PT  - JOURNAL ARTICLE
AU  - Agrawal, Manish
AU  - Abraham, Jame
AU  - Balis, Frank M.
AU  - Edgerly, Maureen
AU  - Stein, Wilfred D.
AU  - Bates, Susan
AU  - Fojo, Tito
AU  - Chen, Clara C.
TI  - Increased <sup>99m</sup>Tc-Sestamibi Accumulation in Normal Liver and Drug-resistant Tumors after the Administration of the Glycoprotein Inhibitor, XR9576
DP  - 2003 Feb 01
TA  - Clinical Cancer Research
PG  - 650--656
VI  - 9
IP  - 2
4099  - http://clincancerres.aacrjournals.org/content/9/2/650.short
4100  - http://clincancerres.aacrjournals.org/content/9/2/650.full
SO  - Clin Cancer Res2003 Feb 01; 9
AB  - 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 99mTc-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 99mTc-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 99mTc-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 99mTc-sestamibi, the tumor:heart 99mTc-sestamibi AUC0–3 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 99mTc-sestamibi efflux in both the normal liver and in drug resistant tumors. This study provides convincing evidence of the existence of XR9576-inhibitable 99mTc-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.