Prognostic significance of tumor oxygenation in humans.

Low tissue oxygen concentration has been shown to be important in the response of human tumors to radiation therapy, chemotherapy and other treatment modalities. Hypoxia is also known to be a prognostic indicator, as hypoxic human tumors are more biologically aggressive and are more likely to recur locally and metastasize. Herein, we discuss and summarize the various methods under investigation to directly or indirectly measure tissue oxygen in vivo. Secondly, we consider the advantages and disadvantages of each of these techniques. These considerations are made in light of our specific hypotheses that hypoxia should be measured as a continuum, not a binary measurement and that moderate, not severe hypoxia is of great biological consequence.

[1]  A. Giaccia,et al.  Opposing effects of hypoxia on expression of the angiogenic inhibitor thrombospondin 1 and the angiogenic inducer vascular endothelial growth factor. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  C. Koch,et al.  The Km for Radiosensitization of Human Tumor Cells by Oxygen is Much Greater than 3 mmHg and is Further Increased by Elevated Levels of Cysteine , 2001, Radiation research.

[3]  C. Coleman,et al.  Clinical trials with hypoxic cell sensitizers: time to retrench or time to push forward? , 1984, International journal of radiation oncology, biology, physics.

[4]  J. Knisely,et al.  Polarographic measurements of oxygen tension in human glioma and surrounding peritumoural brain tissue. , 1999, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[5]  S M Evans,et al.  Detection of hypoxia in human squamous cell carcinoma by EF5 binding. , 2000, Cancer research.

[6]  C. Koch A thin-film culturing technique allowing rapid gas-liquid equilibration (6 sec) with no toxicity to mammalian cells. , 1984, Radiation research.

[7]  G. Semenza,et al.  Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. , 2001, Cancer research.

[8]  J R Griffiths,et al.  BOLD MRI of human tumor oxygenation during carbogen breathing , 2001, Journal of magnetic resonance imaging : JMRI.

[9]  Miss A.O. Penney (b) , 1974, The New Yale Book of Quotations.

[10]  J. Karp,et al.  Noninvasive imaging of tumor hypoxia in rats using the 2-nitroimidazole 18F-EF5 , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[11]  Chapman Jd,et al.  Hypoxic sensitizers--implications for radiation therapy. , 1979 .

[12]  C. Koch,et al.  Detection of individual hypoxic cells in multicellular spheroids by flow cytometry using the 2-nitroimidazole, EF5, and monoclonal antibodies. , 1996, International journal of radiation oncology, biology, physics.

[13]  R. Pötter,et al.  Intratumoral pO2-measurements as predictive assay in the treatment of carcinoma of the uterine cervix. , 1999, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[14]  C. Koch,et al.  Radiosensitization of hypoxic tumor cells by dodecafluoropentane: a gas-phase perfluorochemical emulsion. , 2002, Cancer research.

[15]  Anne Whitehead,et al.  Meta-Analysis of Controlled Clinical Trials , 2002 .

[16]  Hypoxic fraction determinations with the BA1112 rat sarcoma: variation within and among assay techniques. , 1984, Radiation research.

[17]  A. Harris,et al.  Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  S M Evans,et al.  Hypoxia and necrosis in rat 9L glioma and Morris 7777 hepatoma tumors: comparative measurements using EF5 binding and the Eppendorf needle electrode. , 2000, International journal of radiation oncology, biology, physics.

[19]  David J. Yang,et al.  Fluorine-18 fluoromisonidazole tumour to muscle retention ratio for the detection of hypoxia in nasopharyngeal carcinoma , 1996, European Journal of Nuclear Medicine.

[20]  C. Koch,et al.  Importance of thiols in the reductive binding of 2-nitroimidazoles to macromolecules. , 1990, Biochemical pharmacology.

[21]  C. Koch,et al.  Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: implications for hypoxia measurements in vivo by 2-nitroimidazoles , 2001, Cancer Chemotherapy and Pharmacology.

[22]  N. Bleehen,et al.  A clinical phase I toxicity study of Ro 03-8799: plasma, urine, tumour and normal brain pharmacokinetics. , 1986, The British journal of radiology.

[23]  M. Lerman,et al.  Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. , 2001, Cancer research.

[24]  A. Hanlon,et al.  Hypoxic regions exist in human prostate carcinoma. , 1999, Urology.

[25]  R. Gatenby,et al.  Oxygen tension in human tumors: in vivo mapping using CT-guided probes. , 1985, Radiology.

[26]  R. Hill,et al.  A quantitative analysis of the reduction in oxygen levels required to induce up-regulation of vascular endothelial growth factor (VEGF) mRNA in cervical cancer cell lines , 1999, British Journal of Cancer.

[27]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[28]  C. Aquino-Parsons,et al.  Measuring hypoxia in solid tumours--is there a gold standard? , 2001, Acta oncologica.

[29]  B. Fenton,et al.  Quantification of tumour vasculature and hypoxia by immunohistochemical staining and HbO2 saturation measurements , 1999, British Journal of Cancer.

[30]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[31]  P Vaupel,et al.  Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. , 1996, Cancer research.

[32]  S. Dische,et al.  The clinical testing of Ro 03-8799--pharmacokinetics, toxicology, tissue and tumor concentrations. , 1984, International journal of radiation oncology, biology, physics.

[33]  W. Kaelin,et al.  The von Hippel-Lindau tumor suppressor gene. , 2001, Experimental cell research.

[34]  J. D. Chapman,et al.  Binding of 14C-misonidazole to hypoxic cells in V79 spheroids. , 1982, British Journal of Cancer.

[35]  B. Garrecht,et al.  The labelling of EMT-6 tumours in BALB/C mice with 14C-misonidazole. , 1983, The British journal of radiology.

[36]  J. Overgaard,et al.  Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. , 1996, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[37]  D. Nelson,et al.  Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. , 1993, Journal of the National Cancer Institute.

[38]  F. Eschwège,et al.  Intratumoral oxygen tension in metastatic melanoma , 1997, Melanoma research.

[39]  Y Yonekura,et al.  Copper-62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox potential. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[40]  C. Lowenstein,et al.  Intersection of interferon and hypoxia signal transduction pathways in nitric oxide-induced tumor apoptosis. , 2001, Cancer research.

[41]  C. J. Gillespie,et al.  Radiation-Induced Events and Their Time Scale in Mammalian Cells , 1981 .

[42]  R. Hill,et al.  Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[43]  T L Phillips,et al.  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. , 1993, Radiation research.

[44]  P. Kristjansen,et al.  Coregulation of glucose uptake and vascular endothelial growth factor (VEGF) in two small-cell lung cancer (SCLC) sublines in vivo and in vitro. , 2001, Neoplasia.

[45]  S. Rosenberg,et al.  The grading of soft tissue sarcomas results of a clinicohistopathologic correlation in a series of 163 cases , 1984, Cancer.

[46]  Y. Fujibayashi,et al.  Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[47]  H. Lyng,et al.  Correlation of high lactate levels in head and neck tumors with incidence of metastasis. , 1997, The American journal of pathology.

[48]  M. Varia,et al.  A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[49]  R. Fisher,et al.  Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  G. Semenza,et al.  Expression of hypoxia-inducible factor 1alpha in brain tumors: association with angiogenesis, invasion, and progression. , 2000, Cancer.

[51]  David E. Housman,et al.  Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours , 1996, Nature.

[52]  D. Hedley,et al.  Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  G L Rosner,et al.  Pretreatment oxygenation profiles of human soft tissue sarcomas. , 1994, International journal of radiation oncology, biology, physics.

[54]  P. Vaupel,et al.  Heterogeneous oxygenation of rectal carcinomas in humans: a critical parameter for preoperative irradiation? , 1984, Advances in experimental medicine and biology.

[55]  J. Henk,et al.  RADIOTHERAPY AND HYPERBARIC OXYGEN IN HEAD AND NECK CANCER Interim Report of Second Clinical Trial , 1977, The Lancet.

[56]  D. Hedley,et al.  A comparison in individual murine tumors of techniques for measuring oxygen levels. , 1999, International journal of radiation oncology, biology, physics.

[57]  Andreas Dietz,et al.  Predictive Value of the Tumor Oxygenation by Means of pO2 Histography in Patients with Advanced Head and Neck Cancer , 2001, Strahlentherapie und Onkologie.

[58]  P. Kolstad Oxygen Tension and Radiocurability in Cancer of the Cervix , 1964, Acta obstetricia et gynecologica Scandinavica.

[59]  W. Jelkmann,et al.  Vascular endothelial growth factor gene expression in the human breast cancer cell line MX-1 is controlled by O2 availability in vitro and in vivo. , 2001, Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft.

[60]  H. Lyng,et al.  Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. , 1998, British Journal of Cancer.

[61]  A. Harris,et al.  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. , 2001, Cancer research.

[62]  J. Henk Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck cancer: a rationale for hypoxic cell sensitizers? , 1986, International journal of radiation oncology, biology, physics.

[63]  P. Ratcliffe,et al.  Activation of the HIF pathway in cancer. , 2001, Current opinion in genetics & development.

[64]  A. Rauth,et al.  Differences in the toxicity and metabolism of the 2-nitroimidazole misonidazole (Ro-07-0582) in HeLa and Chinese hamster ovary cells. , 1978, Cancer research.

[65]  J. Overgaard Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. , 1994, Oncology research.

[66]  M. Dewhirst,et al.  Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. , 1996, Cancer research.

[67]  H. Lyng,et al.  Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumor oxygenation and vascularization. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[68]  B. Galy,et al.  Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. , 1999, The American journal of pathology.

[69]  D. Bloch,et al.  DNA damage measured by the comet assay in head and neck cancer patients treated with tirapazamine. , 1999, Neoplasia.

[70]  D. P. Jones Renal metabolism during normoxia, hypoxia, and ischemic injury. , 1986, Annual review of physiology.

[71]  C. Koch,et al.  2-Nitroimidazole (EF5) binding predicts radiation resistance in individual 9L s.c. tumors. , 1996, Cancer research.

[72]  L. Harwell,et al.  Detection of hypoxic cells by monoclonal antibody recognizing 2-nitroimidazole adducts. , 1993, Cancer research.

[73]  A. Fyles,et al.  Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer. , 2001, International journal of radiation oncology, biology, physics.

[74]  P Vaupel,et al.  Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. , 1993, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[75]  B. Movsas,et al.  Marking Hypoxia in Rat Prostate Carcinomas with β-d-[125I]Azomycin Galactopyranoside and [99mTc]HL-91: Correlation with Microelectrode Measurements , 2001 .

[76]  L. Giudice,et al.  Regulation of insulin-like growth factor-binding protein-1 by nitric oxide under hypoxic conditions. , 2000, The Journal of clinical endocrinology and metabolism.

[77]  C. Koch,et al.  Measurement of absolute oxygen levels in cells and tissues using oxygen sensors and 2-nitroimidazole EF5. , 2002, Methods in enzymology.

[78]  Rakesh K. Jain,et al.  Vascular and interstitial barriers to delivery of therapeutic agents in tumors , 1990, Cancer and Metastasis Reviews.

[79]  M. Wei,et al.  Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[80]  A. Koong,et al.  Pancreatic tumors show high levels of hypoxia. , 2000, International journal of radiation oncology, biology, physics.

[81]  B. Teicher,et al.  The hypoxic tumor cell: a target for selective cancer chemotherapy. , 1980, Biochemical pharmacology.

[82]  T. Phillips,et al.  Final report on the united states phase i clinical trial of the hypoxic cell radiosensitizer, misonidazole (RO‐07‐0582; NSC #261037) , 1981, Cancer.

[83]  O. S. Nielsen,et al.  Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations , 2001, British Journal of Cancer.

[84]  B. Siim,et al.  Tirapazamine-induced cytotoxicity and DNA damage in transplanted tumors: relationship to tumor hypoxia. , 1997, Cancer research.

[85]  Henry Brem,et al.  Drug delivery to tumors of the central nervous system , 2001, Current neurology and neuroscience reports.

[86]  Jean Charles Gilbert,et al.  Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[87]  W. Curran,et al.  Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[88]  C. Koch,et al.  Mapping of the vascular endothelial growth factor-producing hypoxic cells in multicellular tumor spheroids using a hypoxia-specific marker. , 1995, Cancer research.

[89]  D. Schoenfeld,et al.  Necrosis as a prognostic criterion in malignant supratentorial, astrocytic gliomas , 1983, Cancer.

[90]  J. Overgaard,et al.  Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study. , 1989, International journal of radiation oncology, biology, physics.

[91]  S. Evans,et al.  Cysteine concentrations in rodent tumors: Unexpectedly high values may cause therapy resistance , 1996, International journal of cancer.

[92]  M C Weissler,et al.  Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. , 1998, Cancer research.

[93]  P. Olive,et al.  The Range of Oxygenation in SiHa Tumor Xenografts , 2002, Radiation research.

[94]  J. Fandrey,et al.  Nitric oxide affects the production of reactive oxygen species in hepatoma cells: implications for the process of oxygen sensing. , 2000, Free radical biology & medicine.

[95]  C. Koch,et al.  Biodistribution of the nitroimidazole EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide) in mice bearing subcutaneous EMT6 tumors. , 1996, The Journal of pharmacology and experimental therapeutics.

[96]  K. Kihara,et al.  Regulation of vascular endothelial growth factor transcription by endothelial PAS domain protein 1 (EPAS1) and possible involvement of EPAS1 in the angiogenesis of renal cell carcinoma , 2001, Cancer.

[97]  D. Batlle,et al.  Hypoxia stimulates osteopontin expression and proliferation of cultured vascular smooth muscle cells: potentiation by high glucose. , 2001, Diabetes.

[98]  B. Wouters,et al.  Cells at intermediate oxygen levels can be more important than the "hypoxic fraction" in determining tumor response to fractionated radiotherapy. , 1997, Radiation research.

[99]  C. Ling,et al.  Interaction of misonidazole and oxygen in the radiosensitization of mammalian cells. , 1980, International journal of radiation oncology, biology, physics.

[100]  G. Cruickshank,et al.  Direct measurement of the PO2 distribution in human malignant brain tumours. , 1994, Advances in experimental medicine and biology.

[101]  R K Jain,et al.  Vascular endothelial growth factor (VEGF) modulation by targeting hypoxia-inducible factor-1alpha--> hypoxia response element--> VEGF cascade differentially regulates vascular response and growth rate in tumors. , 2000, Cancer research.

[102]  D J Terris,et al.  Head and Neck Cancer: The Importance of Oxygen , 2000, The Laryngoscope.

[103]  J. Rasey,et al.  Comparison of binding of [3H]misonidazole and [14C]misonidazole in multicell spheroids. , 1985, Radiation research.

[104]  S. Hahn,et al.  Hypoxia in human intraperitoneal and extremity sarcomas. , 2001, International journal of radiation oncology, biology, physics.

[105]  M Molls,et al.  Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. , 1999, International journal of radiation oncology, biology, physics.

[106]  G. Semenza,et al.  Expression of hypoxia‐inducible factor 1α in brain tumors , 2000 .

[107]  C. Koch,et al.  Hypoxic Heterogeneity in Human Tumors: EF5 Binding, Vasculature, Necrosis, and Proliferation , 2001, American journal of clinical oncology.

[108]  D. M. Brown,et al.  Factors influencing intracellular uptake and radiosensitization by 2-nitroimidazoles in vitro. , 1983, Radiation research.

[109]  P. Olive,et al.  Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours , 2000, British Journal of Cancer.

[110]  C J Koch,et al.  Enhanced radiation-sensitivity by preincubation with nitroimidazoles: effect of glutathione depletion. , 1994, International journal of radiation oncology, biology, physics.

[111]  T K Lewellen,et al.  Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. , 1996, International journal of radiation oncology, biology, physics.

[112]  M. Varia,et al.  Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. , 1997, International journal of radiation oncology, biology, physics.

[113]  O. S. Nielsen,et al.  The relationship between tumor oxygenation and cell proliferation in human soft tissue sarcomas. , 1996, International journal of radiation oncology, biology, physics.

[114]  A Dietz,et al.  Repeatability and prognostic impact of the pretreatment pO(2) histography in patients with advanced head and neck cancer. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[115]  A. Fyles,et al.  Oxygenation predicts radiation response and survival in patients with cervix cancer. , 1998, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[116]  M Detmar,et al.  Tumor angiogenesis. , 2000, The journal of investigative dermatology. Symposium proceedings.

[117]  K. Groebe,et al.  Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids , 1995, International journal of cancer.

[118]  A. Harris,et al.  Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density. , 2001, Cancer research.

[119]  P. Workman,et al.  Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors. , 1994, International journal of radiation oncology, biology, physics.

[120]  M. Lerman,et al.  Lowered oxygen tension induces expression of the hypoxia marker MN/carbonic anhydrase IX in the absence of hypoxia-inducible factor 1 alpha stabilization: a role for phosphatidylinositol 3'-kinase. , 2002, Cancer research.

[121]  J. Bussink,et al.  Vascular architecture and hypoxic profiles in human head and neck squamous cell carcinomas , 2000, British Journal of Cancer.

[122]  J. Pastorek,et al.  Expression of MaTu‐MN protein in human tumor cultures and in clinical specimens , 1993, International journal of cancer.

[123]  M. W. D. Dvm Oxygenation of head and neck cancer: Changes during radiotherapy and impact on treatment outcome , 1998 .

[124]  M. Stratford,et al.  Cellular uptake of misonidazole and analogues with acidic or basic functions. , 1985, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[125]  Johan Bussink,et al.  Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. , 2002, Cancer research.

[126]  J. Kaanders,et al.  ARCON: experience in 215 patients with advanced head-and-neck cancer. , 2001, International journal of radiation oncology, biology, physics.

[127]  M. Dewhirst,et al.  Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. , 1997, International journal of radiation oncology, biology, physics.

[128]  A. J. Varghese,et al.  Hypoxia-dependent reduction of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol by Chinese hamster ovary cells and KHT tumor cells in vitro and in vivo. , 1976, Cancer research.

[129]  P. Lambin,et al.  Oxygenation of head and neck tumors , 1993, Cancer.

[130]  M. Parliament,et al.  Imaging tumor hypoxia and tumor perfusion. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[131]  H. Lyng,et al.  Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis , 2000, British Journal of Cancer.

[132]  L. Wiebe,et al.  Nitroimidazole adducts as markers for tissue hypoxia: mechanistic studies in aerobic normal tissues and tumour cells. , 1992, British Journal of Cancer.

[133]  J. Raleigh,et al.  Marking hypoxic cells for complement and cytotoxic T lymphocyte-mediated lysis: using pimonidazole. , 1996, The British journal of cancer. Supplement.

[134]  J. Ballinger,et al.  Imaging hypoxia in tumors. , 2001, Seminars in nuclear medicine.

[135]  H. Lyng,et al.  Polarographic measurement of pO2 in cervix carcinoma. , 1997, Gynecologic oncology.

[136]  A. Maity,et al.  Hypoxia and VEGF mRNA expression in human tumors. , 2001, Neoplasia.

[137]  M. Parliament,et al.  Measurement of hypoxia in human tumours by non-invasive spect imaging of iodoazomycin arabinoside. , 1996, The British journal of cancer. Supplement.

[138]  W. Sly,et al.  Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast. , 2001, The American journal of pathology.

[139]  R. Sciot,et al.  Hypoxia and perfusion measurements in human tumors--initial experience with pimonidazole and IUdR. , 2001, Acta oncologica.

[140]  S M Evans,et al.  Interlaboratory variation in oxygen tension measurement by Eppendorf “Histograph” and comparison with hypoxic marker , 1997, Journal of surgical oncology.

[141]  C. J. Koch,et al.  Fluorescence immunohistochemical detection of hypoxic cells in spheroids and tumours. , 1987, British Journal of Cancer.

[142]  M. Dewhirst,et al.  MIBG inhibits respiration: potential for radio- and hyperthermic sensitization. , 1998, International journal of radiation oncology, biology, physics.

[143]  P H Watson,et al.  Hypoxia-inducible expression of tumor-associated carbonic anhydrases. , 2000, Cancer research.

[144]  D A Bloch,et al.  Tissue oxygen distribution in head and neck cancer patients , 1999, Head & neck.

[145]  N. Bleehen,et al.  Hypoxic cell radiosensitizers in the treatment of high grade gliomas: a new direction using combined Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole). , 1988, International Journal of Radiation Oncology, Biology, Physics.