Abstract
Purpose
One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [11C]tariquidar and [11C]elacridar with the Pgp substrate radiotracer (R)-[11C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model.
Methods
Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp-overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [11C]tariquidar (n = 7), [11C]elacridar (n = 6) and (R)-[11C]verapamil (n = 7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting.
Results
[11C]Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean ± SD areas under the time–activity curves in scan 1 from time 0 to 60 min (AUC0–60) were 38.8 ± 2.2 min and 25.0 ± 5.3 min (p = 0.016, Wilcoxon matched pairs test). [11C]Elacridar and (R)-[11C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil.
Conclusion
Among the tested radiotracers, [11C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [11C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours.
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Acknowledgments
The research leading to these results received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 201380 (“Euripides”) and from the Austrian Science Fund (FWF) project “Transmembrane Transporters in Health and Disease” (SFB F35). The authors thank Thomas Filip and Maria Zsebedics (Seibersdorf Laboratories GmbH) for their skilful help with laboratory animal handling, Christine Höpfner (Seibersdorf Laboratories GmbH) for assistance with cell culture and cytotoxicity assays and Elisabeth Mitterer and Romana Höftberger (Department of Neurology, Medical University of Vienna) for excellent histotechnical assistance.
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Wanek, T., Kuntner, C., Bankstahl, J.P. et al. A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer. Eur J Nucl Med Mol Imaging 39, 149–159 (2012). https://doi.org/10.1007/s00259-011-1941-7
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DOI: https://doi.org/10.1007/s00259-011-1941-7