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NanoPET imaging of [18F]fluoromisonidazole uptake in experimental mouse tumours

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study was to assess the potential and utility of ultra-high-resolution hypoxia imaging in various murine tumour models using the established hypoxia PET tracer [18F]fluoromisonidazole ([18F]FMISO).

Methods

[18F]FMISO PET imaging was performed with the dedicated small-animal PET scanner NanoPET (Oxford Positron Systems) and ten different human tumour xenografts in nude mice as well as B16 melanoma tumours in syngeneic Balb/c mice. For comparison, [18F]fluorodeoxyglucose ([18F]FDG) PET scans were also performed in the mice bearing human tumour xenografts.

Results

In 10 out of 11 experimental tumour models, [18F]FMISO PET imaging allowed clear-cut visualisation of the tumours. Inter- and intratumoural heterogeneity of tracer uptake was evident. In addition to average TMRR (tumour-to-muscle retention ratio including all voxels in a volume of interest (VOI)), the parameters TMRR75% and TMRR5 (tumour-to-muscle retention ratio including voxels of 75% or more of the maximum radioactivity in a VOI and the five hottest pixels, respectively) also served as measures for quantifying the heterogeneous [18F]FMISO uptake in the tumours. The variability observed in [18F]FMISO uptake was related neither to tumour size nor to the injected mass of the radiotracer. The pattern of normoxic and hypoxic regions within the human tumour xenografts, however, correlated with glucose metabolism as revealed by comparison of [18F]FDG and [18F]FMISO images.

Conclusion

This study demonstrates the feasibility and utility of [18F]FMISO for imaging murine tumour models using NanoPET.

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References

  1. Adam MF, Gabalski EC, Bloch DA, Oehlert JW, Brown JM, Elsaid AA, et al. Tissue oxygen distribution in head and neck cancer patients. Head Neck 1999;21:146–53

    Article  PubMed  Google Scholar 

  2. Rasey JS, Koh WJ, Evans ML, Peterson LM, Lewellen TK, Graham MM, et al. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int J Radiat Oncol Biol Phys 1996;36:417–28

    Article  PubMed  Google Scholar 

  3. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285–9

    Article  PubMed  Google Scholar 

  4. Knowles HJ, Harris AL. Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis. Breast Cancer Res 2001;3:318–22

    Article  PubMed  Google Scholar 

  5. Valk PE, Mathis CA, Prados MD, Gilbert JC, Budinger TF. Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med 1992;33:2133–7

    PubMed  Google Scholar 

  6. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 1953;26:638–48

    PubMed  Google Scholar 

  7. Horsman MR, Overgaard J. Overcoming tumour radiation resistance resulting from acute hypoxia. Eur J Cancer 1992;28A:717–8

    Article  PubMed  Google Scholar 

  8. Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 1993;26:45–50

    Article  PubMed  Google Scholar 

  9. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996;56:941–3

    PubMed  Google Scholar 

  10. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2002;2:38–47

    Article  PubMed  Google Scholar 

  11. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509–15

    PubMed  Google Scholar 

  12. Cater DB, Silver IA. Quantitative measurements of oxygen tension in normal tissues and in the tumours of patients before and after radiotherapy. Acta Radiol 1960;53:233–56

    PubMed  Google Scholar 

  13. Bentzen L, Keiding S, Horsman MR, Gronroos T, Hansen SB, Overgaard J. Assessment of hypoxia in experimental mice tumours by [18F]fluoromisonidazole PET and pO2 electrode measurements. Influence of tumour volume and carbogen breathing. Acta Oncol 2002;41:304–12

    Article  PubMed  Google Scholar 

  14. Achermann RE, Ohlerth SM, Rohrer Bley C, Gassmann M, Inteeworn N, Roos M, et al. Oxygenation of spontaneous canine tumors during fractionated radiation therapy. Strahlenther Onkol 2004;180:297–305

    Article  PubMed  Google Scholar 

  15. Nordsmark M, Loncaster J, Chou SC, Havsteen H, Lindegaard JC, Davidson SE, et al. Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma. Int J Radiat Oncol Biol Phys 2001;49:581–6

    Article  PubMed  Google Scholar 

  16. Buchler P, Reber HA, Lavey RS, Tomlinson J, Buchler MW, Friess H, et al. Tumor hypoxia correlates with metastatic tumor growth of pancreatic cancer in an orthotopic murine model. J Surg Res 2004;120:295–303

    Article  PubMed  Google Scholar 

  17. Olive PL, Aquino-Parsons C. Measurement of tumor hypoxia using single-cell methods. Semin Radiat Oncol 2004;14:241–8

    Article  PubMed  Google Scholar 

  18. Dubois L, Landuyt W, Haustermans K, Dupont P, Bormans G, Vermaelen P, et al. Evaluation of hypoxia in an experimental rat tumour model by [18F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer 2004;91:1947–54

    Article  PubMed  Google Scholar 

  19. Evans SM, Judy KD, Dunphy I, Jenkins WT, Nelson PT, Collins R, et al. Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res 2004;64:1886–92

    Article  PubMed  Google Scholar 

  20. Evans SM, Hahn S, Pook DR, Jenkins WT, Chalian AA, Zhang P, et al. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res 2000;60:2018–24

    PubMed  Google Scholar 

  21. Koh WJ, Rasey JS, Evans ML, Grierson JR, Lewellen TK, Graham MM, et al. Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole. Int J Radiat Oncol Biol Phys 1992;22:199–212

    PubMed  Google Scholar 

  22. Ziemer LS, Evans SM, Kachur AV, Shuman AL, Cardi CA, Jenkins WT, et al. Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5. Eur J Nucl Med Mol Imaging 2003;30:259–66

    PubMed  Google Scholar 

  23. Dolbier WR Jr, Li AR, Koch CJ, Shiue CY, Kachur AV. [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Appl Radiat Isot 2001;54:73–80

    Article  PubMed  Google Scholar 

  24. Yang DJ, Wallace S, Cherif A, Li C, Gretzer MB, Kim EE, et al. Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia. Radiology 1995;194:795–800

    PubMed  Google Scholar 

  25. Gronroos T, Bentzen L, Marjamaki P, Murata R, Horsman MR, Keiding S, et al. Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma. Eur J Nucl Med Mol Imaging 2004;31:513–20

    Article  PubMed  Google Scholar 

  26. 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 tumors. Nucl Med Biol 2003;30:317–26

    Article  PubMed  Google Scholar 

  27. Barthel H, Wilson H, Collingridge DR, Brown G, Osman S, Luthra SK, et al. In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography. Br J Cancer 2004;90:2232–42

    PubMed  Google Scholar 

  28. Rischin D, Peters L, Hicks R, Hughes P, Fisher R, Hart R, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 2001;19:535–42

    PubMed  Google Scholar 

  29. Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G, et al. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med 2005;46:253–60

    PubMed  Google Scholar 

  30. Bruehlmeier M, Roelcke U, Schubiger PA, Ametamey SM. Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O. J Nucl Med 2004;45:1851–9

    PubMed  Google Scholar 

  31. Chatziioannou AF. PET scanners dedicated to molecular imaging of small animal models. Mol Imaging Biol 2002;4:47–63

    Article  PubMed  Google Scholar 

  32. Schafers KP. Imaging small animals with positron emission tomography. Nuklearmedizin 2003;42:86–9

    PubMed  Google Scholar 

  33. Myers R, Hume S. Small animal PET. Eur Neuropsychopharmacol 2002;12:545–55

    Article  PubMed  Google Scholar 

  34. Zanzonico P, O’Donoghue J, Chapman JD, Schneider R, Cai S, Larson S, et al. Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning. Eur J Nucl Med Mol Imaging 2004;31:117–28

    Article  PubMed  Google Scholar 

  35. Wen B, Burgman P, Zanzonico P, O’Donoghue J, Cai S, Finn R, et al. A preclinical model for noninvasive imaging of hypoxia-induced gene expression; comparison with an exogenous marker of tumor hypoxia. Eur J Nucl Med Mol Imaging 2004;31:1530–8

    Article  PubMed  Google Scholar 

  36. Lim JL, Berridge MS. An efficient radiosynthesis of [18F]fluoromisonidazole. Appl Radiat Isot 1993;44:1085–91

    Article  PubMed  Google Scholar 

  37. Jeavons AP, Chandler RA, Dettmar CAR. A 3D HIDAC-PET camera with submillimetre resolution for imaging small animals. IEEE Trans Nucl Sci 1999;46:468–73

    Article  Google Scholar 

  38. Missimer J, Madi Z, Honer M, Keller C, Schubiger A, Ametamey SM. Performance evaluation of the 16-module quad-HIDAC small animal PET camera. Phys Med Biol 2004;49:2069–81

    Article  PubMed  Google Scholar 

  39. Reader AJ, Erlandsson K, Flower MA, Ott RJ. Fast accurate iterative reconstruction for low-statistics positron volume imaging. Phys Med Biol 1998;43:835–46

    Article  PubMed  Google Scholar 

  40. Mikolajczyk K, Szabatin M, Rudnicki P, Grodzki M, Burger C. A JAVA environment for medical image data analysis: initial application for brain PET quantitation. Med Inform (Lond) 1998;23:207–14

    Google Scholar 

  41. Bentzen L, Keiding S, Nordsmark M, Falborg L, Hansen SB, Keller J, et al. Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol 2003;67:339-44

    Article  PubMed  Google Scholar 

  42. Prekeges JL, Rasey JS, Grunbaum Z, Krohn KH. Reduction of fluoromisonidazole, a new imaging agent for hypoxia. Biochem Pharmacol 1991;42:2387-95

    Article  PubMed  Google Scholar 

  43. 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 

  44. Bentzen L, Keiding S, Horsman MR, Falborg L, Hansen SB, Overgaard J. Feasibility of detecting hypoxia in experimental mouse tumours with 8F-fluorinated tracers and positron emission tomography—a study evaluating [18F]fluoro-2-deoxy-D-glucose. Acta Oncol 2000;39:629–37

    Article  PubMed  Google Scholar 

  45. Adam MF, Dorie MJ, Brown JM. Oxygen tension measurements of tumors growing in mice. Int J Radiat Oncol Biol Phys 1999;45:171–80

    Article  PubMed  Google Scholar 

  46. Piert M, Machulla HJ, Becker G, Aldinger P, Winter E, Bares R. Dependency of the [18F]fluoromisonidazole uptake on oxygen delivery and tissue oxygenation in the porcine liver. Nucl Med Biol 2000;27:693–700

    Article  PubMed  Google Scholar 

  47. Kubota K, Tada M, Yamada S, Hori K, Saito S, Iwata R, et al. Comparison of the distribution of fluorine-18 fluoromisonidazole, deoxyglucose and methionine in tumour tissue. Eur J Nucl Med 1999;26:750–7

    Article  PubMed  Google Scholar 

  48. Nunn A, Linder K, Strauss HW. Nitroimidazoles and imaging hypoxia. Eur J Nucl Med 1995;22:265–80

    Article  PubMed  Google Scholar 

  49. Rasey JS, Grunbaum Z, Magee S, Nelson NJ, Olive PL, Durand RE, et al. Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res 1987;111:292–304

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  51. Biskupiak JE, Krohn KA. Second generation hypoxia imaging agents. J Nucl Med 1993;34:411–3

    PubMed  Google Scholar 

  52. Seddon BM, Maxwell RJ, Honess DJ, Grimshaw R, Raynaud F, Tozer GM, et al. Validation of the fluorinated 2-nitroimidazole SR-4554 as a noninvasive hypoxia marker detected by magnetic resonance spectroscopy. Clin Cancer Res 2002;8:2323–35

    PubMed  Google Scholar 

  53. Pedersen MW, Holm S, Lund EL, Hojgaard L, Kristjansen PE. Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. Neoplasia 2001;3:80–7

    Article  PubMed  Google Scholar 

  54. 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  Google Scholar 

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

    Article  PubMed  Google Scholar 

  56. Bos R, van Der Hoeven JJ, van Der Wall E, van Der Groep P, van Diest PJ, Comans EF, et al. Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol 2002;20:379–87

    Article  PubMed  Google Scholar 

  57. 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  Google Scholar 

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Acknowledgements

We thank Paul M. McSheehy, Terence O’Reilly and Ilse Novak for providing the experimental tumour models at our disposal, Claudia Keller for important help in animal experiments and Erika Sinnig for essential laboratory work. Furthermore, the authors thank Valerie Treyer and Nicolas Späth for fruitful discussions during the writing process.

Declaration

The Swiss Federal Veterinary Office approved all experimental procedures and all animal work was performed by licensed investigators.

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Correspondence to Matthias T. Wyss.

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Wyss, M.T., Honer, M., Schubiger, P.A. et al. NanoPET imaging of [18F]fluoromisonidazole uptake in experimental mouse tumours. Eur J Nucl Med Mol Imaging 33, 311–318 (2006). https://doi.org/10.1007/s00259-005-1951-4

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  • DOI: https://doi.org/10.1007/s00259-005-1951-4

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