Reversal of P-Glycoprotein-mediated Multidrug Resistance by a Potent Cyclopropyldibenzosuberane Modulator, LY335979

摘要: Abstract Overexpression of P-glycoprotein (Pgp) by tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics. MDR cells may be sensitized these oncolytics when treated with a Pgp modulator. The present study evaluates LY335979 as modulator both vitro and vivo. (0.1 µm) fully restored sensitivity vinblastine, doxorubicin (Dox), etoposide, Taxol CEM/VLB100 cells. Ly335979 modulated Dox cytotoxicity even (0.5 was removed 24 h prior the assay. blocked [3H]azidopine photoaffinity labeling Mr ∼170,000 plasma membranes competitively inhibited equilibrium binding [3H]vinblastine (Ki ∼0.06 µm). Treatment mice bearing P388/ADR murine leukemia combination or etoposide gave significant increase life span no apparent alteration pharmacokinetics. also enhanced antitumor activity human non-small cell lung carcinoma nude mouse xenograft model. Thus, is an extremely potent, efficacious that apparently lacks pharmacokinetic interactions coadministered anticancer drugs is, therefore, exciting new agent for clinical evaluation reversal Pgp-associated MDR.