Discovery of Anticancer Agents of Diverse Natural Origin

描述(由申请人提供)：在本次修订后的计划项目续签申请中，申请者群体代表三所初级院校。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伯勒分校(UNG)。与会者结合了他们在天然产物的分离、结构鉴定和生物学评价方面的丰富经验，继续开发一个巩固的、综合的计划，以发现不同来源的新型抗癌药物，作为癌症化疗药物开发。将在项目1(OSU)中研究的植物材料将由位于热带国家的知名植物学家在NAPRALERT数据库(项目2；UIC)的帮助下收集，还将获得蓝藻(项目2)和丝状真菌(项目3 U.G)。获得的生物将被提取，并在一系列相关的基于机制、基于细胞和与肿瘤生长相关的分析中进行评估，这些分析目前在俄亥俄州立大学(项目1)、UIC(核心A)、哥伦比亚大学(通过项目3)以及新的制药公司合作伙伴Eisai Inc.(通过俄亥俄州立大学的Core C)进行。已知活性化合物的去复制将在俄亥俄州立大学、UIC和U.G使用计算机化的文献调查和LC-MS与生物测定相结合来完成。在项目1-3中，将采用生物测定定向分离，以阐明有效成分。在俄亥俄州立大学生物统计学小组(核心C)的协助下，将在俄亥俄州立大学(核心B)进行药物化学和药代动力学相关研究，以开发活性天然产品。这样发现的新的活性化合物将在我们的体外和体内生物检测小组(项目1和3，核心A和Eisai)中进行进一步的评估。小组将就进一步开发可能用作抗癌剂的药物做出决定。卫材将(通过核心C)赞助更先进的生物和毒理学测试以及采购更多的铅化合物。该联盟将在NCI项目主任的参与下参与发现过程，并计划定期召开关键科学人员会议(包括我们的外部和OSU内部咨询小组)，以加强由Core C组织的沟通和决策过程。目前有优秀的分离、结构确定、化学修饰、合成、体外和体内生物学评估以及整体项目数据管理设施。 相关性(参见说明)：在美国，癌症约占死亡人数的四分之一，迫切需要新的治疗方法。在这一更新应用中的综合研究的总体目标是从选定的热带雨林植物以及蓝藻和真菌中发现新的化学物质，用于开发癌症化疗药物，特别是对无法通过现有治疗方法治愈的肿瘤。

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.