Research Project
6491806
The main function of the Bioassay Core is to assist the other Projects to identify those retinoids that are the most suitable as probes to study the molecular mechanism of retinoid action and those that have the highest potential as chemotherapeutic agents against breast cancer. Three classes of retinoids that have inhibitory activity against breast cancer growth, will be evaluated: (1) retinoids inducing gene transcription from retinoid response elements; (2) retinoids indirectly repressing gene transcription from AP-1 sites located in the promoter regions of genes involved in cell proliferation; and (3) retinoids inducing apoptosis. The Core will have the tasks of (1) evaluating these compounds for binding affinity to recombinant retinoid receptors to determine agonist or antagonist activity or for the lack of retinoid binding to the receptors in the case of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2- naphthalenecarboxylic acid (AHPN) analogs to limit toxicity (2) determining by an antiangiogenesis assay in chick chorioallantoic membrane the ability of retinoids and AHPN analogs to inhibit vascularization of tumors, a process that promotes tumor growth and spread, to determine optimum candidates for the breast cancer xenograft experiments (3) conducting pharmacological/toxicological/metabolism studies in animals; and (4) systematically analyzing the results of these assays to select the optimum targets for mechanistic studies, lead optimization, further bioevaluation in the drug development process or recommendation for additional study by NCI. Pharmacological/tocixological/metabolism studies will include determination of candidate agent levels in plasma from treated mice to determine drug dosage for breast cancer xenograft inhibition studies toxicological assessment in mice; and determination of major metabolites and autometabolism potential. The NCI Decision Network method for setting selection criteria, marking rankings, and weighing assay results will be used to rank and then select the most promising retinoids as molecular probes or as therapeutic candidates.
