Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells

Resistance to chemotherapy by some human tumors may be due to overexpressio n of membrane-associated transport proteins. The best characterized of thes e is the multidrug resistance (MDR) transporter, P-glycoprotein (Pgp). The aim of this study was to measure the inhibitory effects of a potent new MDR modulator, (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl) pip erazin-1-yl]-2 -hydroxypropoxy}quinoline trihydrochloride (LY335979), in th e drug-resistant cell line HL60/VCR and in normal, human CD56(+) lymphocyte s. We used flow cytometric methods to detect the accumulation of rhodamine 123 and daunorubicin, fluorescent MDR substrates, in these cells. Our resul ts indicate that LY335979 was 500-1500 times more potent than cyclosporin A or verapamil in restoring Pgp substrate accumulation in the MDR cell line HL60/VCR. Moreover, LY335979 could effectively block Pgp function on isolat ed CD56+ lymphocytes (IC50 = 1.2 nM) or CD56(+) lymphocytes in whole blood (IC50 = 174 nM). We conclude that LY335979 is among the most potent Pgp inh ibitors described and that it maintains significant potency in whole-human blood. These latter findings are important for establishing the dosing regi mens of LY335979 for future clinical studies. (C) 2001 Elsevier Science Inc . All rights reserved.