Biological Correlation and Anaysis

生物学关联与分析

• 批准号: 8932994
• 负责人: STEVEN M SWANSON
• 金额: $ 23.54万
• 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/8932994
• 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 Formulations; Drug Kinetics; Evaluation; Fiber; Foundations; Goals; Histone Deacetylase; Histone deacetylase inhibition; Immunodeficient Mouse; Induction of Apoptosis; Instruction; Materials Testing; Molecular; Molecular Target; Mus; Natural Product Drug; Pharmacology; Role; Schedule; Solid; Solubility; Source; 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、色谱组分和纯分离株的生物学评价 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。这种利用生物测定引导分离的策略将为我们提供机会， 复杂混合物中的生物活性。通过核心A发现活性的提取物将进一步纯化， 项目1-3（分别为OSU、UIC和UNCG）和纯分离株将发送给我们进行进一步的研究。 分析.有希望的纯化合物最终将在动物模型中进行进一步测试以评估疗效 和毒性。将进行作用机制研究，以研究纯化合物的分子药理学。 具有最有利的治疗指数的化合物。核心A的主任已经建立了良好的 与本计划项目的所有项目负责人和核心主任合作，并已在此之前 采用了多种用于天然产物药物发现的测定。我们与以下机构的持续工作关系 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完全集成在计划项目中，并为其中的所有项目提供服务。核心A的具体目标是 （1）对每个程序提供的提取物和组分进行基于细胞的测定。这些分析将 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 20 S蛋白酶体。我们将与核心C合作，以确定最活跃的部分，并与该计划 领导人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）试验中测试纯化合物，以确认活性， 确定最有前途的铅在体内研究。我们的第三个目标是评估我们最重要的活动， 有前途的体内活性纯化合物。在我们的动物研究进行之前，核心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。基于这些研究的数据，我们将与核心B合作， 建立中空纤维或肿瘤异种移植物研究的最佳制剂和给药方案， 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， 证明是有效的抗癌剂，在小鼠中具有有限的毒性。本文中概述的生物测定法 核心与核心B和核心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，Pastai，Inc。 相关性（参见说明）： 该计划项目的总体目标是从自然来源中分离新的代理人， 癌症的治疗。核心A的作用是使用各种分子、细胞和生物学方法提供生物学测试。 和动物为基础的系统，以确定有前途的线索，以进一步发展。核心A将获得材料 对于三个项目中的每一个项目的测试，与核心C一起进行统计分析，确定 核心B可以进行修饰以增强活性，并且Kidai，Inc可以进一步开发以用于临床。