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Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage

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Abstract

Purpose

Tumour hypoxia and elevated glycolysis (Warburg effect) predict poor prognosis. Each parameter is assessable separately with positron emission tomography, but they are linked through anaerobic glycolysis (Pasteur effect). Here, we compare the oxygenation-dependent retention of fluoroazomycin arabinoside ([18F]FAZA), a promising but not well-characterised hypoxia-specific tracer, and fluorodeoxyglucose ([18F]FDG) in four carcinoma cell lines.

Methods

Cells seeded on coverslips were positioned in modified Petri dishes that allow physically separated cells to share the same tracer-containing medium pool. Following oxic, hypoxic or anoxic tracer incubation, coverslips were analysed for radioactivity ([18F]FDG + [18F]FAZA) or re-incubated in tracer-free oxygenated medium and then measured ([18F]FAZA). Next, we tested the reliability of [18F]FDG as a relative measure of glucose metabolic rate. Finally, from two cell lines, xenografts were established in mice, and the tracer distribution between hypoxic and well-oxygenated areas were deduced from tissue sections.

Results

Three hours of anoxia strongly stimulated [18F]FAZA retention with anoxic-to-oxic uptake ratios typically above 30. Three out of four cell lines displayed similar selectivity of [18F]FDG versus glucose, but oxic uptake and anoxic-to-oxic uptake ratio of [18F]FDG varied considerably. Although less pronounced, [18F]FAZA also showed superior in vivo hypoxia specificity compared with [18F]FDG.

Conclusions

[18F]FAZA displays excellent in vitro characteristics for hypoxia imaging including modest cell-to-cell line variability and no binding in oxic cells. In contrast, the usability of [18F]FDG as a surrogate marker for hypoxia is questionable due to large variations in baseline (oxic) glucose metabolism and magnitudes of the Pasteur effects.

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References

  1. Allal AS, Slosman DO, Kebdani T, Allaoua M, Lehmann W, Dulguerov P. Prediction of outcome in head-and-neck cancer patients using the standardized uptake value of 2-[18F]fluoro-2-deoxy-D-glucose. Int J Radiat Oncol Biol Phys 2004;59:1295–300.

    PubMed  CAS  Google Scholar 

  2. Riedl CC, Akhurst T, Larson S, Stanziale SF, Tuorto S, Bhargava A, et al. 18F-FDG PET scanning correlates with tissue markers of poor prognosis and predicts mortality for patients after liver resection for colorectal metastases. J Nucl Med 2007;48:771–5.

    Article  PubMed  Google Scholar 

  3. Vansteenkiste JF, Stroobants SG, Dupont PJ, De Leyn PR, Verbeken EK, Deneffe GJ, et al. Prognostic importance of the standardized uptake value on 18F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: an analysis of 125 cases. Leuven Lung Cancer Group. J Clin Oncol 1999;17:3201–6.

    PubMed  CAS  Google Scholar 

  4. Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1996;41:31–9.

    PubMed  CAS  Google Scholar 

  5. Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumour oxygenation in 397 head and neck tumours after primary radiation therapy. An international multi-center study. Radiother Oncol 2005;77:18–24.

    Article  PubMed  Google Scholar 

  6. Nordsmark M, Alsner J, Keller J, Nielsen OS, Jensen OM, Horsman MR, et al. Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br J Cancer 2001;84:1070–5.

    Article  PubMed  CAS  Google Scholar 

  7. Lee ST, Scott AM. Hypoxia positron emission tomography imaging with 18F-fluoromisonidazole. Semin Nucl Med 2007;37:451–61.

    Article  PubMed  Google Scholar 

  8. Piert M, Machulla HJ, Picchio M, Reischl G, Ziegler S, Kumar P, et al. Hypoxia-specific tumour imaging with 18F-fluoroazomycin arabinoside. J Nucl Med 2005;46:106–13.

    PubMed  Google Scholar 

  9. Sorger D, Patt M, Kumar P, Wiebe LI, Barthel H, Seese A, et al. [18F]Fluoroazomycinarabinofuranoside (18FAZA) and [18F]Fluoromisonidazole (18FMISO): a comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumours. Nucl Med Biol 2003;30:317–26.

    Article  PubMed  CAS  Google Scholar 

  10. Reischl G, Dorow DS, Cullinane C, Katsifis A, Roselt P, Binns D, et al. Imaging of tumor hypoxia with [124I]IAZA in comparison with [18F]FMISO and [18F]FAZA—first small animal PET results. J Pharm Pharm Sci 2007;10:203–11.

    PubMed  CAS  Google Scholar 

  11. Dorow DS, Cullinane C, Conus N, Roselt P, Binns D, McCarthy TJ, et al. Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033. Eur J Nucl Med Mol Imaging 2006;33:441–52.

    Article  PubMed  Google Scholar 

  12. Beck R, Röper B, Carlsen JM, Huisman MC, Lebschi JA, Andratschke N, et al. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J Nucl Med 2007;48:973–80.

    Article  PubMed  CAS  Google Scholar 

  13. Busk M, Horsman MR, Jakobsen S, Keiding S, van der Kogel AJ, Bussink J, et al. Imaging hypoxia in xenografted and murine tumours with 18F-Fluoroazomycin Arabinoside: a comparative study involving microPET, autoradiography, pO2-polarography and fluorescence microscopy. Int J Radiat Oncol Biol Phys 2008;70:1202–12.

    PubMed  CAS  Google Scholar 

  14. Souvatzoglou M, Grosu AL, Röper B, Krause BJ, Beck R, Reischl G, et al. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging 2007;34:1566–75.

    Article  PubMed  CAS  Google Scholar 

  15. Warburg O. On respiratory impairment in cancer cells. Science 1956;124:269–70.

    PubMed  CAS  Google Scholar 

  16. Minn H, Joensuu H, Ahonen A, Klemi P. Fluorodeoxyglucose imaging: a method to assess the proliferative activity of human cancer in vivo. Comparison with DNA flow cytometry in head and neck tumours. Cancer 1988;61:1776–81.

    Article  PubMed  CAS  Google Scholar 

  17. Porter JR. Louis PASTEUR; achievements and disappointments, 1861. Bacteriol Rev 1961;25:389–403.

    PubMed  CAS  Google Scholar 

  18. Pugachev A, Ruan S, Carlin S, Larson SM, Campa J, Ling CC, et al. Dependence of FDG uptake on tumour microenvironment. Int J Radiat Oncol Biol Phys 2005;62:545–53.

    PubMed  CAS  Google Scholar 

  19. Bentzen L, Keiding S, Horsman MR, Falborg L, Hansen SB, Overgaard J. Feasibility of detecting hypoxia in experimental mouse tumours with 18F-fluorinated tracers and positron emission tomography—a study evaluating [18F]Fluoro-2-deoxy-D-glucose. Acta Oncol 2000;39:629–37.

    Article  PubMed  CAS  Google Scholar 

  20. Gagel B, Reinartz P, Dimartino E, Zimny M, Pinkawa M, Maneschi P, et al. pO2 Polarography versus positron emission tomography [18F]fluoromisonidazole, [18F]-2-fluoro-2¢-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia. Strahlenther Onkol 2004;180:616–22.

    Article  PubMed  Google Scholar 

  21. Rajendran JG, Mankoff DA, O’Sullivan F, Peterson LM, Schwartz DL, Conrad EU, et al. Hypoxia and glucose metabolism in malignant tumours: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res 2004;10:2245–52.

    Article  PubMed  CAS  Google Scholar 

  22. Ng CE, Keng PC, Sutherland RM. Density distributions of human squamous carcinoma cells: influence of growth conditions, proliferative status and DNA content. Int J Cancer 1986;38:413–8.

    Article  PubMed  CAS  Google Scholar 

  23. Lamb JF, Ogden PH. Transient changes in permeability in HeLa and L cells during detachment from a substrate. Q J Exp Physiol 1987;72:189–99.

    PubMed  CAS  Google Scholar 

  24. Rasey JS, Nelson NJ, Chin L, Evans ML, Grunbaum Z. Characteristics of the binding of labeled fluoromisonidazole in cells in vitro. Radiat Res 1990;122:301–8.

    Article  PubMed  CAS  Google Scholar 

  25. Rasey JS, Hofstrand PD, Chin LK, Tewson TJ. Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumour hypoxia. J Nucl Med 1999;40:1072–9.

    PubMed  CAS  Google Scholar 

  26. Ballinger JR, Kee JW, Rauth AM. In vitro and in vivo evaluation of a technetium-99m-labeled 2-nitroimidazole (BMS181321) as a marker of tumour hypoxia. J Nucl Med 1996;37:1023–31.

    PubMed  CAS  Google Scholar 

  27. Lehtio K, Oikonen V, Nyman S, Gronroos T, Roivainen A, Eskola O, et al. Quantifying tumour hypoxia with fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) and PET using the tumour to plasma ratio. Eur J Nucl Med Mol Imaging 2003;30:101–8.

    Article  PubMed  Google Scholar 

  28. Gagel B, Piroth M, Pinkawa M, Reinartz P, Zimny M, Kaiser HJ, et al. pO2 polarography, contrast enhanced color duplex sonography (CDS), [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography: validated methods for the evaluation of therapy-relevant tumour oxygenation or only bricks in the puzzle of tumour hypoxia? BMC Cancer 2007;7:113.

    Article  PubMed  Google Scholar 

  29. Rajendran JG, Wilson DC, Conrad EU, Peterson LM, Bruckner JD, Rasey JS, et al. [18F]FMISO and [18F]FDG PET imaging in soft tissue sarcomas: correlation of hypoxia, metabolism and VEGF expression. Eur J Nucl Med Mol Imaging 2003;30:695–704.

    PubMed  CAS  Google Scholar 

  30. Spence AM, Muzi M, Graham MM, O’Sullivan F, Krohn KA, Link JM, et al. Glucose metabolism in human malignant gliomas measured quantitatively with PET, 1-[C-11]glucose and FDG: analysis of the FDG lumped constant. J Nucl Med 1998;39:440–8.

    PubMed  CAS  Google Scholar 

  31. Wienhard K. Measurement of glucose consumption using [18F]fluorodeoxyglucose. Methods 2002;27:218–25.

    Article  PubMed  CAS  Google Scholar 

  32. Krohn KA, Mankoff DA, Muzi M, Link JM, Spence AM. True tracers: comparing FDG with glucose and FLT with thymidine. Nucl Med Biol 2005;32:663–71.

    Article  PubMed  CAS  Google Scholar 

  33. Sasajima T, Miyagawa T, Oku T, Gelovani JG, Finn R, Blasberg R. Proliferation-dependent changes in amino acid transport and glucose metabolism in glioma cell lines. Eur J Nucl Med Mol Imaging 2004;31:1244–56.

    Article  PubMed  CAS  Google Scholar 

  34. Minn H, Clavo AC, Grenman R, Wahl RL. In vitro comparison of cell proliferation kinetics and uptake of tritiated fluorodeoxyglucose and L-methionine in squamous-cell carcinoma of the head and neck. J Nucl Med 1995;36:252–8.

    PubMed  CAS  Google Scholar 

  35. Higashi K, Clavo AC, Wahl RL. Does FDG uptake measure proliferative activity of human cancer cells? In vitro comparison with DNA flow cytometry and tritiated thymidine uptake. J Nucl Med 1993;34:414–9.

    PubMed  CAS  Google Scholar 

  36. Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med 1995;36:1625–32.

    PubMed  CAS  Google Scholar 

  37. Minn H, Clavo AC, Wahl RL. Influence of hypoxia on tracer accumulation in squamous-cell carcinoma: in vitro evaluation for PET imaging. Nucl Med Biol 1996;23:941–6.

    Article  PubMed  CAS  Google Scholar 

  38. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006;3:187–97.

    Article  PubMed  CAS  Google Scholar 

  39. Busk M, Horsman MR, Kristjansen PEG, van der Kogel AJ, Bussink J, Overgaard J. Aerobic glycolysis in cancers: implications for the usability of oxygen-responsive genes and fluorodeoxuglucose-PET as markers of hypoxia. Int J Cancer 2008;122:2726–34.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Ms. M. Simonsen from the PET Centre (Aarhus University Hospital, Aarhus, Denmark) and Ms. I. M. Thuesen from the Department of Experimental and Clinical Oncology (Aarhus University Hospital, Aarhus, Denmark) for excellent technical and practical assistance.

Financial support

This study was supported by EC FP6 funding (Contract no. LSHC-CT-2004-50578), the Danish Cancer Society and the Danish Research Agency.

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Experimental Clinical Oncology, Aarhus University Hospital, Noerrebrogade 44, 8000, Aarhus C, Denmark

    Morten Busk, Michael R. Horsman & Jens Overgaard

  2. PET Centre, Aarhus University Hospital, Aarhus, Denmark

    Steen Jakobsen

  3. Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Johan Bussink & Albert van der Kogel

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  1. Morten Busk
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  2. Michael R. Horsman
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Correspondence to Morten Busk.

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Busk, M., Horsman, M.R., Jakobsen, S. et al. Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage. Eur J Nucl Med Mol Imaging 35, 2294–2303 (2008). https://doi.org/10.1007/s00259-008-0888-9

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  • DOI: https://doi.org/10.1007/s00259-008-0888-9

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