ASSESSMENT OF THE NATURE INTENSITY & BASIS OF SYNERGISM

自然强度评估

• 批准号: 2685819
• 负责人: WILLIAM Robert GRECO
• 金额: $ 24.87万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2685819
• 关键词: antineoplastics; computer program /software; dihydrofolate reductase; dosage; drug interactions; drug metabolism; enzyme inhibitors; folate antagonist; mathematical model; model design /development; polyglutamates; statistics /biometry; tissue /cell culture

DESCRIPTION: The overall aim of the project is to complete the final stage of development of a paradigm for assessing the nature and intensity of empirical drug combined-action called the universal response surface approach (URSA). The following subprojects will be completed: (i) the validity and utility of a set of theoretical/empirical mathematical/statistical models, which were derived to describe concentration-effect (dose-response) phenomena and agent interaction, will be investigated in laboratory studies of anticancer agents and combinations of agents with three assays: a total growth assay (TGA), a colony count assay (CCA), and an individual colony formation assay (iCFA). The laboratory emphasis will be on the two clonogenic assays. Much of the work completed during the previous funding period with the TGA will be replicated in a more limited manner with the clonogenic assays. With the TGA, the applicant will emphasize the conduct of combined-action experiments with three or more agents. (ii) Based upon the results of subproject #1, older models will be modified when appropriate, and newer models will be created and tested when needed. Improvements will also be made to design and model-fitting techniques. (iii) The mechanistic basis of the super synergy found between dihydrofolate reductase inhibitors and polyglutamylatable antifolates will be explored with several intracellular assays, including assays of folate and antifolate polyglutamate distributions. (iv) The software package, SYNFIT, developed under RR10742, will be revised and distributed. Comments will be solicited from users, and appropriate additional improvements and enhancements made. A special effort will be made to enhance user aids, such as the tutorial, manual, and HELP functions. This will facilitate the proper use of the statistical approach.

描述：该项目的总体目标是完成最后阶段 发展一种模式，以评估 经验药物联合作用称为通用响应面 方法（URSA）。 将完成下列次级项目： 有效性和实用性的一套理论/经验 数学/统计模型，用于描述 浓度-效应（剂量-反应）现象和药物相互作用，将 在抗癌药物和组合的实验室研究中进行研究 通过三种测定法对试剂进行分析：总生长测定法（TGA）、菌落计数法 在一个实施方案中，所述方法包括单克隆形成测定（CCA）和个体集落形成测定（iCFA）。 的 实验室的重点将放在两个克隆形成试验上。 大部分工作 将复制在前一个资助期内与TGA一起完成的项目 以更有限的方式与克隆形成测定。 有了TGA， 申请人将强调进行联合作用实验， 三个或更多的代理人。 (ii)根据子项目#1的结果，旧 将在适当的时候修改模型，并创建更新的模型 并在需要时进行测试。 还将改进设计和 模型拟合技术 (iii)超协同效应的机理基础 在二氢叶酸还原酶抑制剂和聚谷氨酰化酶之间发现 抗叶酸剂将通过几种细胞内试验进行研究，包括 叶酸和抗叶酸聚谷氨酸分布的测定。 (iv)的 根据RR 10742开发的软件包SYNTFIT将进行修订， 发放 将征求用户的意见，并适当 进行了额外的改进和增强。 一项特别的努力将是 用于增强用户辅助功能，如教程、手册和HELP功能。 这将有助于正确使用统计方法。