ASSESSMENT OF THE NATURE INTENSITY & BASIS OF SYNERGISM

描述：该项目的总体目标是完成最后阶段 发展一种评估疾病性质和强度的范例 经验药物联合作用称为通用响应面 进场(URSA)。将完成以下分项目：(I) 一套理论/经验的有效性和实用性 数学/统计模型，这些模型是为了描述 浓度-效应(剂量-反应)现象和药剂相互作用 在抗癌药物及其组合的实验室研究中进行研究 三种检测方法：总生长试验(TGA)、菌落计数 和个体集落形成试验(ICFA)。这个 实验室的重点将放在两种克隆生成分析上。大部分工作 在上一个资助期内完成的TGA将被复制 以更有限的方式与克隆性分析。有了TGA， 申请者将强调进行联合行动实验与 三个或三个以上的代理。(2)根据次级项目#1的结果，较老 将在适当的时候修改模型，并创建较新的模型 并在需要时进行测试。还将对设计和设计进行改进 模型拟合技术。(三)超级协同的机制基础 在二氢叶酸还原酶抑制剂和聚谷氨酰胺之间发现 抗叶酸将通过几种细胞内分析方法进行探索，包括 叶酸和抗叶酸多聚谷氨酸分布的测定。(Iv) 在RR10742下开发的软件包SYNFIT将进行修订和 分布式的。将征求用户的意见，并适当 进行了其他改进和增强。一项特别努力将是 用于增强用户辅助功能，如教程、手册和帮助功能。 这将有助于正确使用统计方法。

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.