TC-99M-SESTAMIBI IS A SUBSTRATE FOR P-GLYCOPROTEIN AND THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN

Tc-99m-sestamibi (Tc-99m-MIBI) is a substrate for the P-glycoprotein ( P-gp) pump but it is not known whether it is a substrate for the multi drug resistance-associated protein (MRP) pump. Therefore, Tc-99m-MIBI was evaluated in the GLC(4) cell line and its doxorubicin-resistant MR P-, but not P-gp-, overexpressing GLC(4)/ADR sublines as well as in th e S1 cell line and its MRP-transfected subline S1-MRP. Tc-99m-MIBI con centration decreased in the GLC(4)/ADR sublines with increasing MRP ov erexpression and was lower in S1-MRP than in S1. Tc-99m-MIBI plus vinc ristine increased Tc-99m-MIBI concentration in GLC(4) lines compared w ith Tc-99m-MIBI alone. Tc-99m-MIBI efflux raised with increasing MRP e xpression in the GLC(4) lines. Glutathione depletion elevated Tc-99m-M IBI concentration in GLC(4)/ADR(150x). Cross resistance for Tc-99-MIBI , used to test cytotoxicity of the Tc compound, was observed in GLC(4) /ADR(150x) vs GLC(4). Tc-99-MIBI induced a synergistic effect on vincr istine cytotoxicity in GLC(4)/ADR(150x). These results show that Tc-99 m-MIBI is involved in MRP-mediated efflux. The fact that Tc-99m-MIBI e fflux is influenced by MDR1 and MRP expression must be taken into acco unt when this gamma-rays-emitting complex is tested for tumour efflux measurements.