DEVELOPING NEW SOURCES OF ANTICANCER DRUGS: ENDEMIC COASTAL MACROLICHENS AND THEIR ASCOMYCETES AND BASIDIOMYCETES MYCOBIONTS

在此修订后的计划项目续签申请中，申请者组代表三个主要成员 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。参与者们将他们巨大的 在天然产物的分离、结构鉴定和生物学评价方面的经验将继续 为发现新的抗癌药物制定一个综合、综合的计划 作为癌症化疗药物开发的不同来源。项目中拟研究的植物材料 1(OSU)将由热带国家的资深植物学家在世界卫生组织的协助下收集 NAPRALERT数据库(项目2；UIC)、蓝藻(项目2)和丝状真菌(项目3 也将访问)。获得的生物将被提取出来，并在不同的电池中进行评估 俄亥俄州立大学目前运行的相关的基于机制、基于细胞和肿瘤生长相关的分析 (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，卫材公司，马萨诸塞州安多弗(通过OSU的Core C)。已知活性化合物的去复制将 在OSU、UIC和UNG使用计算机化的文献调查和LC-MS来完成 生物检测。在项目1-3中，将使用生物测定定向分离，以阐明活性 原则。通过药物化学和药代动力学引领活性天然产品的开发- 相关研究将在俄勒冈州州立大学(核心B)进行，由俄勒冈州州立大学生物统计小组(核心C)协助。 这样发现的新的活性化合物将在我们的体外和体内小组中进行进一步的评估 生物分析(项目1和3，核心A和卫材)。将就进一步的 潜在用作抗癌剂的试剂的开发。生物和生物的更高级状态 毒理测试以及大量铅化合物的采购将由 卫材(通过核心C)。该财团将在NCI计划总监的参与下 发现进程，并计划定期举行关键科学人员会议(包括我们的外部 和OSU内部咨询小组)，以加强沟通和决策进程，将 由Core C组织，在分离、结构确定、化学修饰、 可以进行合成、体外和体内生物学评估，以及整体项目数据管理。 相关性(请参阅说明)： 在美国，大约四分之一的死亡与癌症有关，而新的治疗方法是 急需之物。在这一更新应用中发现小说是综合研究的总体目标 来自选定的热带雨林植物以及蓝藻和真菌的化学品，用于开发为 癌症化疗药物，尤其是用于目前治疗方法不能治愈的肿瘤。

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 pharmacokinetics- related 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 isplation, 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.