Biological Correlation and Anaysis

生物学关联与分析

• 批准号: 9070622
• 负责人: STEVEN M SWANSON
• 金额: $ 23.69万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9070622
• 关键词: Animal Model; Animals; Antineoplastic Agents; Apoptosis; Biological; Biological Assay; Biological Testing; Cancer cell line; Cell Cycle Arrest; Cells; Chemicals; Clinic; Collaborations; Complex Mixtures; Data; Development; Dose; Drug Kinetics; Evaluation; Fiber; Formulation; Foundations; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Immunodeficient Mouse; Induction of Apoptosis; Instruction; Materials Testing; Molecular; Molecular Target; Mus; Natural Product Drug; Pharmacology; Role; Schedule; Solid; Solubility; Source; Statistical Data Interpretation; Structure-Activity Relationship; System; Testing; Therapeutic Index; Toxic effect; Translations; Work; base; cancer therapy; drug discovery; in vivo; member; multicatalytic endopeptidase complex; novel; programs; research study; screening; tumor xenograft

Core A will focus on biological evaluation of extracts, chromatographic fractions, and pure isolates prepared by all of the Projects within the Program in order to help prioritize subsequent biological and chemical work. This strategy of using bioassay-guided isolation will afford us the opportunity to pursue biological activity within complex mixtures. Extracts found active by Core A will be further purified by Projects 1-3 (OSU, UIC, and UNCG, respectively) and the pure isolates will be sent to us for further analysis. Promising pure compounds will ultimately be further tested in animal models to assess efficacy and toxicity. Mechanism of action studies will be conducted to study the molecular pharmacology of pure compounds with the most favorable therapeutic indices. The Director of Core A has well-established collaborations with all ofthe Project Leaders and Core Directors of this Program Project and has previously employed a variety of assays for natural product drug discovery. Our ongoing working relationships with other Projects and Cores and our ability to develop new biological assays as needed will assure that Core A is fully integrated in the program project and serves all projects therein. The Specific Aims for Core A are to (1) conduct cell-based assays on extracts and fractions provided by each Program. These assays will score the activity of specific molecular targets including inhibition of histone deacetylase (HDAC) or the 20S proteasome. We will work with Core C to determine the most active fractions and with the Program Leaders to decide which fractions will serve as source material for compound isolation. Our second aim is to test pure compounds in cell-free molecular target (HDAC & proteasome) assays to confirm activity and identify the most promising leads for in vivo studies. Our third aim is to assess the activity of our most promising active pure compounds in vivo. Before our animal studies are conducted, Core B will develop analytical assays, assess solubility, prepare appropriate formulations as needed and conduct preliminary pharmacokinetic and toxicity experiments. Based on data from these studies, we will work with Core B to establish the optimal formulation and dosing schedule for hollow fiber or tumor xenografts studies in immunodeficient mice. Further pharmacological studies will be performed on those pure compounds that prove to be effective anticancer agents with limited toxicity in mice. The biological assays outlined in this Core, used in concert with Cores B and C, will provide a solid foundation of support for all the Projects within the program and our industrial partner, Eisai, Inc. RELEVANCE (See instructions): The overarching goal of this Program Project is to isolate novel agents from natural sources for the treatment of cancer. The role of Core A is to provide biological testing using a variety of molecular, cellular and animal based systems to identify promising leads for further development. Core A will obtain materials for testing from each of the three Programs, work with Core C on statistical analysis, identify leads that Core B can modify to enhance activity and Eisai, Inc can further develop for translation into the clinic.

核心 A 将重点关注提取物、色谱馏分和纯分离物的生物学评价 由该计划内的所有项目准备，以帮助优先考虑后续的生物和 化学工作。这种使用生物测定引导分离的策略将为我们提供追求的机会 复杂混合物中的生物活性。发现核心 A 具有活性的提取物将通过以下方法进一步纯化： 项目 1-3（分别为 OSU、UIC 和 UNCG）和纯菌株将发送给我们进行进一步研究 分析。有前途的纯化合物最终将在动物模型中进行进一步测试以评估功效 和毒性。将进行作用机制研究以研究纯药物的分子药理学 具有最有利治疗指数的化合物。核心A的总监已经建立了完善的 与该计划项目的所有项目负责人和核心董事合作，并且之前曾 采用多种测定法来发现天然产物药物。我们与以下机构的持续合作关系 其他项目和核心以及我们根据需要开发新生物测定的能力将确保核心 A完全融入方案项目并服务其中的所有项目。核心 A 的具体目标是 (1) 对每个计划提供的提取物和级分进行基于细胞的测定。这些测定将 对特定分子靶标的活性进行评分，包括组蛋白脱乙酰酶 (HDAC) 或 20S蛋白酶体。我们将与 Core C 合作确定最活跃的部分并与该计划合作 领导者决定哪些馏分将作为化合物分离的源材料。我们的第二个目标是 在无细胞分子靶标（HDAC 和蛋白酶体）测定中测试纯化合物，以确认活性和 确定最有希望进行体内研究的先导化合物。我们的第三个目标是评估我们最重要的人的活动 有前景的体内活性纯化合物。在我们进行动物研究之前，Core B 将开发 分析测定，评估溶解度，根据需要制备适当的制剂并进行初步 药代动力学和毒性实验。根据这些研究的数据，我们将与 Core B 合作 建立中空纤维或肿瘤异种移植研究的最佳配方和给药方案 免疫缺陷小鼠。将对那些纯化合物进行进一步的药理学研究 被证明是有效的抗癌剂，对小鼠的毒性有限。本文概述的生物测定 核心与核心B和C配合使用，将为所有项目提供坚实的支持基础 在该计划和我们的工业合作伙伴卫材公司 (Eisai, Inc.) 的范围内。 相关性（参见说明）： 该计划的总体目标是从天然来源中分离出新制剂，用于 癌症的治疗。 Core A 的作用是使用各种分子、细胞来提供生物测试 和基于动物的系统，以确定有希望进一步开发的线索。核心A将获得材料 对于三个计划中每一个的测试，与核心 C 一起进行统计分析，确定潜在客户 Core B 可以进行修改以增强活性，卫材公司可以进一步开发以转化为临床。