The antiestrogen tamoxifen (tam) is the most frequently used drug in breast cancer management today. Unfortunately its use is limited by the eventual development of acquired resistance in all patients, by mechanisms that are largely unknown. Clinical evidence as well as preliminary data from our laboratory, using both human breast cancer cells in an in vivo nude-mouse model as well as clinical samples from patients, suggests that """"""""tam resistance"""""""" is associated with the acquired ability of tam over time to stimulate rather than to inhibit tumor growth. This tam-stimulated growth is characterized by lower tam levels in tumor extracts and by an altered tam metabolite profile in the tumor. These data have led us to the hypothesis that one mechanism of acquired tam resistance is altered uptake and metabolism of tam by the tumor itself, leading to a relative abundance of estrogenic metabolites that then stimulate tumor growth. To further test our hypothesis, the following specific aims are proposed: 1. To identify and quantify tam and its antiestrogenic and estrogenic metabolites in tam sensitive and tam resistant tumors in the nude mouse model. These studies will determine whether acquired tam resistance is due to decreased accumulation of drug in the tumor, induction of tam metabolism, and/or accumulation of known estrogenic metabolites within the tumor itself. 2. To serially measure tam and its metabolites in tumor, liver, uterus, and serum to determine whether an altered metabolic profile with time signals the appearance of resistance. We will also determine whether tumor metabolism or systemic metabolism is primarily responsible for the altered tumor metabolite, profile characteristic of resistance. 3. To determine if acquired tam resistance can be reversed or whether antiestrogen resistance can be delayed by new steroidal antiestrogens, non-isomerizable tam analogs, or newly synthesized tam analogs designed to chemically block conversion to estrogenic metabolites. 4. To test the hypothesis that reduced tam accumulation in resistant tumors is due to an active efflux mechanism, and to determine if tam resistant tumors show cross resistance to other chemotherapeutic agents. 5. To quantify tam and its metabolites in serum, peripheral leukocytes, and tumors from patients who are responding to tam compared to those with acquired resistance, in order to confirm that a similar pattern of altered tam metabolism is also observed in patients. These studies will yield new and important information on the mechanisms of acquired tamoxifen resistance and its possible reversal that will have immediate clinical application for breast cancer.
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