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

Abstract

Purpose

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.

Procedures

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.

Results

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).

Conclusions

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.

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References

  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 74:1372–1380

    CAS  Article  PubMed  Google 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 48:3499–3513

    CAS  Article  PubMed  Google 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 7:40–50

    CAS  Article  PubMed  PubMed Central  Google 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:e58938

    CAS  Article  PubMed  PubMed Central  Google 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 32:257–263

    CAS  Article  PubMed  Google 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 18:1303–1312

    CAS  Article  PubMed  Google 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 55:983–988

    CAS  Article  PubMed  Google 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 41:1327–1335

    CAS  Article  PubMed  Google 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 74:1555–1567

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Barthel H, Aboagye E, Price P (2003) Reply. Cancer Res 63:8560–8560

    CAS  Google Scholar 

  11. 11.

    Toyohara J, Fujibayashi Y (2003) Trends in nucleoside tracers for PET imaging of cell proliferation. Nucl Med Biol 30:681–685

    Article  PubMed  Google 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 45:695–700

    PubMed  Google 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 102:1555–1577

    CAS  Article  PubMed  PubMed Central  Google 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 6:63

    Article  PubMed  PubMed Central  Google 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 76:7096–7105

    CAS  Article  PubMed  Google 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 7:3112–3121

    CAS  Article  PubMed  Google 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 4:1013–1019

    CAS  PubMed  Google 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 22:2084–2091

    CAS  Article  PubMed  Google 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 55:81–97

    CAS  Article  PubMed  Google 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 486:51–61

    CAS  Article  Google 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 58:650–654

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Heidebrecht F, Heidebrecht A, Schulz I et al (2009) Improved semiquantitative Western blot technique with increased quantification range. J Immunol Methods 345:40–48

    CAS  Article  PubMed  Google Scholar 

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Funding Information

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) 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.

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Correspondence to Andreas H. Jacobs.

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The authors declare that they have no conflict of interest.

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

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Schelhaas, S., Heinzmann, K., Honess, D.J. et al. 3′-Deoxy-3′-[18F]Fluorothymidine Uptake Is Related to Thymidine Phosphorylase Expression in Various Experimental Tumor Models. Mol Imaging Biol 20, 194–199 (2018). https://doi.org/10.1007/s11307-017-1125-3

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Key words

  • [18F]FLT
  • PET
  • Thymidine phosphorylase
  • Oncology