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

Publisher Website
Google Scholar
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. 99mTc‐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 GLC4/ADR, which overexpress P‐glycoprotein and MRP1, respectively. The mean active efflux coefficient ka, which is proportional to the ratio of maximal efflux rate VM to the apparent Michaelis‐Menten constant Km, used to characterise the efficiency of the active efflux, was very similar being 1.9 ± 0.6×10−11 s−1 cells ml and 1.3 ± 0.5×10−11 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 ka parameter is about 100‐times lower for TC‐MIBI than for anthracycline).

This publication has 0 references indexed in Scilit: