Review Article
No access
Published Online: 11 September 2014

The Clinical Importance of Assessing Tumor Hypoxia: Relationship of Tumor Hypoxia to Prognosis and Therapeutic Opportunities

Publication: Antioxidants & Redox Signaling
Volume 21, Issue Number 10


Tumor hypoxia is a well-established biological phenomenon that affects the curability of solid tumors, regardless of treatment modality. Especially for head and neck cancer patients, tumor hypoxia is linked to poor patient outcomes. Given the biological problems associated with tumor hypoxia, the goal for clinicians has been to identify moderately to severely hypoxic tumors for differential treatment strategies. The “gold standard” for detecting and characterizing of tumor hypoxia are the invasive polarographic electrodes. Several less invasive hypoxia assessment techniques have also shown promise for hypoxia assessment. The widespread incorporation of hypoxia information in clinical tumor assessment is severely impeded by several factors, including regulatory hurdles and unclear correlation with potential treatment decisions. There is now an acute need for approved diagnostic technologies for determining the hypoxia status of cancer lesions, as it would enable clinical development of personalized, hypoxia-based therapies, which will ultimately improve outcomes. A number of different techniques for assessing tumor hypoxia have evolved to replace polarographic pO2 measurements for assessing tumor hypoxia. Several of these modalities, either individually or in combination with other imaging techniques, provide functional and physiological information of tumor hypoxia that can significantly improve the course of treatment. The assessment of tumor hypoxia will be valuable to radiation oncologists, surgeons, and biotechnology and pharmaceutical companies who are engaged in developing hypoxia-based therapies or treatment strategies. Antioxid. Redox Signal. 21, 1516–1554.


I. Introduction
II. The Clinical Importance of Tumor Hypoxia
A. Pathophysiology of hypoxia
B. Hypoxia's negative impact on the effectiveness of curative treatment
1. Hypoxic tumors accumulate and propagate cancer stem cells
2. Hypoxia reduces the effectiveness of radiotherapy
3. Hypoxia increases metastasis risk and reduces the effectiveness of surgery
4. Hypoxic tumors are resistant to the effects of chemotherapy and chemoradiation
C. Hypoxia is prognostic for poor patient outcomes
III. Diagnosis of Tumor Hypoxia
A. Direct methods
1. Oxygen electrode—direct pO2 measurement most used in cancer research
2. Phosphorescence quenching—alternative direct pO2 measurement
3. Electron paramagnetic resonance
4. 19F-magnetic resonance spectroscopy
5. Overhauser-enhanced MRI
B. Endogenous markers of hypoxia
1. Hypoxia-inducible factor-1α
2. Carbonic anhydrase IX
3. Glucose transporter 1
4. Osteopontin
5. A combined IHC panel of protein markers for hypoxia
6. Comet assay
C. Physiologic methods
1. Near-infrared spectroscopy/tomography—widely used for pulse oximetry
2. Photoacoustic tomography
3. Contrast-enhanced color duplex sonography
4. MRI-based measurements
5. Blood oxygen level-dependent MRI
6. Pimonidazole
7. EF5 (pentafluorinated etanidazole)
8. Hypoxia PET imaging—physiologic hypoxia measurement providing tomographic information
a. 18F-fluoromisonidazole
b. 18F-fluoroazomycinarabinofuranoside
c. 18F-EF5 (pentafluorinated etanidazole)
d. 18F-flortanidazole
e. Copper (II) (diacetyl-bis (N4-methylthiosemicarbazone))
f. 18F-FDG imaging of hypoxia
IV. Modifying Hypoxia to Improve Therapeutic Outcomes
A. Use of hypoxia information in radiation therapy planning
B. Use of hypoxia assessment for selection of patients responsive to nimorazole
C. Use of hypoxia assessment for selection of patients responsive to tirapazamine
D. Use of hypoxia assessment for selection of patients responsive to oxygen delivery therapies
V. Concluding Remarks

Get full access to this article

View all available purchase options and get full access to this article.


Adam MF, Gabalski EC, Bloch DA, Oehlert JW, Brown JM, Elsaid AA, Pinto HA, and Terris DJ. Tissue oxygen distribution in head and neck cancer patients. Head Neck 21: 146–153, 1999.
Adams GE, Ahmed I, Sheldon PW, and Stratford IJ. Radiation sensitization and chemopotentiation: RSU 1069, a compound more efficient than misonidazole in vitro and in vivo. Br J Cancer 49: 571–577, 1984.
Airley RE, Loncaster J, Raleigh JA, Harris AL, Davidson SE, Hunter RD, West CM, and Stratford IJ. GLUT-1 and CAIX as intrinsic markers of hypoxia in carcinoma of the cervix: relationship to pimonidazole binding. Int J Cancer 104: 85–91, 2003.
Aquino-Parsons C, Luo C, Vikse CM, and Olive PL. Comparison between the comet assay and the oxygen microelectrode for measurement of tumor hypoxia. Radiother Oncol 51: 179–185, 1999.
Arteel GE, Thurman RG, Yates JM, and Raleigh JA. Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72: 889–895, 1995.
Baba Y, Nosho K, Shima K, Irahara N, Chan AT, Meyerhardt JA, Chung DC, Giovannucci EL, Fuchs CS, and Ogino S. HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol 176: 2292–2301, 2010.
Bache M, Kappler M, Said HM, Staab A, and Vordermark D. Detection and specific targeting of hypoxic regions within solid tumors: current preclinical and clinical strategies. Curr Med Chem 15: 322–338, 2008.
Bache M, Kappler M, Wichmann H, Rot S, Hahnel A, Greither T, Said HM, Kotzsch M, Wurl P, Taubert H, and Vordermark D. Elevated tumor and serum levels of the hypoxia-associated protein osteopontin are associated with prognosis for soft tissue sarcoma patients. BMC Cancer 10: 132, 2010.
Bache M, Reddemann R, Said HM, Holzhausen HJ, Taubert H, Becker A, Kuhnt T, Hansgen G, Dunst J, and Vordermark D. Immunohistochemical detection of osteopontin in advanced head-and-neck cancer: prognostic role and correlation with oxygen electrode measurements, hypoxia-inducible-factor-1alpha-related markers, and hemoglobin levels. Int J Radiat Oncol Biol Phys 66: 1481–1487, 2006.
Basken NE and Green MA. Cu(II) bis(thiosemicarbazone) radiopharmaceutical binding to serum albumin: further definition of species dependence and associated substituent effects. Nucl Med Biol 36: 495–504, 2009.
Baudelet C and Gallez B. How does blood oxygen level-dependent (BOLD) contrast correlate with oxygen partial pressure (pO2) inside tumors? Magn Reson Med 48: 980–986, 2002.
Beasley NJ, Leek R, Alam M, Turley H, Cox GJ, Gatter K, Millard P, Fuggle S, and Harris AL. Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res 62: 2493–2497, 2002.
Bennewith KL and Dedhar S. Targeting hypoxic tumour cells to overcome metastasis. BMC Cancer 11: 504, 2011.
Bentzen L, Keiding S, Nordsmark M, Falborg L, Hansen SB, Keller J, Nielsen OS, and Overgaard J. Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol 67: 339–344, 2003.
Betensky RA, Louis DN, and Cairncross JG. Influence of unrecognized molecular heterogeneity on randomized clinical trials. J Clin Oncol 20: 2495–2499, 2002.
Betof AS, Rabbani ZN, Hardee ME, Kim SJ, Broadwater G, Bentley RC, Snyder SA, Vujaskovic Z, Oosterwijk E, Harris LN, Horton JK, Dewhirst MW, and Blackwell KL. Carbonic anhydrase IX is a predictive marker of doxorubicin resistance in early-stage breast cancer independent of HER2 and TOP2A amplification. Br J Cancer 106: 916–922, 2012.
Bollineni VR, Wiegman EM, Pruim J, Groen HJ, and Langendijk JA. Hypoxia imaging using positron emission tomography in non-small cell lung cancer: implications for radiotherapy. Cancer Treat Rev 38: 1027–1032, 2012.
Bourke VA, Zhao D, Gilio J, Chang CH, Jiang L, Hahn EW, and Mason RP. Correlation of radiation response with tumor oxygenation in the Dunning prostate R3327-AT1 tumor. Int J Radiat Oncol Biol Phys 67: 1179–1186, 2007.
Boushel R, Langberg H, Olesen J, Gonzales-Alonzo J, Bulow J, and Kjaer M. Monitoring tissue oxygen availability with near infrared spectroscopy (NIRS) in health and disease. Scand J Med Sci Sports 11: 213–222, 2001.
Bowen SR, van der Kogel AJ, Nordsmark M, Bentzen SM, and Jeraj R. Characterization of positron emission tomography hypoxia tracer uptake and tissue oxygenation via electrochemical modeling. Nucl Med Biol 38: 771–780, 2011.
Brizel DM, Dodge RK, Clough RW, and Dewhirst MW. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 53: 113–117, 1999.
Brizel DM, Prosnitz RG, Hunter S, Fisher SR, Clough RL, Downey MA, and Scher RL. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 58: 1418–1423, 2004.
Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Bean JM, Prosnitz LR, and Dewhirst MW. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 56: 941–943, 1996.
Brockton N, Dort J, Lau H, Hao D, Brar S, Klimowicz A, Petrillo S, Diaz R, Doll C, and Magliocco A. High stromal carbonic anhydrase IX expression is associated with decreased survival in P16-negative head-and-neck tumors. Int J Radiat Oncol Biol Phys 80: 249–257, 2011.
Brown JM. The hypoxic cell: a target for selective cancer therapy—eighteenth and Bruce F. Cain Memorial Award lecture. Cancer Res 59: 5863–5870, 1999.
Brown JM, Diehn M, and Loo BW Jr. Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer. Int J Radiat Oncol Biol Phys 78: 323–327, 2010.
Brown JM and Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4: 437–447, 2004.
Bruehlmeier M, Roelcke U, Schubiger PA, and Ametamey SM. Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O. J Nucl Med 45: 1851–1859, 2004.
Burgman P, Odonoghue JA, Humm JL, and Ling CC. Hypoxia-Induced increase in FDG uptake in MCF7 cells. J Nucl Med 42: 170–175, 2001.
Busk M, Horsman MR, Jakobsen S, Keiding S, van der Kogel AJ, Bussink J, and Overgaard J. 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 70: 1202–1212, 2008.
Canning MT, Postovit LM, Clarke SH, and Graham CH. Oxygen-mediated regulation of gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells. Exp Cell Res 267: 88–94, 2001.
Carmeliet P and Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10: 417–427, 2011.
Casey G. Oxygen transport and the use of pulse oximetry. Nurs Stand 15: 46–53, 2001.
Cerniglia GJ, Pore N, Tsai JH, Schultz S, Mick R, Choe R, Xing X, Durduran T, Yodh AG, Evans SM, Koch CJ, Hahn SM, Quon H, Sehgal CM, Lee WM, and Maity A. Epidermal growth factor receptor inhibition modulates the microenvironment by vascular normalization to improve chemotherapy and radiotherapy efficacy. PLoS One 4: e6539, 2009.
Chae SS, Kamoun WS, Farrar CT, Kirkpatrick ND, Niemeyer E, de Graaf AM, Sorensen AG, Munn LL, Jain RK, and Fukumura D. Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin Cancer Res 16: 3618–3627, 2010.
Chang J, Wen B, Kazanzides P, Zanzonico P, Finn RD, Fichtinger G, and Ling CC. A robotic system for 18F-FMISO PET-guided intratumoral pO2 measurements. Med Phys 36: 5301–5309, 2009.
Chang Q, Jurisica I, Do T, and Hedley DW. Hypoxia predicts aggressive growth and spontaneous metastasis formation from orthotopically grown primary xenografts of human pancreatic cancer. Cancer Res 71: 3110–3120, 2011.
Chao KS, Bosch WR, Mutic S, Lewis JS, Dehdashti F, Mintun MA, Dempsey JF, Perez CA, Purdy JA, and Welch MJ. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 49: 1171–1182, 2001.
Chao KS, Ozyigit G, Tran BN, Cengiz M, Dempsey JF, and Low DA. Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 55: 312–321, 2003.
Chapman JD, Franko AJ, and Sharplin J. A marker for hypoxic cells in tumours with potential clinical applicability. Br J Cancer 43: 546–550, 1981.
Chen L, Zhang Z, Kolb HC, Walsh JC, Zhang J, and Guan Y. 18F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with (18)F-FMISO. Nucl Med Commun 33: 1096–1102, 2012.
Chen YJ, Wei YY, Chen HT, Fong YC, Hsu CJ, Tsai CH, Hsu HC, Liu SH, and Tang CH. Osteopontin increases migration and MMP-9 up-regulation via alphavbeta3 integrin, FAK, ERK, and NF-kappaB-dependent pathway in human chondrosarcoma cells. J Cell Physiol 221: 98–108, 2009.
Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, Gatter KC, Ratcliffe P, and Harris AL. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 19: 3660–3668, 2001.
Chiche J, Brahimi-Horn MC, and Pouyssegur J. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med 14: 771–794, 2010.
Choe R and Yodh AG. Diffuse Optical Tomography of the Breast. Valencia, CA: American Scientific Publishers, 2006, p. 600.
Chong LM and Hunt MA. IMRT for Head and Neck Cancer. Madison, WI: Medical Physics Publishing, 2003.
Chopra S, Foltz WD, Milosevic MF, Toi A, Bristow RG, Menard C, and Haider MA. Comparing oxygen-sensitive MRI (BOLD R2*) with oxygen electrode measurements: a pilot study in men with prostate cancer. Int J Radiat Biol 85: 805–813, 2009.
Choyke PL, Dwyer AJ, and Knopp MV. Functional tumor imaging with dynamic contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 17: 509–520, 2003.
Clark LC Jr., Ackerman JL, Thomas SR, Millard RW, Hoffman RE, Pratt RG, Ragle-Cole H, Kinsey RA, and Janakiraman R. Perfluorinated organic liquids and emulsions as biocompatible NMR imaging agents for 19F and dissolved oxygen. Adv Exp Med Biol 180: 835–845, 1984.
Collet G, Skrzypek K, Grillon C, Matejuk A, Hafni-Rhabi BE, Lamerant N, and Kieda C. Hypoxia control to normalize pathologic angiogenesis: potential role for endothelial precursor cells and miRNAs regulation. Vascul Pharmacol 56: 252–261, 2012.
Collingridge DR, Piepmeier JM, Rockwell S, and Knisely JP. Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. Radiother Oncol 53: 127–131, 1999.
Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN, Clouthier SG, and Wicha MS. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109: 2784–2789.
Cooper RA, Carrington BM, Loncaster JA, Todd SM, Davidson SE, Logue JP, Luthra AD, Jones AP, Stratford I, Hunter RD, and West CM. Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix. Radiother Oncol 57: 53–59, 2000.
Dai N, Bao Q, Lu A, and Li J. Protein expression of osteopontin in tumor tissues is an independent prognostic indicator in gastric cancer. Oncology 72: 89–96, 2007.
Danhier F, Danhier P, Magotteaux N, De Preter G, Ucakar B, Karroum O, Jordan B, Gallez B, and Preat V. Electron paramagnetic resonance highlights that the oxygen effect contributes to the radiosensitizing effect of paclitaxel. PLoS One 7: e40772, 2012.
Davda S and Bezabeh T. Advances in methods for assessing tumor hypoxia in vivo: implications for treatment planning. Cancer Metastasis Rev 25: 469–480, 2006.
Dawson LA, Anzai Y, Marsh L, Martel MK, Paulino A, Ship JA, and Eisbruch A. Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 46: 1117–1126, 2000.
Dean M, Fojo T, and Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 5: 275–284, 2005.
Dehdashti F, Grigsby PW, Lewis JS, Laforest R, Siegel BA, and Welch MJ. Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone). J Nucl Med 49: 201–205, 2008.
Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, and Welch MJ. 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: 1233–1238, 2003.
Dehdashti F, Mintun MA, Lewis JS, Bradley J, Govindan R, Laforest R, Welch MJ, and Siegel BA. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging 30: 844–850, 2003.
Dence CS, Ponde DE, Welch MJ, and Lewis JS. Autoradiographic and small-animal PET comparisons between (18)F-FMISO, (18)F-FDG, (18)F-FLT and the hypoxic selective (64)Cu-ATSM in a rodent model of cancer. Nucl Med Biol 35: 713–720, 2008.
Dengler J, Frenzel C, Vajkoczy P, Wolf S, and Horn P. Cerebral tissue oxygenation measured by two different probes: challenges and interpretation. Intensive Care Med 37: 1809–1815, 2011.
Dent JG and Netter KJ. Errors in oxygen tension measurements caused by halothane. Br J Anaesth 48: 195–197, 1976.
Di Martino EF, Gagel B, Schramm O, Maneschi P, and Westhofen M. Evaluation of tumor oxygenation by color duplex sonography: a new approach. Otolaryngol Head Neck Surg 132: 765–769, 2005.
Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL, and Clarke MF. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458: 780–783, 2009.
Dietz A, Vanselow B, Rudat V, Conradt C, Weidauer H, Kallinowski F, and Dollner R. Prognostic impact of reoxygenation in advanced cancer of the head and neck during the initial course of chemoradiation or radiotherapy alone. Head Neck 25: 50–58, 2003.
Dietz DW, Dehdashti F, Grigsby PW, Malyapa RS, Myerson RJ, Picus J, Ritter J, Lewis JS, Welch MJ, and Siegel BA. 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 51: 1641–1648, 2008.
Dings RP, Loren M, Heun H, McNiel E, Griffioen AW, Mayo KH, and Griffin RJ. Scheduling of radiation with angiogenesis inhibitors anginex and Avastin improves therapeutic outcome via vessel normalization. Clin Cancer Res 13: 3395–3402, 2007.
Dirix P, Vandecaveye V, De Keyzer F, Stroobants S, Hermans R, and Nuyts S. Dose painting in radiotherapy for head and neck squamous cell carcinoma: value of repeated functional imaging with (18)F-FDG PET, (18)F-fluoromisonidazole PET, diffusion-weighted MRI, and dynamic contrast-enhanced MRI. J Nucl Med 50: 1020–1027, 2009.
Dische S, Machin D, and Chassagne D. A trial of Ro 03–8799 (pimonidazole) in carcinoma of the uterine cervix: an interim report from the Medical Research Council Working Party on advanced carcinoma of the cervix. Radiother Oncol 26: 93–103, 1993.
Dische S, Saunders MI, Bennett MH, Dunphy EP, Des Rochers C, Stratford MR, Minchinton AI, and Wardman P. A comparison of the tumour concentrations obtainable with misonidazole and Ro 03–8799. Br J Radiol 59: 911–917, 1986.
Donaldson SB, Betts G, Bonington SC, Homer JJ, Slevin NJ, Kershaw LE, Valentine H, West CM, and Buckley DL. Perfusion estimated with rapid dynamic contrast-enhanced magnetic resonance imaging correlates inversely with vascular endothelial growth factor expression and pimonidazole staining in head-and-neck cancer: a pilot study. Int J Radiat Oncol Biol Phys 81: 1176–1183, 2011.
Doss M, Zhang JJ, Belanger MJ, Stubbs JB, Hostetler ED, Alpaugh K, Kolb HC, and Yu JQ. Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT. Nucl Med Commun 31: 1016–1024, 2010.
Dubois LJ, Lieuwes NG, Janssen MH, Peeters WJ, Windhorst AD, Walsh JC, Kolb HC, Ollers MC, Bussink J, van Dongen GA, van der Kogel A, and Lambin P. Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging. Proc Natl Acad Sci U S A 108: 14620–14625, 2011.
Dunphy I, Vinogradov SA, and Wilson DF. Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence. Anal Biochem 310: 191–198, 2002.
Dunst J, Stadler P, Becker A, Lautenschlager C, Pelz T, Hansgen G, Molls M, and Kuhnt T. Tumor volume and tumor hypoxia in head and neck cancers. The amount of the hypoxic volume is important. Strahlenther Onkol 179: 521–526, 2003.
Eichhorn ME, Strieth S, Luedemann S, Kleespies A, Noth U, Passon A, Brix G, Jauch KW, Bruns CJ, and Dellian M. Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment. Cancer Biol Ther 7: 1006–1013, 2008.
Elas M, Ahn KH, Parasca A, Barth ED, Lee D, Haney C, and Halpern HJ. Electron paramagnetic resonance oxygen images correlate spatially and quantitatively with Oxylite oxygen measurements. Clin Cancer Res 12: 4209–4217, 2006.
Elas M, Bell R, Hleihel D, Barth ED, McFaul C, Haney CR, Bielanska J, Pustelny K, Ahn KH, Pelizzari CA, Kocherginsky M, and Halpern HJ. Electron paramagnetic resonance oxygen image hypoxic fraction plus radiation dose strongly correlates with tumor cure in FSa fibrosarcomas. Int J Radiat Oncol Biol Phys 71: 542–549, 2008.
Elas M, Magwood JM, Butler B, Li C, Wardak R, Barth ED, Epel B, Rubinstein S, Pelizzari CA, Weichselbaum RR, and Halpern HJ. EPR Oxygen Images Predict Tumor Control by a 50% Tumor Control Radiation Dose. Cancer Res 73: 5328–5335, 2013.
Eriksen JG and Overgaard J. Lack of prognostic and predictive value of CA IX in radiotherapy of squamous cell carcinoma of the head and neck with known modifiable hypoxia: an evaluation of the DAHANCA 5 study. Radiother Oncol 83: 383–388, 2007.
Eschmann SM, Paulsen F, Bedeshem C, Machulla HJ, Hehr T, Bamberg M, and Bares R. Hypoxia-imaging with (18)F-Misonidazole and PET: changes of kinetics during radiotherapy of head-and-neck cancer. Radiother Oncol 83: 406–410, 2007.
Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G, Machulla HJ, and Bares R. 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: 253–260, 2005.
Esipova TV, Karagodov A, Miller J, Wilson DF, Busch TM, and Vinogradov SA. Two new “protected” oxyphors for biological oximetry: properties and application in tumor imaging. Anal Chem 83: 8756–8765, 2011.
Evans SM, Du KL, Chalian AA, Mick R, Zhang PJ, Hahn SM, Quon H, Lustig R, Weinstein GS, and Koch CJ. Patterns and levels of hypoxia in head and neck squamous cell carcinomas and their relationship to patient outcome. Int J Radiat Oncol Biol Phys 69: 1024–1031, 2007.
Evans SM, Fraker D, Hahn SM, Gleason K, Jenkins WT, Jenkins K, Hwang WT, Zhang P, Mick R, and Koch CJ. EF5 binding and clinical outcome in human soft tissue sarcomas. Int J Radiat Oncol Biol Phys 64: 922–927, 2006.
Evans SM, Hahn S, Pook DR, Jenkins WT, Chalian AA, Zhang P, Stevens C, Weber R, Weinstein G, Benjamin I, Mirza N, Morgan M, Rubin S, McKenna WG, Lord EM, and Koch CJ. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res 60: 2018–2024, 2000.
Evans SM, Hahn SM, Magarelli DP, Zhang PJ, Jenkins WT, Fraker DL, Hsi RA, McKenna WG, and Koch CJ. Hypoxia in human intraperitoneal and extremity sarcomas. Int J Radiat Oncol Biol Phys 49: 587–596, 2001.
Evans SM, Jenkins KW, Chen HI, Jenkins WT, Judy KD, Hwang WT, Lustig RA, Judkins AR, Grady MS, Hahn SM, and Koch CJ. The relationship among hypoxia, proliferation, and outcome in patients with de novo glioblastoma: a pilot study. Transl Oncol 3: 160–169, 2010.
Evans SM, Judy KD, Dunphy I, Jenkins WT, Nelson PT, Collins R, Wileyto EP, Jenkins K, Hahn SM, Stevens CW, Judkins AR, Phillips P, Geoerger B, and Koch CJ. Comparative measurements of hypoxia in human brain tumors using needle electrodes and EF5 binding. Cancer Res 64: 1886–1892, 2004.
Frederiksen LJ, Siemens DR, Heaton JP, Maxwell LR, Adams MA, and Graham CH. Hypoxia induced resistance to doxorubicin in prostate cancer cells is inhibited by low concentrations of glyceryl trinitrate. J Urol 170: 1003–1007, 2003.
Gaertner FC, Souvatzoglou M, Brix G, and Beer AJ. Imaging of hypoxia using PET and MRI. Curr Pharm Biotechnol 13: 552–570, 2012.
Gagel B, DiMartino E, Schramm O, Pinkawa M, Piroth M, Demirel C, Maneschi P, Stanzel S, Asadpour B, Westhofen M, and Eble MJ. Contrast-enhanced color duplex sonography (CDS): an alternative for the evaluation of therapy-relevant tumor oxygenation? Strahlenther Onkol 182: 604–609, 2006.
Gagel B, Piroth M, Pinkawa M, Reinartz P, Zimny M, Kaiser HJ, Stanzel S, Asadpour B, Demirel C, Hamacher K, Coenen HH, Scholbach T, Maneschi P, DiMartino E, and Eble MJ. pO polarography, contrast enhanced color duplex sonography (CDS), [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography: validated methods for the evaluation of therapy-relevant tumor oxygenation or only bricks in the puzzle of tumor hypoxia? BMC Cancer 7: 113, 2007.
Gagel B, Reinartz P, Dimartino E, Zimny M, Pinkawa M, Maneschi P, Stanzel S, Hamacher K, Coenen HH, Westhofen M, Bull U, and Eble MJ. pO2 Polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2′-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia. Strahlenther Onkol 180: 616–622, 2004.
Gallez B, Baudelet C, and Jordan BF. Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications. NMR Biomed 17: 240–262, 2004.
Gammon L, Biddle A, Heywood HK, Johannessen AC, and Mackenzie IC. Sub-sets of cancer stem cells differ intrinsically in their patterns of oxygen metabolism. PLoS One 8: e62493.
Garcia-Parra R, Wood D, Shah RB, Siddiqui J, Hussain H, Park H, Desmond T, Meyer C, and Piert M. Investigation on tumor hypoxia in resectable primary prostate cancer as demonstrated by 18F-FAZA PET/CT utilizing multimodality fusion techniques. Eur J Nucl Med Mol Imaging 38: 1816–1823, 2011.
Gatenby RA, Kessler HB, Rosenblum JS, Coia LR, Moldofsky PJ, Hartz WH, and Broder GJ. Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int J Radiat Oncol Biol Phys 14: 831–838, 1988.
Gaustad JV, Simonsen TG, Leinaas MN, and Rofstad EK. Sunitinib treatment does not improve blood supply but induces hypoxia in human melanoma xenografts. BMC Cancer 12: 388, 2012.
Giaccia AJ. Hypoxic stress proteins: survival of the fittest. Semin Radiat Oncol 6: 46–58, 1996.
Giatromanolaki A and Harris AL. Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer. Anticancer Res 21: 4317–4324, 2001.
Goethals L, Debucquoy A, Perneel C, Geboes K, Ectors N, De Schutter H, Penninckx F, McBride WH, Begg AC, and Haustermans KM. Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers. Int J Radiat Oncol Biol Phys 65: 246–254, 2006.
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, and Giaccia AJ. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379: 88–91, 1996.
Graham CH, Forsdike J, Fitzgerald CJ, and Macdonald-Goodfellow S. Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. Int J Cancer 80: 617–623, 1999.
Graham MM, Peterson LM, Link JM, Evans ML, Rasey JS, Koh WJ, Caldwell JH, and Krohn KA. Fluorine-18-fluoromisonidazole radiation dosimetry in imaging studies. J Nucl Med 38: 1631–1636, 1997.
Graves EE, Vilalta M, Cecic IK, Erler JT, Tran PT, Felsher D, Sayles L, Sweet-Cordero A, Le QT, and Giaccia AJ. Hypoxia in models of lung cancer: implications for targeted therapeutics. Clin Cancer Res 16: 4843–4852, 2010.
Gray LH, Conger AD, Ebert M, Hornsey S, and Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26: 638–648, 1953.
Griffiths JR and Robinson SP. The OxyLite: a fibre-optic oxygen sensor. Br J Radiol 72: 627–630, 1999.
Gross MW, Karbach U, Groebe K, Franko AJ, and Mueller-Klieser W. Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids. Int J Cancer 61: 567–573, 1995.
Grosu AL, Piert M, Weber WA, Jeremic B, Picchio M, Schratzenstaller U, Zimmermann FB, Schwaiger M, and Molls M. Positron emission tomography for radiation treatment planning. Strahlenther Onkol 181: 483–499, 2005.
Grosu AL, Souvatzoglou M, Roper B, Dobritz M, Wiedenmann N, Jacob V, Wester HJ, Reischl G, Machulla HJ, Schwaiger M, Molls M, and Piert M. 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 69: 541–551, 2007.
Hamada K, Sasaki T, Koni PA, Natsui M, Kishimoto H, Sasaki J, Yajima N, Horie Y, Hasegawa G, Naito M, Miyazaki J, Suda T, Itoh H, Nakao K, Mak TW, Nakano T, and Suzuki A. The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev 19: 2054–2065, 2005.
Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Grone HJ, Hammerling GJ, Arnold B, and Ganss R. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453: 410–414, 2008.
Harrison LB, Chadha M, Hill RJ, Hu K, and Shasha D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 7: 492–508, 2002.
Havelund BM, Holdgaard PC, Rafaelsen SR, Mortensen LS, Theil J, Bender D, Ploen J, Spindler KL, and Jakobsen A. Tumour hypoxia imaging with 18F-fluoroazomycinarabinofuranoside PET/CT in patients with locally advanced rectal cancer. Nucl Med Commun 34: 155–161, 2013.
Helczynska K, Kronblad A, Jogi A, Nilsson E, Beckman S, Landberg G, and Pahlman S. Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res 63: 1441–1444, 2003.
Hendrickson K, Phillips M, Smith W, Peterson L, Krohn K, and Rajendran J. Hypoxia imaging with [F-18] FMISO-PET in head and neck cancer: potential for guiding intensity modulated radiation therapy in overcoming hypoxia-induced treatment resistance. Radiother Oncol 101: 369–375, 2011.
Hockel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, Knapstein PG, and Vaupel P. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol 26: 45–50, 1993.
Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, and Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56: 4509–4515, 1996.
Hockel M and Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93: 266–276, 2001.
Holland JP, Lewis JS, and Dehdashti F. Assessing tumor hypoxia by positron emission tomography with Cu-ATSM. Q J Nucl Med Mol Imaging 53: 193–200, 2009.
Hoogsteen IJ, Marres HA, Bussink J, van der Kogel AJ, and Kaanders JH. Tumor microenvironment in head and neck squamous cell carcinomas: predictive value and clinical relevance of hypoxic markers. A review. Head Neck 29: 591–604, 2007.
Hoskin PJ, Carnell DM, Taylor NJ, Smith RE, Stirling JJ, Daley FM, Saunders MI, Bentzen SM, Collins DJ, d'Arcy JA, and Padhani AP. Hypoxia in prostate cancer: correlation of BOLD-MRI with pimonidazole immunohistochemistry-initial observations. Int J Radiat Oncol Biol Phys 68: 1065–1071, 2007.
Hoskin PJ, Sibtain A, Daley FM, and Wilson GD. GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON. Br J Cancer 89: 1290–1297, 2003.
Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, and Abraham RT. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22: 7004–7014, 2002.
Hui EP, Sung FL, Yu BK, Wong CS, Ma BB, Lin X, Chan A, Wong WL, and Chan AT. Plasma osteopontin, hypoxia, and response to radiotherapy in nasopharyngeal cancer. Clin Cancer Res 14: 7080–7087, 2008.
Ilie M, Mazure NM, Hofman V, Ammadi RE, Ortholan C, Bonnetaud C, Havet K, Venissac N, Mograbi B, Mouroux J, Pouyssegur J, and Hofman P. High levels of carbonic anhydrase IX in tumour tissue and plasma are biomarkers of poor prognostic in patients with non-small cell lung cancer. Br J Cancer 102: 1627–1635, 2010.
Isa AY, Ward TH, West CM, Slevin NJ, and Homer JJ. Hypoxia in head and neck cancer. Br J Radiol 79: 791–798, 2006.
Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, Chin A, Marres HA, de Bree R, van der Kogel AJ, Hoogsteen IJ, Bussink J, Span PN, and Kaanders JH. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol 30: 1777–1783, 2012.
Jenkins WT, Evans SM, and Koch CJ. Hypoxia and necrosis in rat 9L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and the Eppendorf needle electrode. Int J Radiat Oncol Biol Phys 46: 1005–1017, 2000.
Jin F, Brockmeier U, Otterbach F, and Metzen E. New insight into the SDF-1/CXCR4 axis in a breast carcinoma model: hypoxia-induced endothelial SDF-1 and tumor cell CXCR4 are required for tumor cell intravasation. Mol Cancer Res 10: 1021–1031, 2012.
Jonathan RA, Wijffels KI, Peeters W, de Wilde PC, Marres HA, Merkx MA, Oosterwijk E, van der Kogel AJ, and Kaanders JH. The prognostic value of endogenous hypoxia-related markers for head and neck squamous cell carcinomas treated with ARCON. Radiother Oncol 79: 288–297, 2006.
Kaanders JH, Pop LA, Marres HA, Bruaset I, van den Hoogen FJ, Merkx MA, and van der Kogel AJ. ARCON: experience in 215 patients with advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 52: 769–778, 2002.
Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, de Wilde PC, Bussink J, Raleigh JA, and van der Kogel AJ. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res 62: 7066–7074, 2002.
Kappler M, Taubert H, Holzhausen HJ, Reddemann R, Rot S, Becker A, Kuhnt T, Dellas K, Dunst J, Vordermark D, Hansgen G, and Bache M. Immunohistochemical detection of HIF-1alpha and CAIX in advanced head-and-neck cancer. Prognostic role and correlation with tumor markers and tumor oxygenation parameters. Strahlenther Onkol 184: 393–399, 2008.
Kavanagh MC, Tsang V, Chow S, Koch C, Hedley D, Minkin S, and Hill RP. A comparison in individual murine tumors of techniques for measuring oxygen levels. Int J Radiat Oncol Biol Phys 44: 1137–1146, 1999.
Kayama T, Yoshimoto T, Fujimoto S, and Sakurai Y. Intratumoral oxygen pressure in malignant brain tumor. J Neurosurg 74: 55–59, 1991.
Khan N, Mupparaju S, Hou H, Williams BB, and Swartz H. Repeated assessment of orthotopic glioma pO(2) by multi-site EPR oximetry: a technique with the potential to guide therapeutic optimization by repeated measurements of oxygen. J Neurosci Methods 204: 111–117, 2012.
Kieda C, El Hafny-Rahbi B, Collet G, Lamerant-Fayel N, Grillon C, Guichard A, Dulak J, Jozkowicz A, Kotlinowski J, Fylaktakidou KC, Vidal A, Auzeloux P, Miot-Noirault E, Beloeil JC, Lehn JM, and Nicolau C. Stable tumor vessel normalization with pO(2) increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment. J Mol Med (Berl) 91: 883–899, 2013.
Kim SJ, Rabbani ZN, Dewhirst MW, Vujaskovic Z, Vollmer RT, Schreiber EG, Oosterwijk E, and Kelley MJ. Expression of HIF-1alpha, CA IX, VEGF, and MMP-9 in surgically resected non-small cell lung cancer. Lung Cancer 49: 325–335, 2005.
Kim SJ, Rabbani ZN, Vollmer RT, Schreiber EG, Oosterwijk E, Dewhirst MW, Vujaskovic Z, and Kelley MJ. Carbonic anhydrase IX in early-stage non-small cell lung cancer. Clin Cancer Res 10: 7925–7933, 2004.
Koch CJ, Evans SM, and Lord EM. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)a cet amide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br J Cancer 72: 869–874, 1995.
Koch CJ, Hahn SM, Rockwell K Jr., Covey JM, McKenna WG, and Evans SM. 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 48: 177–187, 2001.
Koch CJ, Scheuermann JS, Divgi C, Judy KD, Kachur AV, Freifelder R, Reddin JS, Karp J, Stubbs JB, Hahn SM, Driesbaugh J, Smith D, Prendergast S, and Evans SM. Biodistribution and dosimetry of (18)F-EF5 in cancer patients with preliminary comparison of (18)F-EF5 uptake versus EF5 binding in human glioblastoma. Eur J Nucl Med Mol Imaging 37: 2048–2059, 2010.
Kodibagkar VD, Wang X, and Mason RP. Physical principles of quantitative nuclear magnetic resonance oximetry. Front Biosci 13: 1371–1384, 2008.
Koh WJ, Rasey JS, Evans ML, Grierson JR, Lewellen TK, Graham MM, Krohn KA, and Griffin TW. Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole. Int J Radiat Oncol Biol Phys 22: 199–212, 1992.
Komar G, Seppanen M, Eskola O, Lindholm P, Gronroos TJ, Forsback S, Sipila H, Evans SM, Solin O, and Minn H. 18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med 49: 1944–1951, 2008.
Konecky SD, Choe R, Corlu A, Lee K, Wiener R, Srinivas SM, Saffer JR, Freifelder R, Karp JS, Hajjioui N, Azar F, and Yodh AG. Comparison of diffuse optical tomography of human breast with whole-body and breast-only positron emission tomography. Med Phys 35: 446–455, 2008.
Kong CS, Narasimhan B, Cao H, Kwok S, Erickson JP, Koong A, Pourmand N, and Le QT. The relationship between human papillomavirus status and other molecular prognostic markers in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 74: 553–561, 2009.
Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, and Vierra M. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 48: 919–922, 2000.
Kumar P, Stypinski D, Xia H, McEwan AJB, Machulla H-J, and Wiebe LI. 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 42: 3–16, 1999.
Kunkel M, Reichert TE, Benz P, Lehr HA, Jeong JH, Wieand S, Bartenstein P, Wagner W, and Whiteside TL. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer 97: 1015–1024, 2003.
Kunz M and Ibrahim SM. Molecular responses to hypoxia in tumor cells. Mol Cancer 2: 23, 2003.
Laforest R, Dehdashti F, Lewis JS, and Schwarz SW. Dosimetry of 60/61/62/64Cu-ATSM: a hypoxia imaging agent for PET. Eur J Nucl Med Mol Imaging 32: 764–770, 2005.
Lally BE, Rockwell S, Fischer DB, Collingridge DR, Piepmeier JM, and Knisely JP. The interactions of polarographic measurements of oxygen tension and histological grade in human glioma. Cancer J 12: 461–466, 2006.
Lartigau E, Le Ridant AM, Lambin P, Weeger P, Martin L, Sigal R, Lusinchi A, Luboinski B, Eschwege F, and Guichard M. Oxygenation of head and neck tumors. Cancer 71: 2319–2325, 1993.
Lawrence YR, Vikram B, Dignam JJ, Chakravarti A, Machtay M, Freidlin B, Takebe N, Curran WJ Jr., Bentzen SM, Okunieff P, Coleman CN, and Dicker AP. NCI-RTOG translational program strategic guidelines for the early-stage development of radiosensitizers. J Natl Cancer Inst 105: 11–24, 2012.
Le QT, Chen E, Salim A, Cao H, Kong CS, Whyte R, Donington J, Cannon W, Wakelee H, Tibshirani R, Mitchell JD, Richardson D, O'Byrne KJ, Koong AC, and Giaccia AJ. An evaluation of tumor oxygenation and gene expression in patients with early stage non-small cell lung cancers. Clin Cancer Res 12: 1507–1514, 2006.
Le QT, Kong C, Lavori PW, O'Byrne K, Erler JT, Huang X, Chen Y, Cao H, Tibshirani R, Denko N, Giaccia AJ, and Koong AC. 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: 167–175, 2007.
Le QT, Kovacs MS, Dorie MJ, Koong A, Terris DJ, Pinto HA, Goffinet DR, Nowels K, Bloch D, and Brown JM. Comparison of the comet assay and the oxygen microelectrode for measuring tumor oxygenation in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 56: 375–383, 2003.
Le QT, Taira A, Budenz S, Jo Dorie M, Goffinet DR, Fee WE, Goode R, Bloch D, Koong A, Martin Brown J, and Pinto HA. Mature results from a randomized Phase II trial of cisplatin plus 5-fluorouracil and radiotherapy with or without tirapazamine in patients with resectable Stage IV head and neck squamous cell carcinomas. Cancer 106: 1940–1949, 2006.
Lee CP, Payne GS, Oregioni A, Ruddle R, Tan S, Raynaud FI, Eaton D, Campbell MJ, Cross K, Halbert G, Tracy M, McNamara J, Seddon B, Leach MO, Workman P, and Judson I. A phase I study of the nitroimidazole hypoxia marker SR4554 using 19F magnetic resonance spectroscopy. Br J Cancer 101: 1860–1868, 2009.
Lee DJ, Cosmatos D, Marcial VA, Fu KK, Rotman M, Cooper JS, Ortiz HG, Beitler JJ, Abrams RA, Curran WJ, et al. Results of an RTOG phase III trial (RTOG 85–27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int J Radiat Oncol Biol Phys 32: 567–576, 1995.
Lee DJ, Pajak TF, Stetz J, Order SE, Weissberg JB, and Fischer JJ. A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a RTOG randomized study (#79–04). Int J Radiat Oncol Biol Phys 16: 465–470, 1989.
Lee JW, Bae SH, Jeong JW, Kim SH, and Kim KW. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med 36: 1–12, 2004.
Lee NY, Mechalakos JG, Nehmeh S, Lin Z, Squire OD, Cai S, Chan K, Zanzonico PB, Greco C, Ling CC, Humm JL, and Schoder H. 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 70: 2–13, 2008.
Lee SW, Back GM, Yi BY, Choi EK, Ahn SD, Shin SS, Kim JH, Kim SY, Lee BJ, Nam SY, Choi SH, Kim SB, Park JH, Lee KK, Park SH, and Kim JH. Preliminary results of a phase I/II study of simultaneous modulated accelerated radiotherapy for nondisseminated nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 65: 152–160, 2006.
Lewis JS, Sharp TL, Laforest R, Fujibayashi Y, and Welch MJ. Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation. J Nucl Med 42: 655–661, 2001.
Li M-L, Oh J-T, XIe X, Ku G, Wang W, Li C, Lungu GF, Stoica G, and Wang LV. Simultaneous molecular and hypoxia imaging of brain tumors in vivo using spectroscopic photoacoustic tomography. Proc IEEE 96: 481–489, 2008.
Li SP, Padhani AR, and Makris A. Dynamic contrast-enhanced magnetic resonance imaging and blood oxygenation level-dependent magnetic resonance imaging for the assessment of changes in tumor biology with treatment. J Natl Cancer Inst Monogr 2011: 103–107, 2011.
Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, and Rich JN. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15: 501–513, 2009.
Lim AM, Corry J, Collins M, Peters L, Hicks RJ, D'Costa I, Coleman A, Chua M, Solomon B, and Rischin D. A phase II study of induction carboplatin and gemcitabine followed by chemoradiotherapy for the treatment of locally advanced nasopharyngeal carcinoma. Oral Oncol 49: 468–474, 2013.
Lim AM, Rischin D, Fisher R, Cao H, Kwok K, Truong D, McArthur GA, Young RJ, Giaccia A, Peters L, and Le QT. Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial. Clin Cancer Res 18: 301–307, 2012.
Lin LL, Silvoniemi A, Stubbs JB, Rengan R, Suilamo S, Solin O, Divgi C, Eskola O, Sorger JM, Stabin MG, Kachur A, Hahn SM, Gronroos TJ, Forsback S, Evans SM, Koch CJ, and Minn H. Radiation dosimetry and biodistribution of the hypoxia tracer (1)(8)F-EF5 in oncologic patients. Cancer Biother Radiopharm 27: 412–419, 2012.
Loncaster JA, Carrington BM, Sykes JR, Jones AP, Todd SM, Cooper R, Buckley DL, Davidson SE, Logue JP, Hunter RD, and West CM. Prediction of radiotherapy outcome using dynamic contrast enhanced MRI of carcinoma of the cervix. Int J Radiat Oncol Biol Phys 54: 759–767, 2002.
Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC, Pastorek J, Ratcliffe PJ, Stratford IJ, and West CM. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res 61: 6394–6399, 2001.
Lu X and Kang Y. Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16: 5928–5935, 2010.
Lungu GF, Li ML, Xie X, Wang LV, and Stoica G. In vivo imaging and characterization of hypoxia-induced neovascularization and tumor invasion. Int J Oncol 30: 45–54, 2007.
Lyng H, Sundfor K, Trope C, and Rofstad EK. Disease control of uterine cervical cancer: relationships to tumor oxygen tension, vascular density, cell density, and frequency of mitosis and apoptosis measured before treatment and during radiotherapy. Clin Cancer Res 6: 1104–1112, 2000.
Lyng H, Vorren AO, Sundfor K, Taksdal I, Lien HH, Kaalhus O, and Rofstad EK. Assessment of tumor oxygenation in human cervical carcinoma by use of dynamic Gd-DTPA-enhanced MR imaging. J Magn Reson Imaging 14: 750–756, 2001.
Mack PC, Redman MW, Chansky K, Williamson SK, Farneth NC, Lara PN Jr., Franklin WA, Le QT, Crowley JJ, and Gandara DR. Lower osteopontin plasma levels are associated with superior outcomes in advanced non-small-cell lung cancer patients receiving platinum-based chemotherapy: SWOG Study S0003. J Clin Oncol 26: 4771–4776, 2008.
Mahy P, De Bast M, Gallez B, Gueulette J, Koch CJ, Scalliet P, and Gregoire V. In vivo colocalization of 2-nitroimidazole EF5 fluorescence intensity and electron paramagnetic resonance oximetry in mouse tumors. Radiother Oncol 67: 53–61, 2003.
Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, and Giraudo E. Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest 119: 3356–3372, 2009.
Marotta D, Karar J, Jenkins WT, Kumanova M, Jenkins KW, Tobias JW, Baldwin D, Hatzigeorgiou A, Alexiou P, Evans SM, Alarcon R, Maity A, Koch C, and Koumenis C. In vivo profiling of hypoxic gene expression in gliomas using the hypoxia marker EF5 and laser-capture microdissection. Cancer Res 71: 779–789, 2011.
Matsumoto S, Hyodo F, Subramanian S, Devasahayam N, Munasinghe J, Hyodo E, Gadisetti C, Cook JA, Mitchell JB, and Krishna MC. Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice. J Clin Invest 118: 1965–1973, 2008.
Matsumoto S, Yasui H, Batra S, Kinoshita Y, Bernardo M, Munasinghe JP, Utsumi H, Choudhuri R, Devasahayam N, Subramanian S, Mitchell JB, and Krishna MC. Simultaneous imaging of tumor oxygenation and microvascular permeability using Overhauser enhanced MRI. Proc Natl Acad Sci U S A 106: 17898–17903, 2009.
Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragones J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, and Carmeliet P. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136: 839–851, 2009.
McKenna DJ, McKeown SR, and McKelvey-Martin VJ. Potential use of the comet assay in the clinical management of cancer. Mutagenesis 23: 183–190, 2008.
Medina RA and Owen GI. Glucose transporters: expression, regulation and cancer. Biol Res 35: 9–26, 2002.
Meng X, Kong FM, and Yu J. Implementation of hypoxia measurement into lung cancer therapy. Lung Cancer 75: 146–150, 2012.
Moeller BJ, Cao Y, Li CY, and Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5: 429–441, 2004.
Mortensen LS, Busk M, Nordsmark M, Jakobsen S, Theil J, Overgaard J, and Horsman MR. Accessing radiation response using hypoxia PET imaging and oxygen sensitive electrodes: a preclinical study. Radiother Oncol 99: 418–423, 2011.
Mortensen LS, Buus S, Nordsmark M, Bentzen L, Munk OL, Keiding S, and Overgaard J. Identifying hypoxia in human tumors: a correlation study between 18F-FMISO PET and the Eppendorf oxygen-sensitive electrode. Acta Oncol 49: 934–940, 2010.
Mortensen LS, Johansen J, Kallehauge J, Primdahl H, Busk M, Lassen P, Alsner J, Sorensen BS, Toustrup K, Jakobsen S, Petersen J, Petersen H, Theil J, Nordsmark M, and Overgaard J. 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 105: 14–20, 2012.
Mottram JC. A factor of importance in the radio sensitivity of tumours. Br J Radiol 9: 606–614, 1936.
Movsas B, Chapman JD, Horwitz EM, Pinover WH, Greenberg RE, Hanlon AL, Iyer R, and Hanks GE. Hypoxic regions exist in human prostate carcinoma. Urology 53: 11–18, 1999.
Nehmeh SA, Lee NY, Schroder H, Squire O, Zanzonico PB, Erdi YE, Greco C, Mageras G, Pham HS, Larson SM, Ling CC, and Humm JL. Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer. Int J Radiat Oncol Biol Phys 70: 235–242, 2008.
Newbold K, Castellano I, Charles-Edwards E, Mears D, Sohaib A, Leach M, Rhys-Evans P, Clarke P, Fisher C, Harrington K, and Nutting C. An exploratory study into the role of dynamic contrast-enhanced magnetic resonance imaging or perfusion computed tomography for detection of intratumoral hypoxia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 74: 29–37, 2009.
Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris DJ, and Overgaard J. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77: 18–24, 2005.
Nordsmark M, Eriksen JG, Gebski V, Alsner J, Horsman MR, and Overgaard J. Differential risk assessments from five hypoxia specific assays: the basis for biologically adapted individualized radiotherapy in advanced head and neck cancer patients. Radiother Oncol 83: 389–397, 2007.
Nordsmark M, Loncaster J, Aquino-Parsons C, Chou SC, Gebski V, West C, Lindegaard JC, Havsteen H, Davidson SE, Hunter R, Raleigh JA, and Overgaard J. The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: a prospective international multi-center study. Radiother Oncol 80: 123–131, 2006.
Nordsmark M and Overgaard J. 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: 39–43, 2000.
Nordsmark M and Overgaard J. Tumor hypoxia is independent of hemoglobin and prognostic for loco-regional tumor control after primary radiotherapy in advanced head and neck cancer. Acta Oncol 43: 396–403, 2004.
Nordsmark M, Overgaard M, and Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 41: 31–39, 1996.
Nyflot MJ, Harari PM, Yip S, Perlman SB, and Jeraj R. Correlation of PET images of metabolism, proliferation and hypoxia to characterize tumor phenotype in patients with cancer of the oropharynx. Radiother Oncol 105: 36–40, 2012.
Okamoto S, Shiga T, Yasuda K, Ito YM, Magota K, Kasai K, Kuge Y, Shirato H, and Tamaki N. High reproducibility of tumor hypoxia evaluated by 18F-fluoromisonidazole PET for head and neck cancer. J Nucl Med 54: 201–207, 2013.
Olive PL, Durand RE, Jackson SM, Le Riche JC, Luo C, Ma R, McLaren DB, Aquino-Parsons C, Thomson TA, and Trotter T. The comet assay in clinical practice. Acta Oncol 38: 839–844, 1999.
Olive PL, Durand RE, Le Riche J, Olivotto IA, and Jackson SM. Gel electrophoresis of individual cells to quantify hypoxic fraction in human breast cancers. Cancer Res 53: 733–736, 1993.
Oronsky BT, Knox SJ, and Scicinski J. Six degrees of separation: the oxygen effect in the development of radiosensitizers. Transl Oncol 4: 189–198, 2011.
This reference has been deleted.
Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res 6: 509–518, 1994.
Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck—a systematic review and meta-analysis. Radiother Oncol 100: 22–32, 2011.
Overgaard J, Eriksen JG, Nordsmark M, Alsner J, and Horsman MR. Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial. Lancet Oncol 6: 757–764, 2005.
Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, Lindelov B, and Jorgensen K. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5–85. Radiother Oncol 46: 135–146, 1998.
Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, Bentzen J, Bastholt L, Hansen O, Johansen J, Andersen L, and Evensen JF. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 362: 933–940, 2003.
Peters L and Rischin D. Elusive goal of targeting tumor hypoxia for therapeutic gain. J Clin Oncol 30: 1741–1743, 2012.
Piert M, Machulla HJ, Picchio M, Reischl G, Ziegler S, Kumar P, Wester HJ, Beck R, McEwan AJ, Wiebe LI, and Schwaiger M. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med 46: 106–113, 2005.
Pogue BW, Paulsen KD, O'Hara JA, Wilmot CM, and Swartz HM. Estimation of oxygen distribution in RIF-1 tumors by diffusion model-based interpretation of pimonidazole hypoxia and eppendorf measurements. Radiat Res 155: 15–25, 2001.
Popple RA, Ove R, and Shen S. Tumor control probability for selective boosting of hypoxic subvolumes, including the effect of reoxygenation. Int J Radiat Oncol Biol Phys 54: 921–927, 2002.
Postema EJ, McEwan AJ, Riauka TA, Kumar P, Richmond DA, Abrams DN, and Wiebe LI. 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: 1565–1573, 2009.
Rademakers SE, Lok J, van der Kogel AJ, Bussink J, and Kaanders JH. Metabolic markers in relation to hypoxia; staining patterns and colocalization of pimonidazole, HIF-1alpha, CAIX, LDH-5, GLUT-1, MCT1 and MCT4. BMC Cancer 11: 167, 2011.
Rajendran JG, Mankoff DA, O'Sullivan F, Peterson LM, Schwartz DL, Conrad EU, Spence AM, Muzi M, Farwell DG, and Krohn KA. Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res 10: 2245–2252, 2004.
Rajendran JG, Schwartz DL, O'Sullivan J, Peterson LM, Ng P, Scharnhorst J, Grierson JR, and Krohn KA. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res 12: 5435–5441, 2006.
Raleigh JA, Chou SC, Arteel GE, and Horsman MR. Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. Radiat Res 151: 580–589, 1999.
Rasey JS, Grunbaum Z, Magee S, Nelson NJ, Olive PL, Durand RE, and Krohn KA. Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res 111: 292–304, 1987.
Rischin D, Fisher R, Peters L, Corry J, and Hicks R. Hypoxia in head and neck cancer: studies with hypoxic positron emission tomography imaging and hypoxic cytotoxins. Int J Radiat Oncol Biol Phys 69: S61–S63, 2007.
Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, and Peters LJ. 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 24: 2098–2104, 2006.
Rischin D, Peters L, Fisher R, Macann A, Denham J, Poulsen M, Jackson M, Kenny L, Penniment M, Corry J, Lamb D, and McClure B. Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin, and Radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol 23: 79–87, 2005.
Rischin D, Peters L, Hicks R, Hughes P, Fisher R, Hart R, Sexton M, D'Costa I, and von Roemeling R. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol 19: 535–542, 2001.
Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, Trotti A, Bernier J, Bourhis J, Ringash J, Henke M, and Kenny L. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 28: 2989–2995, 2010.
Roizin-Towle L and Hall EJ. The effect of bleomycin on aerated and hypoxic cells in vitro, in combination with irradiation. Int J Radiat Oncol Biol Phys 5: 1491–1494, 1979.
Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Akerud P, De Mol M, Salomaki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, and Carmeliet P. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19: 31–44, 2011.
Rowinsky EK. Novel radiation sensitizers targeting tissue hypoxia. Oncology (Williston Park) 13: 61–70, 1999.
Rudat V, Stadler P, Becker A, Vanselow B, Dietz A, Wannenmacher M, Molls M, Dunst J, and Feldmann HJ. Predictive value of the tumor oxygenation by means of pO2 histography in patients with advanced head and neck cancer. Strahlenther Onkol 177: 462–468, 2001.
Rudat V, Vanselow B, Wollensack P, Bettscheider C, Osman-Ahmet S, Eble MJ, and Dietz A. Repeatability and prognostic impact of the pretreatment pO(2) histography in patients with advanced head and neck cancer. Radiother Oncol 57: 31–37, 2000.
Rumsey WL, Vanderkooi JM, and Wilson DF. Imaging of phosphorescence: a novel method for measuring oxygen distribution in perfused tissue. Science 241: 1649–1651, 1988.
Russell J, Carlin S, Burke SA, Wen B, Yang KM, and Ling CC. Immunohistochemical detection of changes in tumor hypoxia. Int J Radiat Oncol Biol Phys 73: 1177–1186, 2009.
Samouilov A, Caia GL, Kesselring E, Petryakov S, Wasowicz T, and Zweier JL. Development of a hybrid EPR/NMR coimaging system. Magn Reson Med 58: 156–166, 2007.
Scholbach T, Scholbach J, Krombach GA, Gagel B, Maneschi P, and Di Martino E. New method of dynamic color doppler signal quantification in metastatic lymph nodes compared to direct polarographic measurements of tissue oxygenation. Int J Cancer 114: 957–962, 2005.
Seeber LM, Horree N, Vooijs MA, Heintz AP, van der Wall E, Verheijen RH, and van Diest PJ. The role of hypoxia inducible factor-1alpha in gynecological cancer. Crit Rev Oncol Hematol 78: 173–184, 2011.
Seiwert TY, Salama JK, and Vokes EE. The chemoradiation paradigm in head and neck cancer. Nat Clin Pract Oncol 4: 156–171, 2007.
Semenza GL. Involvement of hypoxia-inducible factor 1 in human cancer. Intern Med 41: 79–83, 2002.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3: 721–732, 2003.
Semenza GL. Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta 1813: 1263–1268, 2011.
Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med 365: 537–547, 2011.
Severinghaus JW, Weiskopf RB, Nishimura M, and Bradley AF. Oxygen electrode errors due to polarographic reduction of halothane. J Appl Physiol 31: 640–642, 1971.
Shao Q, Morgounova E, Jiang C, Choi J, Bischof J, and Ashkenazi S. In vivo photoacoustic lifetime imaging of tumor hypoxia in small animals. J Biomed Opt 18: 076019, 2013.
Souvatzoglou M, Grosu AL, Roper B, Krause BJ, Beck R, Reischl G, Picchio M, Machulla HJ, Wester HJ, and Piert M. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging 34: 1566–1575, 2007.
Stadler P, Becker A, Feldmann HJ, Hansgen G, Dunst J, Wurschmidt F, and Molls M. Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys 44: 749–754, 1999.
Stanz K, Liu B, Minsong C, Reinecke D, Miller K, and Kruger R. Photoacoustic spectoscopic imaging of intra-tumor heterogeneity and molecular identification. SPIE Proc 6086: 605–608, 2006.
Stone HB, Brown JM, Phillips TL, and Sutherland RM. Oxygen in human tumors: correlations between methods of measurement and response to therapy. Summary of a workshop held November 19–20, 1992, at the National Cancer Institute, Bethesda, Maryland. Radiat Res 136: 422–434, 1993.
Subarsky P and Hill RP. The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis 20: 237–250, 2003.
Sullivan R and Graham CH. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev 26: 319–331, 2007.
Tanaka N, Kato H, Inose T, Kimura H, Faried A, Sohda M, Nakajima M, Fukai Y, Miyazaki T, Masuda N, Fukuchi M, and Kuwano H. Expression of carbonic anhydrase 9, a potential intrinsic marker of hypoxia, is associated with poor prognosis in oesophageal squamous cell carcinoma. Br J Cancer 99: 1468–1475, 2008.
Tannock IF. Conventional cancer therapy: promise broken or promise delayed? Lancet 351 Suppl 2: SII9–SII16, 1998.
Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KS, Chapman JD, Eckelman WC, Fyles AW, Giaccia AJ, Hill RP, Koch CJ, Krishna MC, Krohn KA, Lewis JS, Mason RP, Melillo G, Padhani AR, Powis G, Rajendran JG, Reba R, Robinson SP, Semenza GL, Swartz HM, Vaupel P, Yang D, Croft B, Hoffman J, Liu G, Stone H, and Sullivan D. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 82: 699–757, 2006.
Taylor NJ, Baddeley H, Goodchild KA, Powell ME, Thoumine M, Culver LA, Stirling JJ, Saunders MI, Hoskin PJ, Phillips H, Padhani AR, and Griffiths JR. BOLD MRI of human tumor oxygenation during carbogen breathing. J Magn Reson Imaging 14: 156–163, 2001.
Teicher BA. Hypoxia and drug resistance. Cancer Metastasis Rev 13: 139–168, 1994.
Teicher BA, Holden SA, al-Achi A, and Herman TS. Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res 50: 3339–3344, 1990.
Terris DJ. Head and neck cancer: the importance of oxygen. Laryngoscope 110: 697–707, 2000.
Thomlinson RH and Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9: 539–549, 1955.
Thorwarth D, Eschmann SM, Holzner F, Paulsen F, and Alber M. Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiother Oncol 80: 151–156, 2006.
Thorwarth D, Eschmann SM, Paulsen F, and Alber M. Hypoxia dose painting by numbers: a planning study. Int J Radiat Oncol Biol Phys 68: 291–300, 2007.
Toma-Dasu I, Uhrdin J, Antonovic L, Dasu A, Nuyts S, Dirix P, Haustermans K, and Brahme A. Dose prescription and treatment planning based on FMISO-PET hypoxia. Acta Oncol 51: 222–230, 2012.
Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, and Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64: 3731–3736, 2004.
Toustrup K, Sorensen BS, Lassen P, Wiuf C, Alsner J, and Overgaard J. Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol 102: 122–129, 2012.
Tran LB, Bol A, Labar D, Jordan B, Magat J, Mignion L, Gregoire V, and Gallez B. Hypoxia imaging with the nitroimidazole 18F-FAZA PET tracer: a comparison with OxyLite, EPR oximetry and 19F-MRI relaxometry. Radiother Oncol 105: 29–35, 2012.
Turaka A, Buyyounouski MK, Hanlon AL, Horwitz EM, Greenberg RE, and Movsas B. Hypoxic prostate/muscle PO2 ratio predicts for outcome in patients with localized prostate cancer: long-term results. Int J Radiat Oncol Biol Phys 82: e433–e439, 2012.
Valable S, Petit E, Roussel S, Marteau L, Toutain J, Divoux D, Sobrio F, Delamare J, Barre L, and Bernaudin M. Complementary information from magnetic resonance imaging and (18)F-fluoromisonidazole positron emission tomography in the assessment of the response to an antiangiogenic treatment in a rat brain tumor model. Nucl Med Biol 38: 781–793, 2011.
van Loon J, Janssen MH, Ollers M, Aerts HJ, Dubois L, Hochstenbag M, Dingemans AM, Lalisang R, Brans B, Windhorst B, van Dongen GA, Kolb H, Zhang J, De Ruysscher D, and Lambin P. PET imaging of hypoxia using [18F]HX4: a phase I trial. Eur J Nucl Med Mol Imaging 37: 1663–1668, 2010.
Vanderkooi JM and Wilson DF. A new method for measuring oxygen concentration in biological systems. Adv Exp Med Biol 200: 189–193, 1986.
Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist 9 Suppl 5: 10–17, 2004.
Vaupel P. Pathophysiology of Solid Tumors. Berlin, Heidelberg: Springer-Verlag, 2009.
Vaupel P and Harrison L. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9 Suppl 5: 4–9, 2004.
Vaupel P, Hockel M, and Mayer A. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9: 1221–1235, 2007.
Vaupel P, Mayer A, Briest S, and Hockel M. Oxygenation gain factor: a novel parameter characterizing the association between hemoglobin level and the oxygenation status of breast cancers. Cancer Res 63: 7634–7637, 2003.
Vaupel P, Schlenger K, Knoop C, and Hockel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51: 3316–3322, 1991.
Vaupel P, Thews O, and Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 18: 243–259, 2001.
Vergis R, Corbishley CM, Norman AR, Bartlett J, Jhavar S, Borre M, Heeboll S, Horwich A, Huddart R, Khoo V, Eeles R, Cooper C, Sydes M, Dearnaley D, and Parker C. Intrinsic markers of tumour hypoxia and angiogenesis in localised prostate cancer and outcome of radical treatment: a retrospective analysis of two randomised radiotherapy trials and one surgical cohort study. Lancet Oncol 9: 342–351, 2008.
von Pawel J, von Roemeling R, Gatzemeier U, Boyer M, Elisson LO, Clark P, Talbot D, Rey A, Butler TW, Hirsh V, Olver I, Bergman B, Ayoub J, Richardson G, Dunlop D, Arcenas A, Vescio R, Viallet J, and Treat J. Tirapazamine plus cisplatin versus cisplatin in advanced non-small-cell lung cancer: a report of the international CATAPULT I study group. Cisplatin and Tirapazamine in Subjects with Advanced Previously Untreated Non-Small-Cell Lung Tumors. J Clin Oncol 18: 1351–1359, 2000.
Vordermark D and Brown JM. Endogenous markers of tumor hypoxia predictors of clinical radiation resistance? Strahlenther Onkol 179: 801–811, 2003.
Wang J, Foehrenbacher A, Su J, Patel R, Hay MP, Hicks KO, and Wilson WR. The 2-nitroimidazole EF5 is a biomarker for oxidoreductases that activate the bioreductive prodrug CEN-209 under hypoxia. Clin Cancer Res 18: 1684–1695, 2012.
Wasserman TH, Lee DJ, Cosmatos D, Coleman N, Phillips T, Davis L, Marcial V, and Stetz J. Clinical trials with etanidazole (SR-2508) by the Radiation Therapy Oncology Group (RTOG). Radiother Oncol 20 Suppl 1: 129–135, 1991.
Weber GF. The cancer biomarker osteopontin: combination with other markers. Cancer Genomics Proteomics 8: 263–288, 2011.
Wiedenmann N, Hentschel M, Bucher S, Mix M, Adebahr S, Offermann C, Nestle U, Weber W, and Grosu AL. Dynamics of tumor hypoxia in patients undergoing radiochemotherapy for head and neck cancer evaluated with serial 18F-fluoromisonidazole PET. Int J Radiat Oncol 78: S703, 2010.
Williams BB, Khan N, Zaki B, Hartford A, Ernstoff MS, and Swartz HM. Clinical electron paramagnetic resonance (EPR) oximetry using India ink. Adv Exp Med Biol 662: 149–156, 2010.
Wilson DF, Lee WM, Makonnen S, Apreleva S, and Vinogradov SA. Oxygen pressures in the interstitial space of skeletal muscle and tumors in vivo. Adv Exp Med Biol 614: 53–62, 2008.
Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn LL, and Jain RK. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6: 553–563, 2004.
Wolf M, Ferrari M, and Quaresima V. Progress of near-infrared spectroscopy and topography for brain and muscle clinical applications. J Biomed Opt 12: 062104, 2007.
Woods ML, Koch CJ, and Lord EM. Detection of individual hypoxic cells in multicellular spheroids by flow cytometry using the 2-nitroimidazole, EF5, and monoclonal antibodies. Int J Radiat Oncol Biol Phys 34: 93–101, 1996.
Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, and Harris AL. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60: 7075–7083, 2000.
Xia Y, Choi HK, and Lee K. Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem 49: 24–40, 2012.
Yasui H, Matsumoto S, Devasahayam N, Munasinghe JP, Choudhuri R, Saito K, Subramanian S, Mitchell JB, and Krishna MC. Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. Cancer Res 70: 6427–6436, 2010.
Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW, and Semenza GL. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 60: 1541–1545, 2000.
Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, and Simons JW. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 59: 5830–5835, 1999.
Zhu Y, Denhardt DT, Cao H, Sutphin PD, Koong AC, Giaccia AJ, and Le QT. Hypoxia upregulates osteopontin expression in NIH-3T3 cells via a Ras-activated enhancer. Oncogene 24: 6555–6563, 2005.
Ziemer LS, Evans SM, Kachur AV, Shuman AL, Cardi CA, Jenkins WT, Karp JS, Alavi A, Dolbier WR Jr., and Koch CJ. Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5. Eur J Nucl Med Mol Imaging 30: 259–266, 2003.
Ziemer LS, Koch CJ, Maity A, Magarelli DP, Horan AM, and Evans SM. Hypoxia and VEGF mRNA expression in human tumors. Neoplasia 3: 500–508, 2001.
Ziemer LS, Lee WM, Vinogradov SA, Sehgal C, and Wilson DF. Oxygen distribution in murine tumors: characterization using oxygen-dependent quenching of phosphorescence. J Appl Physiol 98: 1503–1510, 2005.
Zimny M, Gagel B, DiMartino E, Hamacher K, Coenen HH, Westhofen M, Eble M, Buell U, and Reinartz P. 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 33: 1426–1431, 2006.
Zips D, Zophel K, Abolmaali N, Perrin R, Abramyuk A, Haase R, Appold S, Steinbach J, Kotzerke J, and Baumann M. Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother Oncol 105: 21–28, 2012.

Information & Authors


Published In

cover image Antioxidants & Redox Signaling
Antioxidants & Redox Signaling
Volume 21Issue Number 10October 1, 2014
Pages: 1516 - 1554
PubMed: 24512032


Published in print: October 1, 2014
Published online: 11 September 2014
Published ahead of print: 9 May 2014
Published ahead of production: 10 February 2014
Accepted: 8 February 2014
Revision received: 30 January 2014
Received: 16 April 2013


Request permissions for this article.




Joseph C. Walsh
Siemens Molecular Imaging, Inc., Culver City, California.
Artem Lebedev
Siemens Molecular Imaging, Inc., Culver City, California.
Edward Aten
Certus International, Inc., Bedford, New Hampshire.
Kathleen Madsen
Certus International, Inc., Chesterfield, Missouri.
Liane Marciano
Certus International, Inc., Bedford, New Hampshire.
Hartmuth C. Kolb
Siemens Molecular Imaging, Inc., Culver City, California.


Reviewing Editors: Claudine Kieda, Periannan Kuppusamy, Ken-Ichiro Matsumoto, Suzanne Monte, Des Richardson, Matteo A. Russo, Gregg Semenza, Chandan K. Sen, Jolanta Tarasuik, Michel Toledano, Laura Vera-Ramirez
Address correspondence to:Dr. Hartmuth C. KolbSiemens Molecular Imaging, Inc.6140 Bristol ParkwayCulver City, CA 90230E-mail: [email protected]

Author Disclosure Statement

Joseph C. Walsh is an employee of Siemens MI, a company that developed PET biomarkers for imaging hypoxia. Artem Lebedev and Hartmuth C. Kolb are former employees of Siemens MI. Kathleen Madsen is a consultant statistician to Siemens Molecular Imaging, with compensation based on fair market value and not tied to outcomes. Edward Aten is acting as Interim Medical Director to Siemens Molecular Imaging, with compensation based on fair market value and not tied to outcomes. Liane Marciano is a consultant to Siemens Molecular Imaging, with compensation based on fair market value and not tied to outcomes.

Metrics & Citations



Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options


View PDF/ePub

Full Text

View Full Text







Copy the content Link

Share on social media

Back to Top