Technetium-99m-tetrofosmin as a substrate for P-glycoprotein: In vitro studies in multidrug resistant breast tumor cells

The accumulation of Tc-99m-tetrofosmin (TFos) was studied in wild-type (WT) and doxorubicin-resistant (Adr(R)) variants of the rat MatB and human MCF-7 breast tumor cell lines to determine whether TFos, like Tc-99m-sestamibi (MIBI), is a substrate for P-glycoprotein (P-gp), a multidrug-resistance transporter. Methods: The time course of accumulation oi TFos and MIBI in WT and Adr(R) cells over 1 hr was studied using single-cell suspensions at 1 x 10(6) cells/ml incubated at 37 degrees C in the presence or absence of PSC833, a potent modulator of P-gp. Modulator dose-response curves were generated for PSC833, cyclosporin A, and verapamil. Results: In both MatB and MCF-7 cells, TFos and MIBI accumulated extensively in WT cells and accumulation was not affected by PSC833. In contrast, Adr(R) cell lines accumulated very little of either tracer, but addition of PSC833 or other modulator increased this accumulation in a dose-dependent fashion. TFos and MIBI did not differ significantly in their behavior. Conclusion: TFos shares with MIBI the property of being a substrate for P-gp and thus TFos may be useful for functional imaging of tumor P-gp status.