Molecular Imaging and Biology

, Volume 20, Issue 2, pp 194–199 | Cite as

3′-Deoxy-3′-[18F]Fluorothymidine Uptake Is Related to Thymidine Phosphorylase Expression in Various Experimental Tumor Models

  • Sonja Schelhaas
  • Kathrin Heinzmann
  • Davina J. Honess
  • Donna-Michelle Smith
  • Heather Keen
  • Sandra Heskamp
  • Timothy H. Witney
  • Laurent Besret
  • Sabrina Doblas
  • John R. Griffiths
  • Eric O. Aboagye
  • Andreas H. JacobsEmail author
Brief Article



We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models.


Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [18F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations.


Expression of TP correlated positively with [18F]FLT SUVmax (ρ = 0.549, P < 0.05). Furthermore, tumors with high TP levels possessed lower levels of thymidine (ρ = − 0.939, P < 0.001).


In a broad range of tumors, [18F]FLT uptake as measured by PET is substantially influenced by TP expression and tumor thymidine concentrations. These data strengthen the role of TP as factor confounding [18F]FLT uptake.

Key words

[18F]FLT PET Thymidine phosphorylase Oncology 


Funding Information

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking ( under grant agreement number 115151, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. This work was also supported by the Deutsche Forschungsgemeinschaft (DFG), Cells-in-Motion Cluster of Excellence (EXC1003-CiM), University of Münster, and the Interdisciplinary Centre for Clinical Research (IZKF, core unit PIX), Münster, Germany.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable institutional and national guidelines for the care and use of animals were followed.

Supplementary material

11307_2017_1125_MOESM1_ESM.pdf (400 kb)
ESM 1 (PDF 400 kb)


  1. 1.
    Paproski RJ, Ng AML, Yao SYM et al (2008) The role of human nucleoside transporters in uptake of 3′-deoxy-3′-fluorothymidine. Mol Pharmacol 74:1372–1380CrossRefPubMedGoogle Scholar
  2. 2.
    Chalkidou A, Landau DB, Odell EW et al (2012) Correlation between Ki-67 immunohistochemistry and 18F-fluorothymidine uptake in patients with cancer: a systematic review and meta-analysis. Eur J Cancer 48:3499–3513CrossRefPubMedGoogle Scholar
  3. 3.
    Schelhaas S, Heinzmann K, Bollineni VR et al (2017) Preclinical applications of 3′-deoxy-3′-[18F]fluorothymidine in oncology—a systematic review. Theranostics 7:40–50CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    McKinley ET, Ayers GD, Smith RA et al (2013) Limits of [18F]-FLT PET as a biomarker of proliferation in oncology. PLoS One 8:e58938CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Barthel H, Perumal M, Latigo J et al (2005) The uptake of 3′-deoxy-3′-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels. Eur J Nucl Med Mol Imaging 32:257–263CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang CC, Yan Z, Li W et al (2012) [(18)F]FLT-PET imaging does not always “light up” proliferating tumor cells. Clin Cancer Res 18:1303–1312CrossRefPubMedGoogle Scholar
  7. 7.
    Schelhaas S, Wachsmuth L, Viel T et al (2014) Variability of proliferation and diffusion in different lung cancer models as measured by 3′-deoxy-3′-18F-fluorothymidine PET and diffusion-weighted MR imaging. J Nucl Med 55:983–988CrossRefPubMedGoogle Scholar
  8. 8.
    Lee SJ, Yeo JS, Lee HJ et al (2014) Thymidine phosphorylase influences [(18)F]fluorothymidine uptake in cancer cells and patients with non-small cell lung cancer. Eur J Nucl Med Mol Imaging 41:1327–1335CrossRefPubMedGoogle Scholar
  9. 9.
    Liekens S, Bronckaers A, Pérez-Pérez M-J, Balzarini J (2007) Targeting platelet-derived endothelial cell growth factor/thymidine phosphorylase for cancer therapy. Biochem Pharmacol 74:1555–1567CrossRefPubMedGoogle Scholar
  10. 10.
    Barthel H, Aboagye E, Price P (2003) Reply. Cancer Res 63:8560–8560Google Scholar
  11. 11.
    Toyohara J, Fujibayashi Y (2003) Trends in nucleoside tracers for PET imaging of cell proliferation. Nucl Med Biol 30:681–685CrossRefPubMedGoogle Scholar
  12. 12.
    Van Waarde A, Cobben DCP, Suurmeijer AJH et al (2004) Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med 45:695–700PubMedGoogle Scholar
  13. 13.
    Workman P, Aboagye EO, Balkwill F et al (2010) Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555–1577CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Heinzmann K, Honess DJ, Lewis DY et al (2016) The relationship between endogenous thymidine concentrations and [(18)F]FLT uptake in a range of preclinical tumour models. EJNMMI Res 6:63CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Schelhaas S, Held A, Wachsmuth L et al (2016) Gemcitabine mechanism of action confounds early assessment of treatment response by 3′-deoxy-3′-[18F]fluorothymidine in preclinical models of lung cancer. Cancer Res 76:7096–7105CrossRefPubMedGoogle Scholar
  16. 16.
    Leyton J, Smith G, Lees M et al (2008) Noninvasive imaging of cell proliferation following mitogenic extracellular kinase inhibition by PD0325901. Mol Cancer Ther 7:3112–3121CrossRefPubMedGoogle Scholar
  17. 17.
    Sawada N, Ishikawa T, Fukase Y et al (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4:1013–1019PubMedGoogle Scholar
  18. 18.
    Cassidy J, Tabernero J, Twelves C et al (2004) XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 22:2084–2091CrossRefPubMedGoogle Scholar
  19. 19.
    Bollineni VR, Kramer GM, Jansma EP et al (2016) A systematic review on [18F]FLT-PET uptake as a measure of treatment response in cancer patients. Eur J Cancer 55:81–97CrossRefPubMedGoogle Scholar
  20. 20.
    Li KM, Clarke SJ, Rivory LP (2003) Quantitation of plasma thymidine by high-performance liquid chromatography—atmospheric pressure chemical ionization mass spectrometry and its application to pharmacodynamic studies in cancer patients. Anal Chim Acta 486:51–61CrossRefGoogle Scholar
  21. 21.
    Han J-Y, Hong EK, Lee SY et al (2005) Thymidine phosphorylase expression in tumour cells and tumour response to capecitabine plus docetaxel chemotherapy in non-small cell lung cancer. J Clin Pathol 58:650–654CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Heidebrecht F, Heidebrecht A, Schulz I et al (2009) Improved semiquantitative Western blot technique with increased quantification range. J Immunol Methods 345:40–48CrossRefPubMedGoogle Scholar

Copyright information

© World Molecular Imaging Society 2017

Authors and Affiliations

  • Sonja Schelhaas
    • 1
  • Kathrin Heinzmann
    • 2
    • 3
  • Davina J. Honess
    • 2
  • Donna-Michelle Smith
    • 2
  • Heather Keen
    • 4
  • Sandra Heskamp
    • 5
  • Timothy H. Witney
    • 3
    • 6
  • Laurent Besret
    • 7
  • Sabrina Doblas
    • 8
  • John R. Griffiths
    • 2
  • Eric O. Aboagye
    • 3
  • Andreas H. Jacobs
    • 1
    • 9
    Email author
  1. 1.European Institute for Molecular Imaging (EIMI)Westfälische Wilhelms-Universität (WWU) MünsterMünsterGermany
  2. 2.Cancer Research UK Cambridge InstituteUniversity of CambridgeCambridgeUK
  3. 3.Comprehensive Cancer Imaging CentreImperial College LondonLondonUK
  4. 4.PHB Imaging GroupAstraZenecaMacclesfieldUK
  5. 5.Department of Radiology and Nuclear MedicineRadboud University Medical CentreNijmegenThe Netherlands
  6. 6.UCL Centre for Advanced Biomedical ImagingUniversity College LondonLondonUK
  7. 7.Sanofi OncologyVitry-sur-SeineFrance
  8. 8.LBI, UMR1149-CRIINSERMParisFrance
  9. 9.Department of Geriatric MedicineJohanniter HospitalBonnGermany

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