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Laboratory of Molecular Radiopharmacology, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Correspondence: For correspondence or reprints contact: David Piwnica-Worms, MD, PhD, Dept. of Radiology, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.
ABSTRACT
The multidrug-resistant P-glycoprotein is a Mr 170,000 plasma membrane protein encoded by the mammalian multidrug resistance gene (MDR) which appears to function as an efflux transporter of a variety of potent chemotherapeutic agents. Methods: To directly demonstrate that 99mTc-sestamibi is recognized by the human P-glycoprotein, we over expressed recombinant human MDR1 P-glycoprotein in host Sf9 insect cells using a baculoviral vector and correlated expression of the gene product with 99mTc-sestamibi accumulation. Results: In parental Sf9 cells and in wild-type baculovral infected (control) cells, 99mTc-sestamibi accumulation asymptotically approached a plateau of 650 fmoles (mg protein)–1 (nMo)–1 and 337 fmoles (mg protein)–1 (nMo)–1, respectively. In MDR1 baculoviral infected cells, P-glycoprotein expression was maximal at 72 hr postinfection, while 99mTc-sestamibi accumulation was reduced to 12 fmole (mgprotein)–1 (nMo)–1. Verapamil (500 µM), the classical MDR modulator, produced an 
300% enhancement of 99mTc-sestamibi accumulation in 519 cells expressing MDRI P-glycoprotein, but only a 50% enhancement in parental Sf9 cells, consistent with verapamil-induced inhibition of P-glycoprotein-mediated 99mTc-sestamibi efflux. Conclusions: These data demonstrate that the recombinant protein is transiently expressed in a functional state capable of drug transport in 519 cell membranes and that 99mTc-sestamibi is a transport substrate recognized by the human MDR1 P-glycoprotein. Technetium-99m-sestamibi may prove useful for functionally characterizing P-glycoprotein expression in human tumors in vivo.
Key Words: multidrug resistance • P-glycoprotein • baculovirus • isonitrile complex • verapamil • technetium-99m-sestamibi
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