Tc-99(m)-sestamibi imaging of inhibition of the multidrug resistance transporter in a mouse xenograft model of human breast cancer

Sestamibi is known to be a substrate for P-glycoprotein, the membrane trans porter which confers multidrug resistance by pumping certain chemotherapeut ic agents out of tumour cells. In this study, the utility of sestamibi imag ing for detecting inhibition of P-glycoprotein (Pgp) function by two potent , second-generation chemosensitizers, PSC833 and GG918, was assessed in a m ouse xenograft model of multidrug-resistant human breast cancer, MCF7-AdrR. Preliminary in vitro studies confirmed that MCF7-AdrR cells accumulate onl y low levels of sestamibi and that both sensitizers inhibit transporter fun ction to a similar extent, resulting in 20-fold higher accumulation of sest amibi. MCF7-AdrR cells were grown as a xenograft in SCID mice and sestamibi kinetics in the tumour were analysed by dynamic imaging (30 frames at a ra te of one frame per minute). Administration of either chemosensitizer produ ced a dose-dependent slowing of the efflux rate of sestamibi compared to un treated rumours. The same effect was evident in two additional parameters: percent activity remaining at 30 min determined by imaging and sestamibi le vels measured in excised tissues. These results show that sestamibi imaging can detect inhibition of Pgp function and suggest that this approach could be used clinically to document effective delivery of chemosensitizers. ((C ) 1999 Lippincott Williams & Wilkins).