ASSESSMENT OF NATURE AND BASIS OF SYNERGISM

该项目的总体目标是验证、探索 更新和传播在CA46732下开发的方法 评估经验药物相互作用的性质和强度(Loewe 协同、罗威拮抗、罗威相加、协同、拮抗和 协同论)，称为通用响应面方法(URSA)。这 关于继续使用CA46732的提案强调迫切需要 探索一系列问题的实验室实验，这些问题产生于 关于药物的数学/统计建模工作的结果 在过去三年中完成的互动。要完成以下任务 单一的、集中的目标是促进URSA产生巨大的积极影响 对在世界范围内进行研究的效果的影响 在抗癌药物组合方面，将完成几个分项目： L。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， 将在实验室研究中进行调查，专门为 这一目标，抗癌药物及其与三种药物的组合 检测、总生长试验(TGA)、菌落计数试验(CCA)和 个体集落形成试验(ICFA)。 2.根据子项目#1的结果，将修改较旧的型号 在适当的时候，将在以下情况下创建和测试较新的型号 需要的。还将在设计和模型装配方面进行改进 技巧。 3.为研究抗癌药物的作用机制 相互作用，开发的经验模型之间的关系 在CA46732下，用一套细胞内的理论模型 我们将探索新陈代谢。 4.软件包的第一个版本--SYNFIT，是根据 CA46732，将被分发，向用户征求意见，以及 进行了适当的改进和增强。具体增强功能 已经制定的计划包括：a)纳入广义非线性 建模程序，经过竞争对手的数值算法进行推广 对非线性模型进行了比较；b)引入了D-最优 和其他统计试验设计程序，经过竞争 比较了这些程序的数值算法；c) 结合3-D图形程序。

The overall aim of the project is to validate, explore the basis of, update, and disseminate the approach developed under CA46732 for assessing the nature and intensity of empirical drug interactions (Loewe synergism, Loewe antagonism, Loewe additivity, synergism, antagonism and coalism), called the universal response surface approach (URSA). This proposal for the continuation of CA46732 emphasizes the critical need for laboratory experiments to explore a set of questions which came about as a result of the mathematical/statistical modeling work on drug interactions completed during the last three years. To accomplish the singular, focused aim of facilitating URSA to make a large positive impact on the conduct of research worldwide into the efficacy of anticancer drug combinations, several subprojects will be completed: l. 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, specifically designed for this goal, 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). 2. 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. 3. In order to investigate the mechanistic basis of anticancer drug interactions, the relationship between the empirical models developed under CA46732, with a set of theoretical models of intracellular metabolism will be explored. 4. The first version of the software package, SYNFIT, developed under CA46732, will be distributed, comments solicited from users, and appropriate improvements and enhancements made. Specific enhancements already planned include: a) the incorporation of generalized nonlinear modeling procedures, after rival numerical algorithms for generalized nonlinear modeling have been compared; b) the incorporation of D-optimal and other statistical experimental design procedures, after rival numerical algorithms for these procedures have been compared; c) the incorporation of 3-D graphical procedures.