Correlation between the kinetics of anthracycline uptake and the resistance factor in cancer cells expressing the multidrug resistance protein or theP-glycoprotein

Multidrug resistance (MDR) in model systems is known to be conferred by two different integral proteins, the 170-kDa P-glycoprotein (Pgp) and the 190- kDa multidrug resistance associated protein (MRP1). One possible pharmacolo gical approach to overcome drug resistance is the use of specific inhibitor s, which enhance the cytotoxicity of known antineoplastic agents. However, while many compounds have been proven to be very efficient in inhibiting Pg p activity only some of them are able to inhibit MRP1. The other Likely app roach is based on the design and synthesis of new non-cross-resistant drugs with physicochemical properties favoring the uptake of the drug by the res istant cells. The intracellular drug retention influences its cytotoxic eff ect. The level of the intracellular drug content is a function of the amoun t of drug transported inside the cell (influx) and the amount of drug expel led from the cell (efflux). In this work, the kinetics of drug uptake and t he kinetics of active efflux of several anthracycline derivatives in both P gp expressing K562/Adr cells and MRP1 expressing GLC4/Adr cells was determi ned. Our data have shown that in both cell lines there is no correlation be tween the resistance Factor and the kinetics of drug efflux by these pumpin g systems. However, a very good correlation between the resistance factor a nd the kinetics of drug uptake has been established in both cell lines: the resistance factor decreases when the kinetics of drug uptake increases; Th is work has clearly shown that when the rate of transmembrane transport of anthracycline is high enough, the efflux mediated by the protein transporte r is not able to pace with it. The protein transporter essentially operates in a futile cycle and the resistance factor is tending to one. It does not mean, however, that when the resistance factor is close to one the anthrac ycline is not transported by the pump. (C) 1999 Elsevier Science B.V. All r ights reserved.