Modulation of the multidrug resistance P-glycoprotein: detection with technetium-99m-sestamibi in vivo.
Overexpression of the multidrug resistance (MDR1) P-glycoprotein (Pgp) has been documented in nearly all forms of human cancers and increased levels of Pgp in some tumors correlate with poor response to treatment. Technetium-99m-sestamibi has recently been validated as a Pgp transport substrate. Pgp is also normally expressed along the biliary canalicular surface of hepatocytes and the luminal side of proximal tubule cells in the kidney, while not expressed in heart.


METHODS
Focused on these organs with known Pgp status, we present the findings on 99mTc-sestamibi scintigraphy of three patients with refractory cancer who were imaged before and after administration of SDZ PSC 833, a second-generation, high-potency modulator of Pgp.


RESULTS
Before treatment with SDZ PSC 833, scintigraphy using 99mTc-sestamibi showed normal, prompt clearance of the radiotracer from the liver and kidneys relative to the heart. After administration of the Pgp modulator, 99mTc-sestamibi was selectively retained in the liver and kidneys.


CONCLUSIONS
Hepatobiliary and renal clearance of 99mTc-sestamibi are Pgp-mediated, and inhibition of Pgp transport in these organs can be successfully imaged using 99mTc-sestamibi in patients. Similar results might be expected with this and related radiopharmaceuticals for functional imaging of Pgp transport and modulation in tumors.
Luker
G D
GD
Mallinckrodt Institute of Radiology, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
Fracasso
P M
PM
Dobkin
J
J
Piwnica-Worms
D
D
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy; D018270:Carcinoma, Ductal, Breast / Q000000981:diagnostic imaging / Q000188:drug therapy; D003524:Cyclosporins / Q000008:administration & dosage; D003536:Cystadenocarcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy; D018432:Drug Resistance, Multiple; D005260:Female; D006801:Humans; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism*; D008099:Liver / Q000000981:diagnostic imaging / Q000378:metabolism*; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage; D011877:Radionuclide Imaging; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D017256:Technetium Tc 99m Sestamibi; D017239:Paclitaxel; C070272:valspodar