Comparison of the kinetics of active efflux of Tc-99m-MIBI in cells with P-glycoprotein-mediated and multidrug-resistance protein-associated multidrug-resistance phenotypes

Abstract

The overexpression of two membrane glycoproteins, P-glycoprotein and multidrug-resistance protein (MRP1) is a major cause of resistance to chemotherapeutic agents in the treatment of human cancers. Both proteins confer a similar multidrug-resistant (MDR) phenotype. Tc-99m-MIBI, a myocardial imaging agent, which is also useful for the detection of a variety of tumours, has been shown to be a substrate for P-glycoprotein and MRP1. It thus may provide additional information about the P-glycoprotein and MRP1 status of tumour cells. In order to obtain information on the substrate specificity of these proteins, we have studied the transport kinetics of Tc-MIBI in two cell lines, K562/ADR and GLC(4)/ADR, which overexpress P-glycoprotein and MRP1, respectively. The mean active efflux coefficient k(a), which is proportional to the ratio of maximal efflux rate V-M to the apparent Michaelis-Menten constant K-m, used to characterise the efficiency of the active efflux, was very similar being 1.9+/-0.6X10(-11) s(-1).cells.ml and 1.3+/-0.5X10(-11) s(-1).cells.ml for drug-resistant K562 and GLC4, respectively. These values are 50-100-times lower than for daunorubicin and other anthracycline derivatives, strongly suggesting that the efficiency of both transporters to pump Tc-MIBI is by far less than that to efflux anthracyclines. Our data show that (a) P-glycoprotein and MRP transporter efficiencies to wash out Tc-MIBI are similar, in spite of a different suspected mechanism of its transport and (b) that both transporters are less efficient to pump Tc-MIBI than to pump anthracyclines (the k(a) parameter is about 100-times lower for TC-MIBI than for anthracycline)