Molecular Imaging and Biology

, Volume 13, Issue 3, pp 399–410

Tumor Hypoxia Imaging

Review Article


There is a need to measure tumor hypoxia in assessing the aggressiveness of tumor and predicting the outcome of therapy. A number of invasive and noninvasive techniques have been exploited to measure tumor hypoxia, including polarographic needle electrodes, immunohistochemical staining, radionuclide imaging (positron emission tomography [PET] and single-photon emission computed tomography [SPECT]), magnetic resonance imaging (MRI), optical imaging (bioluminescence and fluorescence), and so on. This review article summarizes and discusses the pros and cons of each currently available method for measuring tissue oxygenation. Special emphasis was placed on noninvasive imaging hypoxia with emerging new agents and new imaging technologies to detect the molecular events that are relevant to tumor hypoxia.

Key words

Hypoxia Molecular imaging Positron emission tomography (PET) Single-photon emission computed tomography (SPECT) Optical imaging Magnetic resonance imaging (MRI) 


  1. 1.
    Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26:225–239PubMedCrossRefGoogle Scholar
  2. 2.
    Hu M, Polyak K (2008) Microenvironmental regulation of cancer development. Curr Opin Genet Dev 18:27–34PubMedCrossRefGoogle Scholar
  3. 3.
    Fukumura D, Jain RK (2007) Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization. Microvasc Res 74:72–84PubMedCrossRefGoogle Scholar
  4. 4.
    Vaupel P, Mayer A, Hockel M (2004) Tumor hypoxia and malignant progression. Methods Enzymol 381:335–354PubMedCrossRefGoogle Scholar
  5. 5.
    Gray LH, Conger AD, Ebert M, Hornsey S, Scott OCA (1953) The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26:638–648PubMedCrossRefGoogle Scholar
  6. 6.
    Matthews NE, Adams MA, Maxwell LR, Gofton TE, Graham CH (2001) Nitric oxide-mediated regulation of chemosensitivity in cancer cells. J Natl Cancer Inst 93:1879–1885PubMedCrossRefGoogle Scholar
  7. 7.
    Nordsmark M, Bentzen SM, Rudat V et al (2005) Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77:18–24PubMedCrossRefGoogle Scholar
  8. 8.
    Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW (1997) Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 38:285–289PubMedCrossRefGoogle Scholar
  9. 9.
    Hockel M, Vorndran B, Schlenger K, Baussmann E, Knapstein PG (1993) Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix. Gynecol Oncol 51:141–149PubMedCrossRefGoogle Scholar
  10. 10.
    Nordsmark M, Loncaster J, Chou SC et al (2001) Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma. Int J Radiat Oncol Biol Phys 49:581–586PubMedCrossRefGoogle Scholar
  11. 11.
    Nordsmark M, Overgaard J (2000) A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol 57:39–43PubMedCrossRefGoogle Scholar
  12. 12.
    Evans SM, Judy KD, Dunphy I et al (2004) Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res 10:8177–8184PubMedCrossRefGoogle Scholar
  13. 13.
    Powell ME, Collingridge DR, Saunders MI et al (1999) Improvement in human tumour oxygenation with carbogen of varying carbon dioxide concentrations. Radiother Oncol 50:167–171PubMedCrossRefGoogle Scholar
  14. 14.
    Gatenby RA, Moldofsky PJ, Weiner LM (1988) Metastatic colon cancer: correlation of oxygen levels with I-131 F(ab’)2 uptake. Radiology 166:757–759PubMedGoogle Scholar
  15. 15.
    Brizel DM, Scully SP, Harrelson JM et al (1996) Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res 56:5347–5350PubMedGoogle Scholar
  16. 16.
    Pauwels EK, Mariani G (2007) Assessment of tumor tissue oxygenation: agents, methods and clinical significance. Drug News Perspect 20:619–626PubMedCrossRefGoogle Scholar
  17. 17.
    Rumsey WL, Vanderkooi JM, Wilson DF (1988) Imaging of phosphorescence—a novel method for measuring oxygen distribution in perfused tissue. Science 241:1649–1651PubMedCrossRefGoogle Scholar
  18. 18.
    Vinogradov SA, Grosul P, Rozhkov V et al (2003) Oxygen distributions in tissue measured by phosphorescence quenching. Adv Exp Med Biol 510:181–185PubMedGoogle Scholar
  19. 19.
    Lebedev AY, Cheprakov AV, Sakadzic S et al (2009) Dendritic phosphorescent probes for oxygen imaging in biological systems. ACS Appl Mater Interfaces 1:1292–1304PubMedCrossRefGoogle Scholar
  20. 20.
    Pennekamp CW, Bots ML, Kappelle LJ, Moll FL, de Borst GJ (2009) The value of near-infrared spectroscopy measured cerebral oximetry during carotid endarterectomy in perioperative stroke prevention. A review. Eur J Vasc Endovasc Surg 38:539–545PubMedCrossRefGoogle Scholar
  21. 21.
    Jobsis FF (1977) Non-invasive, infra-red monitoring of cerebral O2 sufficiency, blood volume, HbO2-Hb shifts and blood flow. Acta Neurol Scand Suppl 64:452–453PubMedGoogle Scholar
  22. 22.
    Hull EL, Conover DL, Foster TH (1999) Carbogen-induced changes in rat mammary tumour oxygenation reported by near infrared spectroscopy. Br J Cancer 79:1709–1716PubMedCrossRefGoogle Scholar
  23. 23.
    Kim JG, Liu H (2008) Investigation of biphasic tumor oxygen dynamics induced by hyperoxic gas intervention: the dynamic phantom approach. Appl Opt 47:242–252PubMedCrossRefGoogle Scholar
  24. 24.
    Ljungkvist AS, Bussink J, Kaanders JH, van der Kogel AJ (2007) Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat Res 167:127–145PubMedCrossRefGoogle Scholar
  25. 25.
    Chapman JD (1979) Hypoxic sensitizers—implications for radiation therapy. N Engl J Med 301:1429–1432PubMedCrossRefGoogle Scholar
  26. 26.
    Raleigh JA, Calkins-Adams DP, Rinker LH et al (1998) Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res 58:3765–3768PubMedGoogle Scholar
  27. 27.
    Evans SM, Hahn S, Pook DR et al. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res 60:2018–2024Google Scholar
  28. 28.
    Evans SM, Koch CJ (2003) Prognostic significance of tumor oxygenation in humans. Cancer Lett 195:1–16PubMedCrossRefGoogle Scholar
  29. 29.
    Rajendran JG, Schwartz DL, O’Sullivan J et al (2006) Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res 12:5435–5441PubMedCrossRefGoogle Scholar
  30. 30.
    Raleigh JA, Chou SC, Arteel GE, Horsman MR (1999) Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res 151:580–589PubMedCrossRefGoogle Scholar
  31. 31.
    Toma-Dasu I, Dasu A, Brahme A (2009) Quantifying tumour hypoxia by PET imaging—a theoretical analysis. Adv Exp Med Biol 645:267–272PubMedCrossRefGoogle Scholar
  32. 32.
    Massoud TF, Gambhir SS (2007) Integrating noninvasive molecular imaging into molecular medicine: an evolving paradigm. Trends Mol Med 13:183–191PubMedCrossRefGoogle Scholar
  33. 33.
    Willmann JK, van Bruggen N, Dinkelborg LM, Gambhir SS (2008) Molecular imaging in drug development. Nat Rev Drug Discov 7:591–607PubMedCrossRefGoogle Scholar
  34. 34.
    Swartz HM, Clarkson RB (1998) The measurement of oxygen in vivo using EPR techniques. Phys Med Biol 43:1957–1975PubMedCrossRefGoogle Scholar
  35. 35.
    Matsumoto K, English S, Yoo J et al (2004) Pharmacokinetics of a triarylmethyl-type paramagnetic spin probe used in EPR oximetry. Magn Reson Med 52:885–892PubMedCrossRefGoogle Scholar
  36. 36.
    Krohn KA, Link JM, Mason RP (2008) Molecular imaging of hypoxia. J Nucl Med 49(Suppl 2):129S–148SPubMedCrossRefGoogle Scholar
  37. 37.
    Wang X, Xie X, Ku G, Wang LV, Stoica G (2006) Noninvasive imaging of hemoglobin concentration and oxygenation in the rat brain using high-resolution photoacoustic tomography. J Biomed Opt 11:024015PubMedCrossRefGoogle Scholar
  38. 38.
    Padhani A (2010) Science to practice: what does MR oxygenation imaging tell us about human breast cancer hypoxia? Radiology 254:1–3PubMedCrossRefGoogle Scholar
  39. 39.
    Howe FA, Robinson SP, McIntyre DJ, Stubbs M, Griffiths JR (2001) Issues in flow and oxygenation dependent contrast (FLOOD) imaging of tumours. NMR Biomed 14:497–506PubMedCrossRefGoogle Scholar
  40. 40.
    Stubbs M (1999) Application of magnetic resonance techniques for imaging tumour physiology. Acta Oncol 38:845–853PubMedCrossRefGoogle Scholar
  41. 41.
    Tumkur SM, Vu AT, Li LP, Pierchala L, Prasad PV (2006) Evaluation of intra-renal oxygenation during water diuresis: a time-resolved study using BOLD MRI. Kidney Int 70:139–143PubMedCrossRefGoogle Scholar
  42. 42.
    O’Connor JP, Naish JH, Parker GJ et al (2009) Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors. Int J Radiat Oncol Biol Phys 75:1209–1215PubMedCrossRefGoogle Scholar
  43. 43.
    Mason RP (2006) Non-invasive assessment of kidney oxygenation: a role for BOLD MRI. Kidney Int 70:10–11PubMedCrossRefGoogle Scholar
  44. 44.
    Thomas SR, Pratt RG, Millard RW et al (1996) In vivo PO2 imaging in the porcine model with perfluorocarbon F-19 NMR at low field. Magn Reson Imaging 14:103–114PubMedCrossRefGoogle Scholar
  45. 45.
    Mason RP, Shukla H, Antich PP (1993) In vivo oxygen tension and temperature: simultaneous determination using 19F NMR spectroscopy of perfluorocarbon. Magn Reson Med 29:296–302PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao D, Ran S, Constantinescu A, Hahn EW, Mason RP (2003) Tumor oxygen dynamics: correlation of in vivo MRI with histological findings. Neoplasia 5:308–318PubMedGoogle Scholar
  47. 47.
    van der Sanden BP, Heerschap A, Simonetti AW et al. Characterization and validation of noninvasive oxygen tension measurements in human glioma xenografts by 19F-MR relaxometry. Int J Radiat Oncol Biol Phys 44:649–658Google Scholar
  48. 48.
    McNab JA, Yung AC, Kozlowski P (2004) Tissue oxygen tension measurements in the Shionogi model of prostate cancer using 19F MRS and MRI. Magma 17:288–295PubMedCrossRefGoogle Scholar
  49. 49.
    Davda S, Bezabeh T (2006) Advances in methods for assessing tumor hypoxia in vivo: implications for treatment planning. Cancer Metastasis Rev 25:469–480PubMedCrossRefGoogle Scholar
  50. 50.
    Yu JX, Kodibagkar VD, Cui W, Mason RP (2005) 19F: a versatile reporter for non-invasive physiology and pharmacology using magnetic resonance. Curr Med Chem 12:819–848PubMedCrossRefGoogle Scholar
  51. 51.
    Hunjan S, Zhao D, Constantinescu A et al (2001) Tumor oximetry: demonstration of an enhanced dynamic mapping procedure using fluorine-19 echo planar magnetic resonance imaging in the Dunning prostate R3327-AT1 rat tumor. Int J Radiat Oncol Biol Phys 49:1097–1108PubMedCrossRefGoogle Scholar
  52. 52.
    Kwock L, Gill M, McMurry HL et al (1992) Evaluation of a fluorinated 2-nitroimidazole binding to hypoxic cells in tumor-bearing rats by 19F magnetic resonance spectroscopy and immunohistochemistry. Radiat Res 129:71–78PubMedCrossRefGoogle Scholar
  53. 53.
    Salmon HW, Siemann DW (2004) Utility of 19F MRS detection of the hypoxic cell marker EF5 to assess cellular hypoxia in solid tumors. Radiother Oncol 73:359–366PubMedCrossRefGoogle Scholar
  54. 54.
    Lee CP, Payne GS, Oregioni A et al (2009) A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy. Br J Cancer 101:1860–1868PubMedCrossRefGoogle Scholar
  55. 55.
    Rasey JS, Koh WJ, Evans ML et al (1996) 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 36:417–428PubMedCrossRefGoogle Scholar
  56. 56.
    Lehtio K, Eskola O, Viljanen T et al (2004) Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int J Radiat Oncol Biol Phys 59:971–982PubMedCrossRefGoogle Scholar
  57. 57.
    Souvatzoglou M, Grosu AL, Roper B et al (2007) Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging 34:1566–1575PubMedCrossRefGoogle Scholar
  58. 58.
    Koh WJ, Rasey JS, Evans ML et al (1992) Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole. Int J Radiat Oncol Biol Phys 22:199–212PubMedCrossRefGoogle Scholar
  59. 59.
    Lee ST, Scott AM (2007) Hypoxia positron emission tomography imaging with 18f-fluoromisonidazole. Semin Nucl Med 37:451–461PubMedCrossRefGoogle Scholar
  60. 60.
    Gagel B, Reinartz P, Demirel C et al (2006) [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 6:51PubMedCrossRefGoogle Scholar
  61. 61.
    Eschmann SM, Paulsen F, Reimold M et al (2005) 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 46:253–260PubMedGoogle Scholar
  62. 62.
    Rajendran JG, Mankoff DA, O’Sullivan F et al (2004) Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res 10:2245–2252PubMedCrossRefGoogle Scholar
  63. 63.
    Koh WJ, Bergman KS, Rasey JS et al (1995) Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography. Int J Radiat Oncol Biol Phys 33:391–398PubMedCrossRefGoogle Scholar
  64. 64.
    Rajendran JG, Wilson DC, Conrad EU et al (2003) [(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 30:695–704PubMedCrossRefGoogle Scholar
  65. 65.
    Bentzen L, Keiding S, Nordsmark M et al (2003) Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol 67:339–344PubMedCrossRefGoogle Scholar
  66. 66.
    Lehtio K, Oikonen V, Gronroos T et al (2001) 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 42:1643–1652PubMedGoogle Scholar
  67. 67.
    Yang DJ, Wallace S, Cherif A et al (1995) Development of F-18-labeled fluoroerythronitroimidazole as a PET agent for imaging tumor hypoxia. Radiology 194:795–800PubMedGoogle Scholar
  68. 68.
    Barthel H, Wilson H, Collingridge DR et al (2004) In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography. Br J Cancer 90:2232–2242PubMedGoogle Scholar
  69. 69.
    Ziemer LS, Evans SM, Kachur AV et al (2003) Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5. Eur J Nucl Med Mol Imaging 30:259–266PubMedCrossRefGoogle Scholar
  70. 70.
    Evans SM, Kachur AV, Shiue CY et al (2000) Noninvasive detection of tumor hypoxia using the 2-nitroimidazole [18F]EF1. J Nucl Med 41:327–336PubMedGoogle Scholar
  71. 71.
    Koch CJ, Evans SM (2003) Non-invasive PET and SPECT imaging of tissue hypoxia using isotopically labeled 2-nitroimidazoles. Adv Exp Med Biol 510:285–292PubMedGoogle Scholar
  72. 72.
    Komar G, Seppanen M, Eskola O et al (2008) 18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med 49:1944–1951PubMedCrossRefGoogle Scholar
  73. 73.
    Evans SM, Fraker D, Hahn SM et al (2006) EF5 binding and clinical outcome in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 64:922–927PubMedCrossRefGoogle Scholar
  74. 74.
    Dolbier WR Jr, Li AR, Koch CJ, Shiue CY, Kachur AV (2001) [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Appl Radiat Isot 54:73–80PubMedCrossRefGoogle Scholar
  75. 75.
    Kumar P, Emami S, Kresolek Z et al (2009) Synthesis and hypoxia selective radiosensitization potential of beta-2-FAZA and beta-3-FAZL: fluorinated azomycin beta-nucleosides. Med Chem 5:118–129PubMedCrossRefGoogle Scholar
  76. 76.
    Postema EJ, McEwan AJ, Riauka TA et al (2009) Initial results of hypoxia imaging using 1-alpha-D: -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA). Eur J Nucl Med Mol Imaging 36:1565–1573PubMedCrossRefGoogle Scholar
  77. 77.
    Riedl CC, Brader P, Zanzonico PB et al (2008) Imaging hypoxia in orthotopic rat liver tumors with iodine 124-labeled iodoazomycin galactopyranoside PET. Radiology 248:561–570PubMedCrossRefGoogle Scholar
  78. 78.
    Riedl CC, Brader P, Zanzonico P et al (2008) Tumor hypoxia imaging in orthotopic liver tumors and peritoneal metastasis: a comparative study featuring dynamic 18F-MISO and 124I-IAZG PET in the same study cohort. Eur J Nucl Med Mol Imaging 35:39–46PubMedCrossRefGoogle Scholar
  79. 79.
    Zanzonico P, O’Donoghue J, Chapman JD et al (2004) Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning. Eur J Nucl Med Mol Imaging 31:117–128PubMedCrossRefGoogle Scholar
  80. 80.
    Fujibayashi Y, Taniuchi H, Yonekura Y et al (1997) Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med 38:1155–1160PubMedGoogle Scholar
  81. 81.
    Lewis JS, Herrero P, Sharp TL et al (2002) Delineation of hypoxia in canine myocardium using PET and copper(II)-diacetyl-bis(N(4)-methylthiosemicarbazone). J Nucl Med 43:1557–1569PubMedGoogle Scholar
  82. 82.
    O’Donoghue JA, Zanzonico P, Pugachev A et al (2005) Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N 4-methylthiosemicarbazone) positron emission tomography: comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. Int J Radiat Oncol Biol Phys 61:1493–1502PubMedCrossRefGoogle Scholar
  83. 83.
    Takahashi N, Fujibayashi Y, Yonekura Y et al (2000) Evaluation of 62Cu labeled diacetyl-bis(N 4-methylthiosemicarbazone) as a hypoxic tissue tracer in patients with lung cancer. Ann Nucl Med 14:323–328PubMedCrossRefGoogle Scholar
  84. 84.
    Vavere AL, Lewis JS (2007) Cu-ATSM: a radiopharmaceutical for the PET imaging of hypoxia. Dalton Trans 4893–4902Google Scholar
  85. 85.
    Dehdashti F, Grigsby PW, Mintun MA et al (2003) Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys 55:1233–1238PubMedCrossRefGoogle Scholar
  86. 86.
    Lewis J, Laforest R, Buettner T et al (2001) Copper-64-diacetyl-bis(N 4-methylthiosemicarbazone): an agent for radiotherapy. Proc Natl Acad Sci USA 98:1206–1211PubMedCrossRefGoogle Scholar
  87. 87.
    Obata A, Kasamatsu S, Lewis JS et al (2005) Basic characterization of 64Cu-ATSM as a radiotherapy agent. Nucl Med Biol 32:21–28PubMedCrossRefGoogle Scholar
  88. 88.
    Lewis JS, Laforest R, Dehdashti F et al (2008) An imaging comparison of 64Cu-ATSM and 60Cu-ATSM in cancer of the uterine cervix. J Nucl Med 49:1177–1182PubMedCrossRefGoogle Scholar
  89. 89.
    Urtasun RC, Parliament MB, McEwan AJ et al. Measurement of hypoxia in human tumours by non-invasive SPECT imaging of iodoazomycin arabinoside. Br J Cancer Suppl 27:S209–S212Google Scholar
  90. 90.
    Stypinski D, Wiebe LI, McEwan AJ et al (1999) Clinical pharmacokinetics of 123I-IAZA in healthy volunteers. Nucl Med Commun 20:559–567PubMedCrossRefGoogle Scholar
  91. 91.
    Stypinski D, McQuarrie SA, Wiebe LI et al (2001) Dosimetry estimations for 123I-IAZA in healthy volunteers. J Nucl Med 42:1418–1423PubMedGoogle Scholar
  92. 92.
    Iyer RV, Kim E, Schneider RF, Chapman JD (1988) A dual hypoxic marker technique for measuring oxygenation change within individual tumors. Br J Cancer 78:163–169CrossRefGoogle Scholar
  93. 93.
    Mees G, Dierckx R, Vangestel C, Van de Wiele C (2009) Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging 36:1674–1686PubMedCrossRefGoogle Scholar
  94. 94.
    Saitoh J, Sakurai H, Suzuki Y et al (2002) Correlations between in vivo tumor weight, oxygen pressure, 31P NMR spectroscopy, hypoxic microenvironment marking by beta-d-iodinated azomycin galactopyranoside (beta-d-IAZGP), and radiation sensitivity. Int J Radiat Oncol Biol Phys 54:903–909PubMedCrossRefGoogle Scholar
  95. 95.
    Ballinger JR, Kee JW, Rauth AM (1996) In vitro and in vivo evaluation of a technetium-99m-labeled 2-nitroimidazole (BMS181321) as a marker of tumor hypoxia. J Nucl Med 37:1023–1031PubMedGoogle Scholar
  96. 96.
    Hoebers FJ, Janssen HL, Olmos AV et al (2002) Phase 1 study to identify tumour hypoxia in patients with head and neck cancer using technetium-99m BRU 59-21. Eur J Nucl Med Mol Imaging 29:1206–1211PubMedCrossRefGoogle Scholar
  97. 97.
    Yutani K, Kusuoka H, Fukuchi K, Tatsumi M, Nishimura T (1999) Applicability of 99mTc-HL91, a putative hypoxic tracer, to detection of tumor hypoxia. J Nucl Med 40:854–861PubMedGoogle Scholar
  98. 98.
    Liu Z, Stevenson GD, Barrett HH et al. Imaging recognition of multidrug resistance in human breast tumors using 99mTc-labeled monocationic agents and a high-resolution stationary SPECT system. Nucl Med Biol 31:53–65Google Scholar
  99. 99.
    Bussink J, Kaanders JH, van der Kogel AJ (2003) Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother Oncol 67:3–15PubMedCrossRefGoogle Scholar
  100. 100.
    Koukourakis MI, Bentzen SM, Giatromanolaki A et al (2006) Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol 24:727–735PubMedCrossRefGoogle Scholar
  101. 101.
    Koukourakis MI, Giatromanolaki A, Polychronidis A et al (2006) Endogenous markers of hypoxia/anaerobic metabolism and anemia in primary colorectal cancer. Cancer Sci 97:582–588PubMedCrossRefGoogle Scholar
  102. 102.
    Le QT, Kong C, Lavori PW et al (2007) Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 69:167–175PubMedCrossRefGoogle Scholar
  103. 103.
    Wang GL, Jiang BH, Semenza GL (1995) Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1. Biochem Biophys Res Commun 216:669–675PubMedCrossRefGoogle Scholar
  104. 104.
    Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88:1474–1480PubMedGoogle Scholar
  105. 105.
    Semenza GL (2001) Hypoxia-inducible factor 1: control of oxygen homeostasis in health and disease. Pediatr Res 49:614–617PubMedCrossRefGoogle Scholar
  106. 106.
    Maxwell P, Salnikow K (2004) HIF-1: an oxygen and metal responsive transcription factor. Cancer Biol Ther 3:29–35PubMedCrossRefGoogle Scholar
  107. 107.
    Semenza GL (2000) Expression of hypoxia-inducible factor 1: mechanisms and consequences. Biochem Pharmacol 59:47–53PubMedCrossRefGoogle Scholar
  108. 108.
    Zhong H, De Marzo AM, Laughner E et al (1999) Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59:5830–5835PubMedGoogle Scholar
  109. 109.
    Moon EJ, Brizel DM, Chi JT, Dewhirst MW (2007) The potential role of intrinsic hypoxia markers as prognostic variables in cancer. Antioxid Redox Signal 9:1237–1294PubMedCrossRefGoogle Scholar
  110. 110.
    Birner P, Schindl M, Obermair A et al (2000) Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 60:4693–4696PubMedGoogle Scholar
  111. 111.
    Shibata T, Giaccia AJ, Brown JM (2000) Development of a hypoxia-responsive vector for tumor-specific gene therapy. Gene Ther 7:493–498PubMedCrossRefGoogle Scholar
  112. 112.
    Payen E, Bettan M, Henri A et al (2001) Oxygen tension and a pharmacological switch in the regulation of transgene expression for gene therapy. J Gene Med 3:498–504PubMedCrossRefGoogle Scholar
  113. 113.
    Vordermark D, Shibata T, Brown JM (2001) Green fluorescent protein is a suitable reporter of tumor hypoxia despite an oxygen requirement for chromophore formation. Neoplasia 3:527–534PubMedCrossRefGoogle Scholar
  114. 114.
    Harada H, Kizaka-Kondoh S, Hiraoka M (2005) Optical imaging of tumor hypoxia and evaluation of efficacy of a hypoxia-targeting drug in living animals. Mol Imaging 4:182–193PubMedGoogle Scholar
  115. 115.
    Harada H, Hiraoka M, Kizaka-Kondoh S (2002) Antitumor effect of TAT-oxygen-dependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells. Cancer Res 62:2013–2018PubMedGoogle Scholar
  116. 116.
    Harada H, Kizaka-Kondoh S, Hiraoka M (2006) Mechanism of hypoxia-specific cytotoxicity of procaspase-3 fused with a VHL-mediated protein destruction motif of HIF-1alpha containing Pro564. FEBS Lett 580:5718–5722PubMedCrossRefGoogle Scholar
  117. 117.
    Harada H, Kizaka-Kondoh S, Li G et al (2007) Significance of HIF-1-active cells in angiogenesis and radioresistance. Oncogene 26:7508–7516PubMedCrossRefGoogle Scholar
  118. 118.
    Viola RJ, Provenzale JM, Li F et al (2008) In vivo bioluminescence imaging monitoring of hypoxia-inducible factor 1alpha, a promoter that protects cells, in response to chemotherapy. AJR Am J Roentgenol 191:1779–1784PubMedCrossRefGoogle Scholar
  119. 119.
    Mayer A, Wree A, Hockel M et al (2004) Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix. Cancer Res 64:5876–5881PubMedCrossRefGoogle Scholar
  120. 120.
    Lehmann S, Stiehl DP, Honer M et al (2009) Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events. Proc Natl Acad Sci USA 106:14004–14009PubMedCrossRefGoogle Scholar
  121. 121.
    Potter CP, Harris AL (2003) Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br J Cancer 89:2–7PubMedCrossRefGoogle Scholar
  122. 122.
    Ivanov S, Liao SY, Ivanova A et al (2001) Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905–919PubMedCrossRefGoogle Scholar
  123. 123.
    Wykoff CC, Beasley NJ, Watson PH et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075–7083Google Scholar
  124. 124.
    Dubois L, Lieuwes NG, Maresca A et al (2009) Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model. Radiother Oncol 92:423–428PubMedCrossRefGoogle Scholar
  125. 125.
    van Dijk J, Uemura H, Beniers AJ et al. Therapeutic effects of monoclonal antibody G250, interferons and tumor necrosis factor, in mice with renal-cell carcinoma xenografts. Int J Cancer 56:262–268Google Scholar
  126. 126.
    Stillebroer AB, Oosterwijk E, Oyen WJ, Mulders PF, Boerman OC (2007) Radiolabeled antibodies in renal cell carcinoma. Cancer Imaging 7:179–188PubMedCrossRefGoogle Scholar
  127. 127.
    Ahlskog JK, Schliemann C, Marlind J et al (2009) Human monoclonal antibodies targeting carbonic anhydrase IX for the molecular imaging of hypoxic regions in solid tumours. Br J Cancer 101:645–657PubMedCrossRefGoogle Scholar
  128. 128.
    Hoogsteen IJ, Marres HA, Wijffels KI et al (2005) Colocalization of carbonic anhydrase 9 expression and cell proliferation in human head and neck squamous cell carcinoma. Clin Cancer Res 11:97–106PubMedGoogle Scholar
  129. 129.
    Kim SJ, Shin HJ, Jung KY et al (2007) Prognostic value of carbonic anhydrase IX and Ki-67 expression in squamous cell carcinoma of the tongue. Jpn J Clin Oncol 37:812–819PubMedCrossRefGoogle Scholar
  130. 130.
    Mayer A, Hockel M, Vaupel P (2005) Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix. Clin Cancer Res 11:7220–7225PubMedCrossRefGoogle Scholar
  131. 131.
    Westra J, Molema G, Kallenberg CG (2010) Hypoxia-inducible factor-1 as regulator of angiogenesis in rheumatoid arthritis—therapeutic implications. Curr Med Chem 17:254–263PubMedCrossRefGoogle Scholar
  132. 132.
    Macheda ML, Rogers S, Best JD (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202:654–662PubMedCrossRefGoogle Scholar
  133. 133.
    Rogers S, Macheda ML, Docherty SE et al (2002) Identification of a novel glucose transporter-like protein-GLUT-12. Am J Physiol Endocrinol Metab 282:E733–E738PubMedGoogle Scholar
  134. 134.
    Airley RE, Loncaster J, Raleigh JA et al (2003) GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 104:85–91PubMedCrossRefGoogle Scholar
  135. 135.
    Jonathan RA, Wijffels KI, Peeters W et al (2006) The prognostic value of endogenous hypoxia-related markers for head and neck squamous cell carcinomas treated with ARCON. Radiother Oncol 79:288–297PubMedCrossRefGoogle Scholar
  136. 136.
    Grosso AR, Martins S, Carmo-Fonseca M (2008) The emerging role of splicing factors in cancer. EMBO Rep 9:1087–1093PubMedCrossRefGoogle Scholar
  137. 137.
    Martinkova J, Gadher SJ, Hajduch M, Kovarova H (2009) Challenges in cancer research and multifaceted approaches for cancer biomarker quest. FEBS Lett 583:1772–1784PubMedCrossRefGoogle Scholar
  138. 138.
    Koong AC, Denko NC, Hudson KM et al (2000) Candidate genes for the hypoxic tumor phenotype. Cancer Res 60:883–887PubMedGoogle Scholar
  139. 139.
    Lal A, Peters H, St Croix B et al (2001) Transcriptional response to hypoxia in human tumors. J Natl Cancer Inst 93:1337–1343PubMedCrossRefGoogle Scholar
  140. 140.
    Chen JL, Lucas JE, Schroeder T et al (2008) The genomic analysis of lactic acidosis and acidosis response in human cancers. PLoS Genet 4:e1000293PubMedCrossRefGoogle Scholar
  141. 141.
    Starmans MH, Zips D, Wouters BG, Baumann M, Lambin P (2009) The use of a comprehensive tumour xenograft dataset to validate gene signatures relevant for radiation response. Radiother Oncol 92:417–422PubMedCrossRefGoogle Scholar
  142. 142.
    Rho JH, Qin S, Wang JY, Roehrl MH (2008) Proteomic expression analysis of surgical human colorectal cancer tissues: up-regulation of PSB7, PRDX1, and SRP9 and hypoxic adaptation in cancer. J Proteome Res 7:2959–2972PubMedCrossRefGoogle Scholar
  143. 143.
    Picchio M, Beck R, Haubner R et al (2008) Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography. J Nucl Med 49:597–605PubMedCrossRefGoogle Scholar

Copyright information

© Academy of Molecular Imaging and Society for Molecular Imaging 2010

Authors and Affiliations

  1. 1.Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB)National Institutes of Health (NIH)BethesdaUSA
  2. 2.Department of Medical Imaging and Nuclear Medicine, the Fourth Affiliated HospitalHarbin Medical UniversityHarbinPeople’s Republic of China
  3. 3.Imaging Sciences Training Program, Radiology and Imaging SciencesClinical Center and National Institute Biomedical Imaging and BioengineeringBethesdaUSA

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