In the United States, breast cancer is the most common malignancy in women. Although most women with advanced disease initially respond to chemotherapy, most die of recurrent and refractory disease. Emergence of multidrug resistance (MDR) in breast cancer mediated by the MDR1 P-glycoprotein has been associated with poor response to chemotherapy and a shorter overall survival. P-glycoprotein acts as an efflux transporter reducing the intracellular accumulation of many chemotherapeutic drugs. The multidrug resistance-associated protein (MRP), a homologue of P-glycoprotein, may also have a role in therapeutic response in breast cancer, but this is less well defined. Recently, several novel MDR antagonists (modulators) highly selective for P- glycoprotein have been commercially developed with nanomolar potency. Thus, functional identification of P-glycoprotein, and perhaps MRP, at the time of presentation could provide important information which could direct the choice of chemotherapeutic options. We have discovered that Tc-99m-Sestamibi, a commercially available radiopharmaceutical, is recognized as a transport substrate by the human MDR1 P-glycoprotein in vitro and in vivo and may be recognized by MRP, thus enabling functional identification of transporter-mediated resistance by scintigraphy. We propose to test the hypothesis that dynamic imaging of breast tumors with Tc-99m-Sestamibi will predict treatment failure in women with advanced breast carcinoma and determine whether P- glycoprotein and MRP together or independently impact Tc-99m- Sestamibi pharmacokinetics in breast tumors in vivo. These imaging studies will be integrated with a Phase II clinical trial of LY335979 (Eli Lilly and Co.), a potent new MDR modulator selective for inhibition of P-glycoprotein. Patients with advanced breast carcinoma will be imaged before and after administration of LY335979 as a pharmacokinetic endpoint to aid drug development. Functional imaging of the MDR phenotype with radiopharmaceuticals may provide a novel tool to rapidly characterize clinically relevant MDR in human tumors in vivo, target MDR modulators in vivo, and ultimately provide a means to direct patients to molecular-specific cancer therapies.
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