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European Journal of Nuclear Medicine and Molecular Imaging

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01-01-2012 | Original Article

A comparative small-animal PET evaluation of [¹¹C]tariquidar, [¹¹C]elacridar and (R)-[¹¹C]verapamil for detection of P-glycoprotein-expressing murine breast cancer

Authors: Thomas Wanek, Claudia Kuntner, Jens P. Bankstahl, Marion Bankstahl, Johann Stanek, Michael Sauberer, Severin Mairinger, Sabine Strommer, Volker Wacheck, Wolfgang Löscher, Thomas Erker, Markus Müller, Oliver Langer

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 1/2012

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 (AUC_0–60) 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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Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2:48–58.PubMedCrossRef

Sarkadi B, Homolya L, Szakacs G, Varadi A. Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev. 2006;86:1179–236.PubMedCrossRef

Tiwari AK, Sodani K, Dai CL, Ashby Jr CR, Chen ZS. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol. 2011;12:570–94.PubMedCrossRef

Fox E, Bates SE. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev Anticancer Ther. 2007;7:447–59.PubMedCrossRef

Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–34.PubMedCrossRef

Kannan P, John C, Zoghbi SS, Halldin C, Gottesman MM, Innis RB, et al. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin Pharmacol Ther. 2009;86:368–77.PubMedCrossRef

Piwnica-Worms D, Kesarwala AH, Pichler A, Prior JL, Sharma V. Single photon emission computed tomography and positron emission tomography imaging of multi-drug resistant P-glycoprotein – monitoring a transport activity important in cancer, blood-brain barrier function and Alzheimer's disease. Neuroimaging Clin N Am. 2006;16:575–89.PubMedCrossRef

Abraham J, Edgerly M, Wilson R, Chen C, Rutt A, Bakke S, et al. A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine. Clin Cancer Res. 2009;15:3574–82.PubMedCrossRef

Agrawal M, Abraham J, Balis FM, Edgerly M, Stein WD, Bates S, et al. Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576. Clin Cancer Res. 2003;9:650–6.PubMed

10.

Kelly RJ, Draper D, Chen CC, Robey RW, Figg WD, Piekarz RL, et al. A pharmacodynamic study of docetaxel in combination with the P-glycoprotein antagonist tariquidar (XR9576) in patients with lung, ovarian, and cervical cancer. Clin Cancer Res. 2011;17:569–80.PubMedCrossRef

11.

Kurdziel KA, Kalen JD, Hirsch JI, Wilson JD, Agarwal R, Barrett D, et al. Imaging multidrug resistance with 4-[18F]fluoropaclitaxel. Nucl Med Biol. 2007;34:823–31.PubMedCrossRef

12.

Hendrikse NH, de Vries EG, Eriks-Fluks L, van der Graaf WT, Hospers GA, Willemsen AT, et al. A new in vivo method to study P-glycoprotein transport in tumors and the blood-brain barrier. Cancer Res. 1999;59:2411–6.PubMed

13.

Dörner B, Kuntner C, Bankstahl JP, Bankstahl M, Stanek J, Wanek T, et al. Synthesis and small-animal positron emission tomography evaluation of [11C]-elacridar as a radiotracer to assess the distribution of P-glycoprotein at the blood-brain barrier. J Med Chem. 2009;52:6073–82.PubMedCrossRef

14.

Bauer F, Kuntner C, Bankstahl JP, Wanek T, Bankstahl M, Stanek J, et al. Synthesis and in vivo evaluation of [11C]tariquidar, a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor. Bioorg Med Chem. 2010;18:5489–97.PubMedCrossRef

15.

Luurtsema G, Molthoff CF, Schuit RC, Windhorst AD, Lammertsma AA, Franssen EJ. Evaluation of (R)-[11C]verapamil as PET tracer of P-glycoprotein function in the blood-brain barrier: kinetics and metabolism in the rat. Nucl Med Biol. 2005;32:87–93.PubMedCrossRef

16.

Bankstahl JP, Kuntner C, Abrahim A, Karch R, Stanek J, Wanek T, et al. Tariquidar-induced P-glycoprotein inhibition at the rat blood-brain barrier studied with (R)-11C-verapamil and PET. J Nucl Med. 2008;49:1328–35.PubMedCrossRef

17.

Kuntner C, Bankstahl JP, Bankstahl M, Stanek J, Wanek T, Stundner G, et al. Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[11C]verapamil PET. Eur J Nucl Med Mol Imaging. 2010;37:942–53.PubMedCrossRef

18.

Twentyman PR, Reeve JG, Koch G, Wright KA. Chemosensitisation by verapamil and cyclosporin A in mouse tumour cells expressing different levels of P-glycoprotein and CP22 (sorcin). Br J Cancer. 1990;62:89–95.PubMedCrossRef

19.

Lee BD, French KJ, Zhuang Y, Smith CD. Development of a syngeneic in vivo tumor model and its use in evaluating a novel P-glycoprotein modulator, PGP-4008. Oncol Res. 2003;14:49–60.PubMed

20.

Litman T, Brangi M, Hudson E, Fetsch P, Abati A, Ross DD, et al. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J Cell Sci. 2000;113:2011–21.PubMed

21.

Kawamura K, Konno F, Yui J, Yamasaki T, Hatori A, Yanamoto K, et al. Synthesis and evaluation of [11C]XR9576 to assess the function of drug efflux transporters using PET. Ann Nucl Med. 2010;24:403–12.PubMedCrossRef

22.

Kawamura K, Yamasaki T, Konno F, Yui J, Hatori A, Yanamoto K, et al. Evaluation of limiting brain penetration related to P-glycoprotein and breast cancer resistance protein using [11C]GF120918 by PET in mice. Mol Imaging Biol. 2011;13:152–60.PubMedCrossRef

23.

Martin C, Berridge G, Mistry P, Higgins C, Charlton P, Callaghan R. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol. 1999;128:403–11.PubMedCrossRef

24.

Marian T, Szabo G, Goda K, Nagy H, Szincsak N, Juhasz I, et al. In vivo and in vitro multitracer analyses of P-glycoprotein expression-related multidrug resistance. Eur J Nucl Med Mol Imaging. 2003;30:1147–54.PubMedCrossRef

25.

Kannan P, Telu S, Shukla S, Ambudkar SV, Pike VW, Halldin C, et al. The “specific” P-glycoprotein inhibitor tariquidar is also a substrate and an inhibitor for breast cancer resistance protein (BCRP/ABCG2). ACS Chem Neurosci. 2011;2:82–9.CrossRef

26.

Kannan P, Brimacombe KR, Kreisl WC, Liow JS, Zoghbi SS, Telu S, et al. Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET. Proc Natl Acad Sci U S A. 2011;108:2593–8.PubMedCrossRef

Title: A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer
Authors: Thomas Wanek
Claudia Kuntner
Jens P. Bankstahl
Marion Bankstahl
Johann Stanek
Michael Sauberer
Severin Mairinger
Sabine Strommer
Volker Wacheck
Wolfgang Löscher
Thomas Erker
Markus Müller
Oliver Langer
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 1/2012
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-011-1941-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A comparative small-animal PET evaluation of [¹¹C]tariquidar, [¹¹C]elacridar and (R)-[¹¹C]verapamil for detection of P-glycoprotein-expressing murine breast cancer

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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