The pharmacology core service will provide several levels of service each project. These services include (1) the development, or adaptation of existing analytical procedures for detecting novel compounds in biological matrices; (2) the application of these procedures to blood, tumor and surrogate tissues such as peripheral blood white blood cells; (3) the mathematical description of the pharmacokinetics of each novel agent; and most importantly, (4) the development of pharmacodynamic correlations of each agent s pharmacokinetic disposition with biologic outcomes, including antitumor response and perturbation of the specific molecular target. To accomplish these goals, the service will utilize established high performance liquid chromatographic (1- IPLC) assays for analyzing novel inhibitors of l) VEGF in Project 2 (thalidomide and SU-5416; (2) heat shock protein-90 in Project 3 (17-AA-gledanamycin and chlorobiocin). For Project 1, anew gas chromatographic assay will be developed for the signal transduction inhibitor DPIEL. An existing radiolabeled wortmanin assay will be used for detecting this agent in Project 1. The data on plasma and tumor levels of these agents will be analyzed by non-compartmental methods to derive standard pharmacokinetic indices, and most importantly, the area under the plasma (or tumor) concentration x time curve, (AUC), in the tumor-bearing rodent models. Pharmacodynamic correlations will be performed for these pharmacokinetic parameters with, (1) the inhibition of Tumor growth and (2), the degree of perturbation of the molecular target. This will facilitate the overall goal of describing target AUCs which will need to be achieved in human trials of each agent, and the degree of target inhibition achieved by different doses and schedules of each novel agent.
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