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

The overexpression of two membrane glycoproteins, P-glycoprotein and m ultidrug-resistance protein (MRP1) is a major cause of resistance to c hemotherapeutic agents in the treatment of human cancers. Both protein s 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-glycoprote in and MRP1. It thus may provide additional information about the P-gl ycoprotein and MRP1 status of tumour cells. In order to obtain informa tion on the substrate specificity of these proteins, we have studied t he transport kinetics of Tc-MIBI in two cell lines, K562/ADR and GLC(4 )/ADR, which overexpress P-glycoprotein and MRP1, respectively. The me an 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 v alues are 50-100-times lower than for daunorubicin and other anthracyc line derivatives, strongly suggesting that the efficiency of both tran sporters to pump Tc-MIBI is by far less than that to efflux anthracycl ines. Our data show that (a) P-glycoprotein and MRP transporter effici encies to wash out Tc-MIBI are similar, in spite of a different suspec ted mechanism of its transport and (b) that both transporters are less efficient to pump Tc-MIBI than to pump anthracyclines (the k(a) param eter is about 100-times lower for TC-MIBI than for anthracycline).