Despite intense interest in multidrug resistance (MDR) mediated by P-glycoprotein, the mdr1 gene product, there has been little success in altering the course of patients with resistant malignancies. The applicant has developed modulators of MDR through an understanding of the structure activity relationships of phenothiazines and related compounds. This work identified key structural features for modulating activity, and gave insight into the drug binding site on the transporter. He now proposes to develop more effective MDR modulators by synthesizing compounds with the potential for irreversible binding to P-glycoprotein. He has synthesized fluphenazine mustard and propose to use a similar approach to make the mustard derivative of trans-flupenthixol, a more active thioxanthene derivative. He also found that terfenadine (Seldane), a drug with unique pharmacological properties was an active modulator and proposes to follow previously derived structural paradigms to uncover more effective compounds. Preliminary results have shown that one derivative, compound 9917A, is 50-fold more effective than either terfenadine or trans-flupenthixol. The applicant's interest in calcium mediated signal transduction led him to study the enzymes involved in modulating the activity of P-glycoprotein. He found that protein kinase C (PKC); activity was increased in certain MDR lines; could phosphorylate immunopurified P-glycoprotein; activators increased phosphorylation of P-glycoprotein and increased drug resistance and; inhibitors had the opposite effect. Little is known about the mechanism(s) by which the cell recognizes the presence of chemotherapeutic drugs and signals the essential kinases and phosphatases that appear to regulate P-glycoprotein. The applicant proposes that phosphorylation of P-glycoprotein represents a response to cellular stress, and hypothesizes that this is initiated by activation of phospholipase C (PLC). Preliminary studies suggest that PLC is activated in response to heat shock, leading to PKC-mediated phosphorylation of P-glycoprotein. He will determine whether or not this pathway is activated during exposure to chemotherapeutic drugs.
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