REVERSAL OF P-GLYCOPROTEIN-MEDIATED MULTIDRUG-RESISTANCE BY A POTENT CYCLOPROPYLDIBENZOSUBERANE MODULATOR, LY335979

Overexpression of P-glycoprotein (Pgp) by tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics. MDR cells may b e sensitized to these oncolytics when treated with a Pgp modulator. Th e present study evaluates LY335979 as a modulator both in vitro and in vivo. LY335979 (0.1 mu M) fully restored sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol in CEM/VLB(100) cells. LY33597 9 modulated Dox cytotoxicity even when LY335979 (0.5 mu M) was removed 24 h prior to the cytotoxicity assay, LY335979 blocked [H-3]azidopine photoaffinity labeling of the M(r) similar to 170,000 Pgp in CEM/VLB( 100) plasma membranes and competitively inhibited equilibrium binding of [H-3]vinblastine to Pgp (K-i of similar to 0.06 mu M). Treatment of mice bearing P388/ADR murine leukemia cells with LY335979 in combinat ion with Dox or etoposide gave a significant increase in life span wit h no apparent alteration of pharmacokinetics. LY335979 also enhanced t he antitumor activity of Taxol in a MDR human non-small cell lung carc inoma nude mouse xenograft model. Thus, LY335979 is an extremely poten t, efficacious modulator that apparently lacks pharmacokinetic interac tions with coadministered anticancer drugs and is, therefore, an excit ing new agent for clinical evaluation for reversal of Pgp-associated M DR.