Discovery of Anticancer Agents of Diverse Natural Orgin

描述(由申请人提供)：本申请是根据先前提交的评审员的意见进行大幅修订的计划。同样，该计划项目申请者小组以俄亥俄州立大学(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)为代表，他们结合了他们在天然产品分离、结构鉴定和生物学评估方面的丰富合作经验，以完善一个整合的、高度集成的计划，以发现不同来源的新型抗癌药物作为有效的癌症化疗药物进行开发。位于热带国家的资深植物学家将在NAPRALERT数据库的帮助下收集植物材料，还将获得蓝藻和丝状真菌。获得的生物体将被提取，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，目前在俄亥俄州立大学、UIC、RTI和B-MS(项目1-3；核心A和C)。已知活性化合物的去复制将在OSU、UIC和RTI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。将采用生物测定定向分离(OSU、UIC、RTI；分别为项目1-3)来阐明有效成分。俄亥俄州立大学(核心B)将通过合成和药物化学来领导活性天然产品的开发。这样发现的新的活性化合物将在我们的体外和体内生物分析小组(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。小组将就进一步开发可能用作抗癌剂的药物做出决定。B-MS(核心C)将赞助进行更先进的生物和毒理学测试，以及采购更多的铅化合物。将通过国家适应行动方案数据库(核心D)集中管理实验数据。该联盟将在NCI项目主任的参与下参与发现过程，并计划定期举行关键科学人员(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)。为这一拟议项目的所有技术和行政方面提供了一流的设施。 研究与公共卫生的相关性：在美国，四分之一的死亡是由癌症造成的，迫切需要新的治疗方法。该计划项目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，特别是用于目前的治疗方法无法治愈的肿瘤。

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. Relevance of Research to Public Health: Cancer is responsible for one in every four deaths in the United States, and new treatments are urgently needed. It is the overall goal of the integrated studies of this program project to discover novel chemicals from selected tropical rainforest plants, as well as cyanobacteria and fungi, for development as cancer chemotherapeutic agents, particularly for tumors that can not be cured by present treatment methods.