The overall aim of the project is to further develop and validate a new comprehensive concentration-time-effect modeling paradigm, created during the last 3-year funding period of RRI 0742 for single agents and for high order combinations of agents, for anticancer chemotherapy and other pharmacological applications, with new emphases on the measurement of individual cell responses, cell response heterogeneity quantification, assays of molecular targets, and the use of molecularly-targeted agents. The final modeling paradigm which will result from this project is intended to bridge the gap between traditional pharmacometrics and the new era of molecular bioinformatics.
The Specific Aims i nclude: 1. The validity and utility of a new mathematical! . statistical modeling paradigm, derived to describe concentration-time-effect phenomena for single agents and 2-agent, 3-agent, 4-agent and 5-agent combinations, will be investigated in a well-characterized, simple in vitro antiproliferation assay, the total growth assay (TGA). Specific combinations of anticancer agents will include both classic clinically-used agents and novel molecularly-targeted signal transduction inhibitors. 2. A multiplex time lapse video system (mpTLV) with automated image analysis tracking of cells in the digital video record will be developed, to allow detailed analysis of cellular response to anticancer agents to be done rapidly. 3. Mathematical/statistical models of proliferative and cell death response to single anticancer agents and combinations of agents, that include individual cell responses of growth delay, growth slow-down, growth arrest, apoptosis, and other forms of cell death, will be derived to provide a more detailed knowledge of cellular response. 4. D-optimal statistical design methodology for the Hill concentration-effect model developed under RR1 0742 for single agent concentration-effect studies, will be further developed for applications to the complex studies in Specific Aims #1 and #3. 5. An Internet Web site will be created to give the scientific public assess to: the rich data sets generated; the data analysis and modeling tools developed; results; and a discussion room for the general topic of concentration-time-effect and synergy modeling.
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