The goal of this application contains two parts. The first is to determine if the development of P-glycoprotein associated multidrug resistance (MDR) affect the clinical response of a patient to cancer chemotherapy. The second part is to investigate mechanisms regulating P-glycoprotein expression in normal and malignant cells. In model systems, P-glycoprotein has been shown to be causative of MDR and is thought to function as an energy-dependent drug efflux pump. Although other mechanisms of MDR have been proposed, the P-glycoprotein-mediated form is the best documented and appears to have clinical relevance. Since P-glycoprotein expression appears to be a reliable molecular marker for the MDR phenotype, one specific aim is to develop sensitive and specific reagents for the immunohistochemical localization of P- glycoprotein in tumor biopsy samples. One approach which has met with success is to map the epitopes of P-glycoprotein monoclonal antibodies and to use synthetic competing peptides to define epitope-specific staining. This approach will be extended to a number of P-glycoprotein monoclonal antibodies. Such reagents will be used for correlating P-glycoprotein expression and clinical response. The second specific aim is to determine if chemosensitizing agents azidopine and cyclosporin A interact with P-glycoprotein at a similar domain. Such knowledge will form the basis for a molecular understanding of how such structurally different molecules are able to reverse the MDR phenotype. The third specific aim is to study the mechanisms of increased P- glycoprotein expression in tumor cell lines. We particularly wish to investigate the observation that a significant proportion of patients present with P-glycoprotein positive tumors even prior to chemotherapy. This may provide insights into why some tumors are not responsive to chemotherapy from the outset. We believe that accomplishment of the specific aims described in this application will add significantly to our knowledge of malignant development and therapeutic efficacy in human cancer.
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