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Characterization of P-Glycoprotein Transport and Inhibition in Vivo¹

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 [E. B., J. F. K., A. G. J.]; Novartis, East Hanover, New Jersey 07936 [D. C.]; Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 [A. D.]; and Dana-Farber Cancer Institute, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115 [J. M. C.].

The P-glycoprotein is an energy-dependent efflux pump capable of decreasing the intracellular concentration of a broad range of chemotherapeutic agents. [^99mTc]Sestamibi, a P-glycoprotein transport substrate, is a sensitive probe of P-glycoprotein function both in vitro and in vivo. A human tumor model in nude mice was evaluated to determine whether [^99mTc]Sestamibi could detect in vivo differences in P-glycoprotein expression and P-glycoprotein modulation by the reversal agent SDZ PSC 833. Differential [^99mTc]Sestamibi accumulation based upon P-glycoprotein expression was demonstrated in xenografts in vivo. Dose-dependent inhibition of P-glycoprotein function was achieved with SDZ PSC 833. Administration of the reversal agent increased [^99mTc]Sestamibi accumulation in the xenografts expressing P-glycoprotein. These observations show that [^99mTc]Sestamibi as capable of detecting the modulation of P-glycoprotein in a solid tumor model by the reversal agent SDZ PSC 833.

¹ This work was supported by grants from Sandoz Pharmaceuticals, the American Cancer Society (JFRA 420), the Dana-Farber Cancer Institute, Du Pont Merck Pharmaceuticals, and by USPHS Grant R37 CA34970.

² To whom requests for reprints should be addressed, at Section of Pediatric Hematology/Oncology, James Whitcomb Riley Hospital for Children, Room 2720, 702 Barnhill Drive, Indianapolis, IN 46202. E-mail: James_Croop@iucc.iupui.edu.

Received 7/ 1/97. Accepted 11/13/97.

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