Skip to main content
SpringerLink
Log in

Current Clinical Imaging of Hypoxia with PET and Future Perspectives

  • Chapter
  • First Online:
Functional Imaging in Oncology

  • 1683 Accesses

Abstract

Hypoxia is a pathophysiological consequence of structural and functional abnormalities in the blood supply of tumors playing a crucial role in tumor proliferation and malignant progression. As hypoxia leads to radio- and chemoresistances and therefore hampers the success of conventional therapies, the detection and quantification of hypoxic areas that can be distributed heterogeneously within tumors requires to tailor individual therapies which might abrogate these resistances. Different invasive and noninvasive methods are under development and so far employed successfully to determine hypoxic areas. This chapter focuses on the results of the application of positron-emission tomography (PET) tracers for the detection of hypoxia and discusses the advantages and disadvantages of the obtained results.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ACRIN:

American College of Radiology Imaging Network

ATSM:

Diacetyl-bis(N4-methylthiose-micarbazone)

BOLD:

Blood oxygen level dependent

CAIX:

Carbonic anhydrase IX

CT:

Computed tomography

DAHANCA:

Danish Head and Neck Cancer Group

EF5:

2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-[18F]pentafluoro-propyl)-acetamide

EPR:

Electron paramagnetic resonance

FAZA:

Fluoroazomycin arabinoside

FDG:

Fluorodeoxyglucose

FETA:

Fluoroetanidazole

FETNIM:

Fluoroerythronitroimidazole

FMISO:

Fluoromisonidazole

GLUT-1:

Glucose transporter-1

IAZA:

Iodoazomycinarabinoside

GTV:

Gross tumor volume

HIF-1:

Hypoxia-inducible transcription factor-1

HNC:

Head and neck cancer

IMRT:

Intensity-modulated radiation therapy

MISO:

Misonidazole

MRI:

Magnetic resonance imaging

NSCLC:

Non-small cell lung cancer

PET:

Positron Emission Tomography

p.i.:

Post injection

PTSM:

Pyruvaldehyde-bis (N4-methylthiosemicarbazone)

References

  1. West JB. Respiratory physiology – the essentials. Baltimore/London/Los Angeles: Williams & Wilkins; 1999.

    Google Scholar 

  2. Helmlinger G, et al. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997;3:177–82.

    PubMed  CAS  Google Scholar 

  3. Vaupel P, et al. Blood flow, tissue oxygenation, pH distribution, and energy metabolism of murine mammary adenocarcinomas during growth. Adv Exp Med Biol. 1989;248:835–45.

    PubMed  CAS  Google Scholar 

  4. Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11:393–410.

    PubMed  CAS  Google Scholar 

  5. Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–76.

    PubMed  Google Scholar 

  6. Vaupel P, Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist. 2004;9 Suppl 5:4–9.

    PubMed  Google Scholar 

  7. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26:225–39.

    PubMed  CAS  Google Scholar 

  8. Boyer PD, et al. Oxidative phosphorylation and photophosphorylation. Annu Rev Biochem. 1977;46:955–66.

    PubMed  CAS  Google Scholar 

  9. Honig CR. Modern cardiovascular physiology. Boston/Toronto: Little and Brown; 1988.

    Google Scholar 

  10. Zander R, Vaupel P. Proposal for using a standardized terminology on oxygen transport to tissue. Adv Exp Med Biol. 1985;191:965–70.

    PubMed  CAS  Google Scholar 

  11. Crabtree HG, Cramer W. The action of radium on cancer cells. II. Some factors determining the susceptibility of cancer cells to radium. Proc R Soc Lond B. 1933;113:238–50.

    CAS  Google Scholar 

  12. Schwarz G. Desensibilisierung gegen Röntgen- und Radiumstrahlen. Münchener Med Wochenschau. 1909;24:1–2.

    Google Scholar 

  13. Gray LH, et al. 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  CAS  Google Scholar 

  14. Hall EJ. Radiobiology for the radiologist. Philadelphia: Lippincott; 1994.

    Google Scholar 

  15. Comerford KM, et al. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002;62:3387–94.

    PubMed  CAS  Google Scholar 

  16. Thews O, et al. Hypoxia-induced extracellular acidosis increases p-glycoprotein activity and chemoresistance in tumors in vivo via p38 signaling pathway. Adv Exp Med Biol. 2011;701:115–22.

    PubMed  CAS  Google Scholar 

  17. Riva C, et al. Cellular physiology and molecular events in hypoxia-induced apoptosis. Anticancer Res. 1998;18:4729–36.

    PubMed  CAS  Google Scholar 

  18. Shimizu S, et al. Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xL. Nature. 1995;374:811–3.

    PubMed  CAS  Google Scholar 

  19. Soengas MS, et al. Apaf-1 and caspase-9 in p53-dependent apoptosis and tumor inhibition. Science. 1999;284:156–9.

    PubMed  CAS  Google Scholar 

  20. Giaccia AJ. Hypoxic stress proteins: survival of the fittest. Semin Radiat Oncol. 1996;6:46–58.

    PubMed  Google Scholar 

  21. Koch CJ, et al. The effect of hypoxia on the generation time of mammalian cells. Radiat Res. 1973;53:43–8.

    PubMed  CAS  Google Scholar 

  22. Pettersen EO, Lindmo T. Inhibition of cell-cycle progression by acute treatment with various degrees of hypoxia: modifications induced by low concentrations of misonidazole present during hypoxia. Br J Cancer. 1983;48:809–17.

    PubMed  CAS  PubMed Central  Google Scholar 

  23. Yuan J, Glazer PM. Mutagenesis induced by the tumor microenvironment. Mutat Res. 1998;400:439–46.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  25. Pennacchietti S, et al. Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell. 2003;3:347–61.

    PubMed  Google Scholar 

  26. Kang SS, et al. Clinical significance of glucose transporter 1 (GLUT1) expression in human breast carcinoma. Jpn J Cancer Res. 2002;93:1123–8.

    PubMed  CAS  Google Scholar 

  27. Kunkel M, et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer. 2003;97:1015–24.

    PubMed  CAS  Google Scholar 

  28. Younes M, et al. Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival. Cancer. 1997;80:1046–51.

    PubMed  CAS  Google Scholar 

  29. Parkkila S, et al. Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci U S A. 2000;97:2220–4.

    PubMed  CAS  PubMed Central  Google Scholar 

  30. Robertson N, et al. Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res. 2004;64:6160–5.

    PubMed  CAS  Google Scholar 

  31. Weinberg RA. The biology of cancer. New York/Abingdon: Garland Science; 2007.

    Google Scholar 

  32. Aebersold DM, et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 2001;61:2911–6.

    PubMed  CAS  Google Scholar 

  33. Bos R, et al. Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma. Cancer. 2003;97:1573–81.

    PubMed  Google Scholar 

  34. Griffiths EA, et al. Hypoxia-inducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas. Br J Cancer. 2007;96:95–103.

    PubMed  CAS  PubMed Central  Google Scholar 

  35. Swinson DE, et al. Hypoxia-inducible factor-1 alpha in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer. 2004;111:43–50.

    PubMed  CAS  Google Scholar 

  36. Trastour C, et al. HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int J Cancer. 2007;120:1451–8.

    PubMed  CAS  Google Scholar 

  37. Vleugel MM, et al. Differential prognostic impact of hypoxia induced and diffuse HIF-1alpha expression in invasive breast cancer. J Clin Pathol. 2005;58:172–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  38. Jubb AM, et al. Assessment of tumour hypoxia for prediction of response to therapy and cancer prognosis. J Cell Mol Med. 2010;14:18–29.

    PubMed  CAS  Google Scholar 

  39. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.

    PubMed  CAS  Google Scholar 

  40. Krause BJ, et al. PET and PET/CT studies of tumor tissue oxygenation. Q J Nucl Med Mol Imaging. 2006;50:28–43.

    PubMed  CAS  Google Scholar 

  41. Thorwarth D, Alber M. Implementation of hypoxia imaging into treatment planning and delivery. Radiother Oncol. 2010;97:172–5.

    PubMed  Google Scholar 

  42. Astner ST, et al. Imaging of tumor physiology: impacts on clinical radiation oncology. Exp Oncol. 2010;32:149–52.

    PubMed  CAS  Google Scholar 

  43. Lapi SE, et al. Positron emission tomography imaging of hypoxia. PET Clin. 2009;4:39–47.

    PubMed  PubMed Central  Google Scholar 

  44. Carlin S, Humm JL. PET of hypoxia: current and future perspectives. J Nucl Med. 2012;53:1171–4.

    PubMed  CAS  Google Scholar 

  45. Horsman MR, et al. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol. 2012;9:674–87.

    PubMed  CAS  Google Scholar 

  46. Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010;20:51–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  47. Busk M, et al. Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage. Eur J Nucl Med Mol Imaging. 2008;35:2294–303.

    PubMed  CAS  Google Scholar 

  48. Cherk MH, et al. Lack of correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in non-small cell lung cancer assessed by 18F-fluoromisonidazole and 18F-FDG PET. J Nucl Med. 2006;47:1921–6.

    PubMed  CAS  Google Scholar 

  49. Eschmann SM, 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 

  50. Gagel B, et al. [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography in response evaluation after chemo-/radiotherapy of non-small-cell lung cancer: a feasibility study. BMC Cancer. 2006;6:51.

    PubMed  PubMed Central  Google Scholar 

  51. Rajendran JG, et al. [(18)F]FMISO and [(18)F]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 

  52. Rajendran JG, 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.

    PubMed  CAS  Google Scholar 

  53. Thorwarth D, et al. Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiother Oncol. 2006;80:151–6.

    PubMed  CAS  Google Scholar 

  54. Chapman JD. Hypoxic sensitizers – implications for radiation therapy. N Engl J Med. 1979;301:1429–32.

    PubMed  CAS  Google Scholar 

  55. Chapman JD, et al. A marker for hypoxic cells in tumours with potential clinical applicability. Br J Cancer. 1981;43:546–50.

    PubMed  CAS  PubMed Central  Google Scholar 

  56. Brown JM. Clinical trials of radiosensitizers: what should we expect? Int J Radiat Oncol Biol Phys. 1984;10:425–9.

    PubMed  CAS  Google Scholar 

  57. Grunbaum Z, et al. Synthesis and characterization of congeners of misonidazole for imaging hypoxia. J Nucl Med. 1987;28:68–75.

    PubMed  CAS  Google Scholar 

  58. Martin GV, et al. Noninvasive detection of hypoxic myocardium using fluorine-18-fluoromisonidazole and positron emission tomography. J Nucl Med. 1992;33:2202–8.

    PubMed  CAS  Google Scholar 

  59. Prekeges JL, et al. Reduction of fluoromisonidazole, a new imaging agent for hypoxia. Biochem Pharmacol. 1991;42:2387–95.

    PubMed  CAS  Google Scholar 

  60. Tatum JL, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol. 2006;82:699–757.

    PubMed  CAS  Google Scholar 

  61. Mees G, et al. Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging. 2009;36:1674–86.

    PubMed  CAS  PubMed Central  Google Scholar 

  62. Whitmore GF, Varghese AJ. The biological properties of reduced nitroheterocyclics and possible underlying biochemical mechanisms. Biochem Pharmacol. 1986;35:97–103.

    PubMed  CAS  Google Scholar 

  63. Rasey JS, et al. Comparison of binding of [3H]misonidazole and [14C]misonidazole in multicell spheroids. Radiat Res. 1985;101:473–9.

    PubMed  CAS  Google Scholar 

  64. Rasey JS, et al. Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res. 1987;111:292–304.

    PubMed  CAS  Google Scholar 

  65. Krohn KA, et al. Molecular imaging of hypoxia. J Nucl Med. 2008;49 Suppl 2:129S–48.

    PubMed  CAS  Google Scholar 

  66. Padhani A. PET imaging of tumour hypoxia. Cancer Imaging. 2006;6:S117–21.

    PubMed  PubMed Central  Google Scholar 

  67. Graham MM, et al. Fluorine-18-fluoromisonidazole radiation dosimetry in imaging studies. J Nucl Med. 1997;38:1631–6.

    PubMed  CAS  Google Scholar 

  68. Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res. 1994;6:509–18.

    PubMed  CAS  Google Scholar 

  69. Padhani AR, et al. Imaging oxygenation of human tumours. Eur Radiol. 2007;17:861–72.

    PubMed  PubMed Central  Google Scholar 

  70. Nunn A, et al. Nitroimidazoles and imaging hypoxia. Eur J Nucl Med. 1995;22:265–80.

    PubMed  CAS  Google Scholar 

  71. Martin GV, et al. Fluoromisonidazole. A metabolic marker of myocyte hypoxia. Circ Res. 1990;67:240–4.

    PubMed  CAS  Google Scholar 

  72. Piert M, et al. Introducing fluorine-18 fluoromisonidazole positron emission tomography for the localisation and quantification of pig liver hypoxia. Eur J Nucl Med. 1999;26:95–109.

    PubMed  CAS  Google Scholar 

  73. Chang J, et al. A robotic system for 18F-FMISO PET-guided intratumoral pO2 measurements. Med Phys. 2009;36:5301–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  74. Bentzen L, et al. 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.

    PubMed  CAS  Google Scholar 

  75. Dubois L, et al. Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer. 2004;91:1947–54.

    PubMed  CAS  PubMed Central  Google Scholar 

  76. Troost EG, et al. Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol. 2006;80:157–64.

    PubMed  CAS  Google Scholar 

  77. Troost EG, et al. Correlation of [18F]FMISO autoradiography and pimonidazole [corrected] immunohistochemistry in human head and neck carcinoma xenografts. Eur J Nucl Med Mol Imaging. 2008;35:1803–11.

    PubMed  CAS  Google Scholar 

  78. Rasey JS, et al. Quantifying hypoxia with radiolabeled fluoromisonidazole: pre-clinical and clinical studies. In: Machulla H-J, editor. The imaging of hypoxia. Dordrecht: Kluwer Academic Publishers; 1999.

    Google Scholar 

  79. Gagel B, et al. pO(2) Polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2′-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia. Strahlenther Onkol. 2004;180:616–22.

    PubMed  Google Scholar 

  80. Zimny M, et al. FDG – a marker of tumour hypoxia? A comparison with [18F]fluoromisonidazole and pO2-polarography in metastatic head and neck cancer. Eur J Nucl Med Mol Imaging. 2006;33:1426–31.

    PubMed  CAS  Google Scholar 

  81. Valk PE, et al. Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med. 1992;33:2133–7.

    PubMed  CAS  Google Scholar 

  82. Rasey JS, 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.

    PubMed  CAS  Google Scholar 

  83. Grosu AL, et al. Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 2007;69:541–51.

    PubMed  CAS  Google Scholar 

  84. Spence AM, et al. Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin Cancer Res. 2008;14:2623–30.

    PubMed  CAS  Google Scholar 

  85. Bentzen L, et al. Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol. 2003;67:339–44.

    PubMed  CAS  Google Scholar 

  86. Lee NY, et al. Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys. 2008;70:2–13.

    PubMed  CAS  PubMed Central  Google Scholar 

  87. Lin Z, et al. The influence of changes in tumor hypoxia on dose-painting treatment plans based on 18F-FMISO positron emission tomography. Int J Radiat Oncol Biol Phys. 2008;70:1219–28.

    PubMed  PubMed Central  Google Scholar 

  88. Rischin D, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol. 2006;24:2098–104.

    PubMed  Google Scholar 

  89. Jansen JF, et al. Noninvasive assessment of tumor microenvironment using dynamic contrast-enhanced magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography imaging in neck nodal metastases. Int J Radiat Oncol Biol Phys. 2010;77:1403–10.

    PubMed  PubMed Central  Google Scholar 

  90. Cher LM, et al. Correlation of hypoxic cell fraction and angiogenesis with glucose metabolic rate in gliomas using 18F-fluoromisonidazole, 18F-FDG PET, and immunohistochemical studies. J Nucl Med. 2006;47:410–8.

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  92. Yang DJ, et al. Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia. Radiology. 1995;194:795–800.

    PubMed  CAS  Google Scholar 

  93. Grönroos T, et al. Pharmacokinetics of [18F]FETNIM: a potential marker for PET. J Nucl Med. 2001;42:1397–404.

    PubMed  Google Scholar 

  94. Grönroos T, 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.

    PubMed  Google Scholar 

  95. Lehtiö K, et al. Imaging of blood flow and hypoxia in head and neck cancer: initial evaluation with [(15)O]H(2)O and [(18)F]fluoroerythronitroimidazole PET. J Nucl Med. 2001;42:1643–52.

    PubMed  Google Scholar 

  96. Lehtiö K, 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.

    PubMed  Google Scholar 

  97. Lehtiö K, et al. Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;59:971–82.

    PubMed  Google Scholar 

  98. Li L, et al. Comparison of 18F-fluoroerythronitroimidazole and 18F-fluorodeoxyglucose positron emission tomography and prognostic value in locally advanced non-small-cell lung cancer. Clin Lung Cancer. 2010;11:335–40.

    PubMed  Google Scholar 

  99. Vercellino L, et al. Hypoxia imaging of uterine cervix carcinoma with (18)F-FETNIM PET/CT. Clin Nucl Med. 2012;37:1065–8.

    PubMed  Google Scholar 

  100. Reischl G, 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 

  101. Kumar P, et al. Fluoroazomycin arabinoside (FAZA): synthesis, 2H and 3H-labelling and preliminary biological evaluation of a novel 2-nitroimidazole marker of tissue hypoxia. J Label Compd Radiopharm. 1999;42:3–16.

    CAS  Google Scholar 

  102. Kumar P, et al. Microwave-assisted (radio) halogenation of nitroimidazole-based hypoxia markers. Appl Radiat Isot. 2002;57:697–703.

    PubMed  CAS  Google Scholar 

  103. Piert M, et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med. 2005;46:106–13.

    PubMed  Google Scholar 

  104. Sorger D, 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.

    PubMed  CAS  Google Scholar 

  105. Busk M, et al. Imaging hypoxia in xenografted and murine tumors 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 

  106. Tran LB, et al. Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: a comparison with OxyLite, EPR oximetry and 19F-MRI relaxometry. Radiother Oncol. 2012;105:29–35.

    PubMed  CAS  Google Scholar 

  107. Beck R, et al. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J Nucl Med. 2007;48:973–80.

    PubMed  CAS  Google Scholar 

  108. Busk M, et al. PET hypoxia imaging with FAZA: reproducibility at baseline and during fractionated radiotherapy in tumour-bearing mice. Eur J Nucl Med Mol Imaging. 2013;40:186–97.

    PubMed  CAS  Google Scholar 

  109. Havelund BM, et al. Tumour hypoxia imaging with 18F-fluoroazomycinarabinofuranoside PET/CT in patients with locally advanced rectal cancer. Nucl Med Commun. 2013;34:155–61.

    PubMed  CAS  Google Scholar 

  110. Souvatzoglou M, 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.

    PubMed  CAS  Google Scholar 

  111. Postema EJ, et al. Initial results of hypoxia imaging using 1-alpha-D: -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA). Eur J Nucl Med Mol Imaging. 2009;36:1565–73.

    PubMed  CAS  Google Scholar 

  112. Mortensen LS, et al. FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. Radiother Oncol. 2012;105:14–20.

    PubMed  Google Scholar 

  113. Tewson TJ. Synthesis of [18F]fluoroetanidazole: a potential new tracer for imaging hypoxia. Nucl Med Biol. 1997;24:755–60.

    PubMed  CAS  Google Scholar 

  114. Barthel H, 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  CAS  PubMed Central  Google Scholar 

  115. Rasey JS, et al. Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia. J Nucl Med. 1999;40:1072–9.

    PubMed  CAS  Google Scholar 

  116. Evans SM, et al. Noninvasive detection of tumor hypoxia using the 2-nitroimidazole [18F]EF1. J Nucl Med. 2000;41:327–36.

    PubMed  CAS  Google Scholar 

  117. Christian N, et al. Determination of tumour hypoxia with the PET tracer [18F]EF3: improvement of the tumour-to-background ratio in a mouse tumour model. Eur J Nucl Med Mol Imaging. 2007;34:1348–54.

    PubMed  CAS  Google Scholar 

  118. Ziemer LS, 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  CAS  Google Scholar 

  119. Koch CJ, et al. Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles. Cancer Chemother Pharmacol. 2001;48:177–87.

    PubMed  CAS  Google Scholar 

  120. Dolbier Jr WR, et al. [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Appl Radiat Isot. 2001;54:73–80.

    PubMed  CAS  Google Scholar 

  121. Komar G, et al. 18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med. 2008;49:1944–51.

    PubMed  Google Scholar 

  122. Evans SM, et al. Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res. 2004;64:1886–92.

    PubMed  CAS  Google Scholar 

  123. Evans SM, et al. EF5 binding and clinical outcome in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys. 2006;64:922–7.

    PubMed  CAS  Google Scholar 

  124. Wood KA, et al. [(64)Cu]diacetyl-bis(N(4)-methyl-thiosemicarbazone) – a radiotracer for tumor hypoxia. Nucl Med Biol. 2008;35:393–400.

    PubMed  CAS  Google Scholar 

  125. Vavere AL, Lewis JS. Cu-ATSM: a radiopharmaceutical for the PET imaging of hypoxia. Dalton Trans. 2007; (43):4893–4902

    Google Scholar 

  126. Lewis JS, et al. Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med. 1999;40:177–83.

    PubMed  CAS  Google Scholar 

  127. Dearling JL, et al. Copper bis(thiosemicarbazone) complexes as hypoxia imaging agents: structure-activity relationships. J Biol Inorg Chem. 2002;7:249–59.

    PubMed  CAS  Google Scholar 

  128. Lewis JS, et al. Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation. J Nucl Med. 2001;42:655–61.

    PubMed  CAS  Google Scholar 

  129. Fujibayashi Y, et al. Comparative studies of Cu-64-ATSM and C-11-acetate in an acute myocardial infarction model: ex vivo imaging of hypoxia in rats. Nucl Med Biol. 1999;26:117–21.

    PubMed  CAS  Google Scholar 

  130. Yuan H, et al. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med. 2006;47:989–98.

    PubMed  CAS  Google Scholar 

  131. Burgman P, et al. Cell line-dependent differences in uptake and retention of the hypoxia-selective nuclear imaging agent Cu-ATSM. Nucl Med Biol. 2005;32:623–30.

    PubMed  CAS  Google Scholar 

  132. Matsumoto K, et al. The influence of tumor oxygenation on hypoxia imaging in murine squamous cell carcinoma using [64Cu]Cu-ATSM or [18F]fluoromisonidazole positron emission tomography. Int J Oncol. 2007;30:873–81.

    PubMed  CAS  Google Scholar 

  133. Bowen SR, et al. Characterization of positron emission tomography hypoxia tracer uptake and tissue oxygenation via electrochemical modeling. Nucl Med Biol. 2011;38:771–80.

    PubMed  CAS  PubMed Central  Google Scholar 

  134. Katano K, et al. The copper export pump ATP7B modulates the cellular pharmacology of carboplatin in ovarian carcinoma cells. Mol Pharmacol. 2003;64:466–73.

    PubMed  CAS  Google Scholar 

  135. Grigsby PW, et al. Comparison of molecular markers of hypoxia and imaging with (60)Cu-ATSM in cancer of the uterine cervix. Mol Imaging Biol. 2007;9:278–83.

    PubMed  Google Scholar 

  136. Dehdashti F, et al. Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med. 2008;49:201–5.

    PubMed  CAS  Google Scholar 

  137. Dehdashti F, et al. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging. 2003;30:844–50.

    PubMed  CAS  Google Scholar 

  138. Dietz DW, et al. Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study. Dis Colon Rectum. 2008;51:1641–8.

    PubMed  Google Scholar 

  139. Chao KS, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2001;49:1171–82.

    PubMed  CAS  Google Scholar 

  140. Lewis JS, et al. An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in cancer of the uterine cervix. J Nucl Med. 2008;49:1177–82.

    PubMed  Google Scholar 

  141. Pastorekova S, et al. Tumor-associated carbonic anhydrases and their clinical significance. Adv Clin Chem. 2006;42:167–216.

    PubMed  CAS  Google Scholar 

  142. Wykoff CC, et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000;60:7075–83.

    PubMed  CAS  Google Scholar 

  143. Hoeben BA, et al. PET of hypoxia with 89Zr-labeled cG250-F(ab′)2 in head and neck tumors. J Nucl Med. 2010;51:1076–83.

    PubMed  CAS  Google Scholar 

  144. Liao SY, et al. Identification of the MN/CA9 protein as a reliable diagnostic biomarker of clear cell carcinoma of the kidney. Cancer Res. 1997;57:2827–31.

    PubMed  CAS  Google Scholar 

  145. Murakami Y, et al. MN/CA9 gene expression as a potential biomarker in renal cell carcinoma. BJU Int. 1999;83:743–7.

    PubMed  CAS  Google Scholar 

  146. Uemura H, et al. MN/CA IX/G250 as a potential target for immunotherapy of renal cell carcinomas. Br J Cancer. 1999;81:741–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  147. Lawrentschuk N, et al. Investigation of hypoxia and carbonic anhydrase IX expression in a renal cell carcinoma xenograft model with oxygen tension measurements and (1)(2)(4)I-cG250 PET/CT. Urol Oncol. 2011;29:411–20.

    PubMed  CAS  Google Scholar 

  148. Folkman J. Angiogenesis. Annu Rev Med. 2006;57:1–18.

    PubMed  CAS  Google Scholar 

  149. Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc Res. 2010;86:236–42.

    PubMed  CAS  PubMed Central  Google Scholar 

  150. Cowden Dahl KD, et al. Hypoxia-inducible factor regulates alphavbeta3 integrin cell surface expression. Mol Biol Cell. 2005;16:1901–12.

    PubMed  CAS  PubMed Central  Google Scholar 

  151. Langen KJ, Eschmann SM. Correlative imaging of hypoxia and angiogenesis in oncology. J Nucl Med. 2008;49:515–6.

    PubMed  Google Scholar 

  152. Picchio M, et al. Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography. J Nucl Med. 2008;49:597–605.

    PubMed  Google Scholar 

  153. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–47.

    PubMed  CAS  Google Scholar 

  154. Ling CC, et al. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys. 2000;47:551–60.

    PubMed  CAS  Google Scholar 

  155. Bentzen SM, Gregoire V. Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription. Semin Radiat Oncol. 2011;21:101–10.

    PubMed  PubMed Central  Google Scholar 

  156. Busk M, et al. Resolution in PET hypoxia imaging: voxel size matters. Acta Oncol. 2008;47:1201–10.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Molecular Imaging and Radiochemistry, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Mareike Roscher & Björn Wängler

  2. Institute of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Biomedical Chemistry, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Carmen Wängler

  3. Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

    Stefan O. Schönberg

Authors
  1. Mareike Roscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carmen Wängler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan O. Schönberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Björn Wängler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Björn Wängler .

Editor information

Editors and Affiliations

  1. Health Time Group, Jaén, Spain

    Antonio Luna

  2. Dept. of MRI, Clínica Girona, Girona, Spain

    Joan C. Vilanova

  3. Botafogo - Rio de Janeiro/RJ, Brazil

    L. Celso Hygino da Cruz Jr.

  4. Centro de Diagnóstico Dr. Enrique Rossi, Buenos Aires, Argentina

    Santiago E. Rossi

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Roscher, M., Wängler, C., Schönberg, S.O., Wängler, B. (2014). Current Clinical Imaging of Hypoxia with PET and Future Perspectives. In: Luna, A., Vilanova, J., Hygino da Cruz Jr., L., Rossi, S. (eds) Functional Imaging in Oncology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40412-2_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-40412-2_11

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-40411-5

  • Online ISBN: 978-3-642-40412-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation