Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576.
99mTc-sestamibi, a substrate of the multidrug transporter P-glycoprotein (Pgp), has been used as a functional imaging agent for the multidrug resistance-1 (MDR1) phenotype. In vitro, retention of (99m)Tc-sestamibi by cells that overexpress Pgp can be enhanced by the addition of Pgp inhibitors. XR9576 (Tariquidar) is a potent and selective noncompetitive inhibitor of Pgp that is active at 25-80 nM. A Phase I trial of XR9576 in combination with vinorelbine (Navelbine) was conducted in 26 patients with metastatic cancers. A (99m)Tc-sestamibi scan was obtained at baseline followed 48-96 h later by a second scan 1-3 h after the administration of XR9576. Time activity curves and areas under the curves (AUCs) were obtained for tumor, liver, lung, and heart, and tissue:heart AUC ratios were calculated. XR9576 enhanced (99m)Tc-sestamibi accumulation and retention in the liver of all but two patients with a mean change of +128%. Furthermore, in 13 of 17 patients with tumor masses visible by (99m)Tc-sestamibi, the tumor:heart (99m)Tc-sestamibi AUC(0-3 h) increased after the administration of XR9576, with increases of 36-263% seen in 8 patients. We conclude that in vivo administration of XR9576 inhibits (99m)Tc-sestamibi efflux in both the normal liver and in drug resistant tumors. This study provides convincing evidence of the existence of XR9576-inhibitable (99m)Tc-sestamibi efflux in a large fraction of drug resistant tumors. One can predict that efflux of Pgp substrates also occurs in these tumors. XR9576 provides an efficient way to inhibit this efflux and offers the potential to increase drug exposure in human cancer.
Agrawal
Manish
M
Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Abraham
Jame
J
Balis
Frank M
FM
Edgerly
Maureen
M
Stein
Wilfred D
WD
Bates
Susan
S
Fojo
Tito
T
Chen
Clara C
CC
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D019540:Area Under Curve; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging* / Q000187:drug effects; D008113:Liver Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011804:Quinolines / Q000494:pharmacology*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics*; D014747:Vinblastine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D000077235:Vinorelbine
D000972:Antineoplastic Agents, Phytogenic; D011804:Quinolines; D019275:Radiopharmaceuticals; D014747:Vinblastine; D017256:Technetium Tc 99m Sestamibi; C402343:tariquidar; D000077235:Vinorelbine