated, integrated program for the discovery of novel anticancer agents of diverse origin for development as cancer chemotherapeutic agents. Plant materials to be studied in Project 1 (OSU) will be collected by established botanists located in tropical countries with the assistance of the NAPRALERT database (Project 2; UIC), and cyanobacteria (Project 2) and filamentous fungi (Project 3 UNCG) 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 (Project 1), UIC (Core A), Columbia University (through Project 3), and a new pharmaceutical company partner, Eisai Inc., Andover, MA (through Core C at OSU). Dereplication of known active compounds will be accomplished at OSU, UIC, and UNCG using computerized literature surveys and LC-MS coupled to bioassays. Bioassay-directed fractionation will be employed in Projects 1-3, for the elucidation of active principles. Lead development of active natural products via medicinal chemistry and pharmacokineticsrelated studies will be conducted at OSU (Core B), facilitated by the OSU Biostatistics group (Core C). 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 Eisai). 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 Eisai (through Core C). 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 and OSU Internal Advisory panels) to enhance communication and decision-making processes, to be organized by Core C. Excellent facilities for the isolation, structure determination, chemical modification, synthesis, and in vitro and in vivo biological evaluation, and overall project data management are available. RELEVANCE (See instructions): Cancer is responsible for about one in every four deaths in the United States, and new treatments are urgently needed. It is the overall goal of the integrated studies in this renewal application to discover novel chemicals from selected tropical rainforest plants, as well as cyanobacteria and fungi, for development as cancer chemotherapeutic agents, particularly for tumors not cured by present treatment methods.