Zosuquidar (LY335979) 3HCl is a novel and potent modulator of P-glycoprotein (P-gp) . P-gp is wildly expressed in brain, liver, small intestine and tumor cells and acts as an efflux pump responsible for multidrug resistance in tumor cells. Overexpression of Pgp in tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics . In vitro: In CEM/VLB100 cells, LY335979 treatment (0.1 μM) fully restored the sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol. In CEM/VLB100 plasma membranes, LY335979 blocked [3H]azidopinephotoaffinity labeling of the M(r) approximately 170,000 Pgp and competitively inhibited equilibrium binding of [3H]vinblastine to Pgp with the Ki value of approximately 0.06 μM . In all P-gp-expressing leukemia cell linesincluding K562/HHT40, K562/HHT90, K562/DOX and HL60/DNR, Zosuquidar completely or partially restored drug sensitivity. In primary AML blasts with active P-gp, Zosuquidar enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumabozogamicin (Mylotarg). In vivo: In mice bearing P388/ADR murine leukemia cells,treatment with LY335979 in combination with Dox or etoposide significantly increased in life span with no apparent alteration of pharmacokinetics. In a MDR human non-small cell lung carcinoma nude mouse xenograft model, LY335979 enhanced the antitumor activity of Taxol . Clinical trials: In patients with untreated non-Hodgkin's lymphoma,a phase I/II trial was conducted to investigate the safety and tolerance of zosuquidar. In patients giving three doses of 500 mg of zosuquidar p.o. in combination with CHOX, toxicity was minimal and no enhancement of CHOP-related toxicity was observed . In patients with advanced solid tumours in Phase I study, zosuquidar(100–300 mg/m2) can inhibit vinorelbine clearance to a modest degree.