Discovery of Anticancer Agents of Diverse Natural Origin

多种天然来源的抗癌剂的发现

• 批准号: 9268410
• 负责人: Alan Douglas Kinghorn
• 金额: $ 140.55万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268410
• 关键词: Antineoplastic Agents; Binding Proteins; Biological; Biological Assay; Biological Testing; Biometry; Biostatistics Core; Cell Line; Cells; Cessation of life; Chemicals; Chemistry; Chicago; Chronic Lymphocytic Leukemia; Collection; Communication; Comprehensive Cancer Center; Country; Coupled; Cyanobacterium; Databases; Decision Making; Developing Countries; Development; Disease; Doctor of Philosophy; Drug Industry; Drug Kinetics; Evaluation; Fiber; Formulation; Fractionation; Funding; Goals; Histone Deacetylase; Human Resources; Illinois; In Vitro; Industrialization; Institution; Instruction; Lead; Libraries; Malignant Neoplasms; Metabolism; Methods; Modification; Molds; National Cancer Institute; Natural Products; North Carolina; Ohio; Organism; Participant; Pharmaceutical Chemistry; Pharmacologic Substance; Plants; Play; Principal Investigator; Process; Proteasome Inhibition; Regimen; Research; Research Personnel; Resistance; Resources; Role; Sampling; Small Cell Carcinoma; Solubility; Structure; Supervision; Taxonomy; Testing; Toxicology; United States; Universities; Woman; Work; Xenograft procedure; analog; antitumor drug; base; chemotherapeutic agent; computerized; data management; drug discovery; experience; forest; fungus; in vitro testing; in vivo; in vivo Bioassay; literature survey; meetings; men; novel; novel anticancer drug; programs; scale up; screening; tumor; tumor growth

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.

说明（由申请人提供）： 在本修订后的计划项目续展申请中，申请人群体代表三个主要机构。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 (UNCG)。参与者结合了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，继续开发一个综合的、综合的计划，以发现不同来源的新型抗癌剂，并将其开发为癌症化疗剂。项目 1 (OSU) 中要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）的协助下收集，蓝藻（项目 2）和丝状真菌（项目 3 UNCG）将在也可以访问。获得的生物体将被提取并通过一系列相关的基于机制、基于细胞和肿瘤生长相关的检测进行评估，这些检测目前在 OSU（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卫材公司（位于马萨诸塞州安多佛）（通过 OSU 的 Core C）。 OSU、UIC 和 UNCG 将使用计算机文献调查和 LC-MS 与生物测定相结合来完成已知活性化合物的去重复。项目 1-3 将采用生物测定指导的分馏，以阐明活性成分。在 OSU 生物统计小组（核心 C）的协助下，将在 OSU（核心 B）通过药物化学和药代动力学相关研究主导活性天然产物的开发。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小组（项目 1 和 3、Cores A 和卫材）中进行进一步评估。小组将就进一步开发潜在用作抗癌药物的药物做出决定。更先进的生物和毒理学测试以及大量先导化合物的采购将由卫材（通过核心 C）赞助。该联盟将与 NCI 项目主任一起参与发现过程，并计划定期召开关键科学人员会议（包括我们的外部和 OSU 内部顾问小组），以加强沟通和决策过程，由Core C提供。具有用于分离、结构测定、化学修饰、合成、体外和体内生物学评价以及整体项目数据管理的优良设施。 相关性（参见说明）：在美国，大约四分之一的人死于癌症，因此迫切需要新的治疗方法。这一更新应用中综合研究的总体目标是从选定的热带雨林植物以及蓝细菌和真菌中发现新型化学物质，用于开发癌症化学治疗剂，特别是对于目前治疗方法无法治愈的肿瘤。