Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies

References

• Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989;49:6449–65.
   PubMed Web of Science ®Google Scholar
• Mottram JC. Factor of importance in radiosensitivity of tumors. Br J Radiol 1936;9:606–14.
   Google Scholar
• Holthusen H. Beitrage zu Biologie der Strahlenwirkung. Pfluger’s Arch. Ges. Physiol. 1921;187:1–24.
   Google Scholar
• Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955;9:539–49.
   PubMed Web of Science ®Google Scholar
• Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 1953;26:638–48.
   PubMed Web of Science ®Google Scholar
• Adams GE, Dewey DL. Hydrated electrons and radiobiological sensitization. Biochem Biophys Res Commun 1963;12:473–7.
   PubMed Web of Science ®Google Scholar
• Teicher BA. Hypoxia and drug resistance. Cancer Metastasis Rev 1994;13:139–68.
   PubMed Web of Science ®Google Scholar
• Cosse JP, Michiels C. Tumor hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med Chem 2008;8(7):790–7.
   Google Scholar
• Hill RP, Stanley JA. The response of hypoxic B16 melanoma cells to in vivo treatment with chemotherapeutic agents. Cancer Res 1975; 35:1147–53.
   PubMed Web of Science ®Google Scholar
• Adams GE. Hypoxic cell sensitizers for radiotherapy. Int J Radiat Oncol Biol Phys 1978;4:135–41.
   PubMed Web of Science ®Google Scholar
• Wouters BG, Brown JM. Cells at intermediate oxygen levels can be more important than the “hypoxic fraction” in determining tumor response to fractionated radiotherapy. Radiat Res 1997;147:541–50.
   PubMed Web of Science ®Google Scholar
• Adams GE. Failla Memorial Lecture.Redox, radiation, and reductive bioactivation. Radiat Res 1992;132:129–39.
   PubMed Web of Science ®Google Scholar
• Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 2008;30:393–402.
   PubMed Web of Science ®Google Scholar
• Holmquist-Mengelbier L, Fredlund E, Löfstedt T, Noguera R, Navarro S, Nilsson H, et al. Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 2006;10:413–23.
   PubMed Web of Science ®Google Scholar
• Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008 May 23;30(4):393–402.
   PubMed Web of Science ®Google Scholar
• Wolfbeis OS, Leiner MJP, Posch HE. A new sensing material for optical oxygen measurement, with the indicator embedded in an aqueous phase. Microchim Acta 1986;90(5):359–66.
   Google Scholar
• Lippitsch ME, Pusterhofer J, Leiner MJP, Wolfbeis OS. Fibre-optic oxygen sensor with the fluorescence decay time as the information carrier. Anal Chim Acta 1988;205:1–6.
   Web of Science ®Google Scholar
• Martinez-Manez R, Soto J, Lizondo-Sabater J, Garcia-Breijo E, Gil L, Ibanez J, et al. New potentiometric dissolved oxygen sensors in thick film technology. Sens Actuators B Chem 2004;101:295–301.
   Google Scholar
• Clark LC Jr, Wolf R, Granger D, Taylor Z. Continuous recording of blood oxygen tensions by polarography. J Appl Physiol 1953;6(3):189–93.
   Google Scholar
• Jobst G, Urban G, Jachimowicz A, Kohl F, Tilado O. Thin-film Clark-type oxygen sensor-based on novel polymer membrane systems for in-vivo and biosensor applications. Biosens Bioelectron 1993;8(3–4):123–8.
   Google Scholar
• Kieninger J, Dannenberg A, Aravindalochanan A, Jobst G, Pettersen EO, Urban GA. Amperometric oxygen sensor array with novel chronoamperometric protocols for hypoxic tumor cell cultures. Presented at the International Conference on Solid-State Sensors, Actuators and Microsystems Conference, 2007: Transducers 2007, Lyon, France, pp 1907–10.
   Google Scholar
• Wittkampf M, Chemnitius G-C, Cammann K, Rospert M, Mokwa W. Silicon thin film sensor for measurement of dissolved oxygen. Sens Actuators B Chem 1997;43:40–4.
   Google Scholar
• Brischwein M, Motrescu ER, Cabala E, Otto AM, Grothe H, Wolf B. Functional cellular assays with multiparametric silicon sensor chips. Lab Chip 2003;3(4):234–40.
   Google Scholar
• Pettersen EO, Larsen LH, Ramsing NB, Ebbesen P. Pericellular oxygen depletion during ordinary tissue culturing, measured with oxygen microsensors. Cell Prolif 2005;38:257–67.
   PubMed Web of Science ®Google Scholar
• Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumor regression. Nature 2006;441:437–43.
   PubMed Web of Science ®Google Scholar
• Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003;9:677–84.
   PubMed Web of Science ®Google Scholar
• Semenza GL. Life with oxygen. Science 2007;318:62–4.
   PubMed Web of Science ®Google Scholar
• Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE 2005;(306):re12.
   Google Scholar
• Loenarz C, Schofield CJ. Expanding chemical biology of 2-oxoglutarate oxygenases. Nature Chem Biol 2008;4:152–6.
   PubMed Web of Science ®Google Scholar
• Schofield CJ, Ratcliffe PJ. Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004;5:343–54.
   PubMed Web of Science ®Google Scholar
• Koivunen P, Tiainen P, Hyvarinen J, Williams KE, Sormunen R, Klaus SJ, et al. An endoplasmic reticulum transmembrane prolyl 4-hydroxylase is induced by hypoxia and acts on hypoxia-inducible factor alpha. J Biol Chem 2007;282:30544–52.
   PubMed Web of Science ®Google Scholar
• Clifton IJ, McDonough MA, Ehrismann D, Kershaw NJ, Granatino N, Schofield CJ. Structural studies on 2-oxoglutarate oxygenases and related double-stranded beta-helix fold proteins. J Inorganic Biochem 2006;100:644–69.
   PubMed Web of Science ®Google Scholar
• Hirsila M, Koivunen P, Gunzler V, Kivirikko KI, Myllyharju J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor HIF. J Biol Chem 2003;278:30772–80.
   PubMed Web of Science ®Google Scholar
• Koivunen P, Hirsilä M, Günzler V, Kivirikko KI, Myllyharju J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J Biol Chem. 2004 Mar 12;279(11):9899–904.
   Google Scholar
• Tuckerman JR, Zhao Y, Hewitson KS, Tian YM, Pugh CW, Ratcliffe PJ, et al. Determination and comparison of specific activity of the HIF-prolyl hydroxylases. FEBS Lett 2004;576:145–50.
   Google Scholar
• Ehrismann D, Flashman E, Genn DN, Mathioudakis N, Hewitson KS, Ratcliffe PJ, et al. Studies on the activity of the hypoxia-inducible factor hydroxylases using an oxygen consumption assay. Biochem J 2007;401:227–34.
   PubMed Web of Science ®Google Scholar
• Koivunen P, Hirsila M, Kivirikko KI, Myllyharju J. The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4 hydroxylases. J Biol Chem 2006;281:28712–20.
   Google Scholar
• Chan DA, Sutphin PD, Denko NC, Giaccia AJ. Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1a. J Biol Chem 2002;277:40112–17.
   PubMed Web of Science ®Google Scholar
• Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D, et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004;118:781–94.
   PubMed Web of Science ®Google Scholar
• Knowles HJ, Raval RR, Harris AL, Ratcliffe PJ. Effect of ascorbate on the activity of hypoxia inducible factor (HIF) in cancer cells. Cancer Res 2003; 63:1764–8.
   PubMed Web of Science ®Google Scholar
• Smith TG, Balanos GM, Croft QPP, Talbot NP, Dorrington KL, Ratcliffe PJ, et al. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol 2008;586:5999–6005.
   PubMed Web of Science ®Google Scholar
• Dalgard CL, Lu H, Mohyeldin A, Verma A. Endogenous 2-oxoacids differentially regulate expression of oxygen sensors. Biochem J 2004; 380:419–24.
   PubMedGoogle Scholar
• Hewitson KS, Lienard BM, McDonough MA, Clifton IJ, Butler D, Soares AS, et al. Structural and mechanistic studies on the inhibition of the hypoxia-inducible transcription factor hydroxylases by tricarboxylic acid cycle intermediates. J Biol Chem 2007;282:3293–301.
   PubMed Web of Science ®Google Scholar
• Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Merino M, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005;8:143–53.
   PubMed Web of Science ®Google Scholar
• Koivunen P, Hirsila M, Remes AM, Hassinen IE, Kivirikko KI, Myllyharju J. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 2007;282:4524–32.
   PubMed Web of Science ®Google Scholar
• Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005;7:77–85.
   PubMed Web of Science ®Google Scholar
• Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumors which result from germline FH and SDH mutations. Hum Mol Genet 2005;14:2231–9.
   PubMed Web of Science ®Google Scholar
• Mackenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM, et al. Cell permeating alpha-ketoglutarate derivatives alleviate pseudo-hypoxia in SDH deficient cells. Mol Cell Biol 2007;27:3282–9.
   PubMed Web of Science ®Google Scholar
• Knowles HJ, Mole DR, Ratcliffe PJ, Harris AL. Normoxic stabilization of hypoxia-inducible factor-1alpha by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1. Cancer Res 2006;66:2600–7.
   PubMed Web of Science ®Google Scholar
• Pagé EL, Chan DA, Giaccia AJ, Levine M, Richard DE. Hypoxia-inducible factor-1alpha stabilization in nonhypoxic conditions: role of oxidation and intracellular ascorbate depletion. Mol Biol Cell. 2008 Jan;19(1):86–94.
   Google Scholar
• Vissers MC, Gunningham SP, Morrison MJ, Dachs GU, Currie MJ. Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate. Free Radic Biol Med 2007;42:765–72.
   PubMed Web of Science ®Google Scholar
• Kietzmann T, Görlach A. Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin Cell Dev Biol 2005;16:474–86.
   PubMedGoogle Scholar
• Pan Y, Mansfield KD, Bertozzi CC, Rudenko V, Chan DA, Giaccia AJ, et al. Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol Cell Biol 2007;27:912–25.
   PubMed Web of Science ®Google Scholar
• Bell EL, Klimova TA, Eisenbart J, Moraes CT, Murphy MP, Budinger GR, et al. The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signalling via reactive oxygen species production. J Cell Biol 2007;177:1029–36.
   PubMed Web of Science ®Google Scholar
• Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT. Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab. 2005 Jun;1(6):401–8.
   Google Scholar
• Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT. Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 2008;28:718–31.
   PubMed Web of Science ®Google Scholar
• Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 2005;1:393–9.
   PubMed Web of Science ®Google Scholar
• Matlin AJ, Clark F, Smith CWJ. Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 2005;6:386–98.
   PubMed Web of Science ®Google Scholar
• Kramer A. The structure and function of proteins involved in mammalian pre-mRNA splicing. Annu Rev Biochem 1996;65:367–409.
   PubMed Web of Science ®Google Scholar
• Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes Dev 2003;17:419–37.
   PubMed Web of Science ®Google Scholar
• Srebrow A, Kornblihtt AR. The connection between splicing and cancer. J Cell Sci 2006;119:2635–41.
   PubMed Web of Science ®Google Scholar
• Kalnina Z, Zyakin P, Silina K, Line A. Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 2005;42:342–57.
   PubMedGoogle Scholar
• Veneables JP. Abberant and alternative splicing in cancer. Cancer Res 2004;64:7647–54.
   Google Scholar
• Stoss O, Stoilov P, Daoud R, Hartmann AM, Olbrich M, Stamm S. Misregulation of pre-mRNA splicing that causes human diseases.Concepts and therapeutic strategies. Gene Ther Mol Biol 2000; 5:9–30.
   Google Scholar
• Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC. Mechanism for elimination of a tumor suppresor: aberant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. Proc Natl Acad Sci USA 1999;96:9689–94.
   PubMedGoogle Scholar
• Semenza G. HIF-1 and human disease: one highly involved factor. Genes Dev 2000;14:1983–91.
   PubMed Web of Science ®Google Scholar
• Semenza G. Targeting HIF-1 for cancer therapy. Nat Rev 2003;3:721–32.
   Google Scholar
• Makino Y, Cao R, Svensson K, Bertilsson G, Asman M, Tanaka H, et al. Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 2001;414:550–4.
   PubMed Web of Science ®Google Scholar
• Yamashita T, Ohneda O, Nagano M, Iemitsu M, Makino Y, Tanaka H, et al. Abnormal heart development and lung remodeling in mice lacking the hypoxia-inducible factor-related basic helix-loop-helix PAS protein NEPAS. Mol Cell Biol 2008;28:1285–97.
   PubMed Web of Science ®Google Scholar
• Gothie E, Richard DE, Berra E, Pages G, Pouyssegur J. Identification of alternatively spliced variants of human hypoxia-inducible factor-1α. J Biol Chem 2000;275:6922–7.
   PubMed Web of Science ®Google Scholar
• Chun Y-S, Choi E, Kim T-Y, Kim M-S, Park J-W. A dominant-negative isoform lacking exons 11 and 12 of the human hypoxia-inducible factor-1α gene. Biochem J 2002;362:71–9.
   PubMedGoogle Scholar
• Maynard MA, Qi H, Chung J, Lee EHL, Kondo Y, Hara S, et al. Multiple splice variants of the human HIF-3α locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex. J Biol Chem 2003;278:11032–40.
   PubMed Web of Science ®Google Scholar
• Makino Y, Kanopka A, Wilson WJ, Tanaka H, Poellinger L. Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3alpha locus. J Biol Chem 2002;277:32405–08.
   PubMed Web of Science ®Google Scholar
• Barathova M, Takacova M, Holotnakova T, Gibadulinova A, Ohradanova A, Zatovicova M, et al. Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumor phenotype. Br J Cancer 2008;98:129–36.
   PubMed Web of Science ®Google Scholar
• Wouters BG, van den Beucken T, Magagnin MG, Lambin P, Koumenis C. Targeting hypoxia tolerance in cancer. Drug Resist Updat 2004; 7(1):25–40.
   Google Scholar
• Brown JM, Wilson WR. Exploiting tumor hypoxia in cancer treatment. Nat Rev Cancer 2004;4(6):437–47.
   Google Scholar
• Hockel M, Vaupel P. Biological consequences of tumor hypoxia. Semin Oncol 2001;28(2 Suppl 8):36–41.
   Google Scholar
• Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 2008;8(11):851–64.
   Google Scholar
• Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004;18(23):2893–904.
   PubMedGoogle Scholar
• Connolly E, Braunstein S, Formenti S, Schneider RJ. Hypoxia inhibits protein synthesis through a 4E-BP1 and elongation factor 2 kinase pathway controlled by mTOR and uncoupled in breast cancer cells. Mol Cell Biol 2006;26(10):3955–65.
   Google Scholar
• Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC. Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 2006;21(4):521–31.
   Google Scholar
• Koritzinsky M, Rouschop KM, van den Beucken T, Magagnin MG, Savelkouls K, Lambin P, et al. Phosphorylation of eIF2alpha is required for mRNA translation inhibition and survival during moderate hypoxia. Radiother Oncol 2007;83(3):353–61.
   Google Scholar
• Magagnin MG, van den Beucken T, Sergeant K, Lambin P, Koritzinsky M, Devreese B, et al. The mTOR target 4E-BP1 contributes to differential protein expression during normoxia and hypoxia through changes in mRNA translation efficiency. Proteomics 2008;8(5):1019–28.
   Google Scholar
• Weppler SA, Krause M, Zyromska A, Lambin P, Baumann M, Wouters BG. Response of U87 glioma xenografts treated with concurrent rapamycin and fractionated radiotherapy: possible role for thrombosis. Radiother Oncol 2007;82(1):96–104.
   Google Scholar
• Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 2002;22(21):7405–16.
   Google Scholar
• Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 2005;24(19):3470–81.
   Google Scholar
• Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, Dostie J, et al. Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J 2006;25(5):1114–25.
   Google Scholar
• Koritzinsky M, Seigneuric R, Magagnin MG, van den Beucken T, Lambin P, Wouters BG. The hypoxic proteome is influenced by gene-specific changes in mRNA translation. Radiother Oncol 2005;76(2):177–86.
   Google Scholar
• van den Beucken T, Magagnin MG, Savelkouls K, Lambin P, Koritzinsky M, Wouters BG. Regulation of Cited2 expression provides a functional link between translational and transcriptional responses during hypoxia. Radiother Oncol 2007;83(3):346–52.
   Google Scholar
• Magagnin MG, Sergeant K, van den Beucken T, Rouschop KM, Jutten B, Seigneuric R, et al. Proteomic analysis of gene expression following hypoxia and reoxygenation reveals proteins involved in the recovery from endoplasmic reticulum and oxidative stress. Radiother Oncol 2007;83(3):340–5.
   Google Scholar
• Goetz ME, Luch A. Reactive species: a cell damaging rout assisting to chemical carcinogens. Cancer Lett 2008;266:73–83.
   PubMed Web of Science ®Google Scholar
• Lu W, Ogasawara MA, Huang P. Models of reactive oxygen species in cancer. Drug Discov Today Dis Models 2007;4:67–73.
   PubMedGoogle Scholar
• Lenart J, Dombrowski F, Görlach A, Kietzmann T. Deficiency of manganese superoxide dismutase in hepatocytes disrupts zonated gene expression in mouse liver. Arch Biol Biophys 2007;462:238–44.
   PubMed Web of Science ®Google Scholar
• Hervouet E, Simonnet H, Godinot C. Mitochondria and reactive oxygen species in renal cancer. Biochimie 2007;89:1080–8.
   PubMedGoogle Scholar
• Penta JS, Johnson FM, Wachsman JT, Copeland WC. Mitochondrial DNA in human malignancy. Mutat Res, 2001;488:119–33.
   PubMed Web of Science ®Google Scholar
• Sarti P, Avigliano L, Görlach A, Brüne B. Superoxide and nitric oxide—participation in cell communication. Cell Death Differ 2002;9:1160–2.
   Google Scholar
• Görlach A, Kietzmann T, Hess J. Redox signaling through NADPH oxidases – involvement in vascular proliferation and coagulation. Ann NY Acad Sci 2002;973:505–7.
   PubMed Web of Science ®Google Scholar
• Forman HJ, Fukuto JM, Miller T, Zhang H, Rinna A, Levy S. The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal. Arch Biochem Biophys 2008;477:183–95.
   PubMed Web of Science ®Google Scholar
• Tonks NK. Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 2006;7:833–46.
   PubMed Web of Science ®Google Scholar
• Clerkin JS, Naughton R, Quiney C, Cotter TG. Mechanisms of ROS modulated cell survival during carcinogenesis. Cancer Lett 2008;266:30–6.
   PubMed Web of Science ®Google Scholar
• Görlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, et al. Thrombin activates the HIF-1 signaling pathway in vascular smooth muscle cells. Role of the p22phox-containing NADPH oxidase. Circ Res 2001;89:47–54.
   PubMed Web of Science ®Google Scholar
• Görlach A, Kietzmann T. Superoxide and derived reactive oxygen species in the regulation of hypoxia-inducible factors. Methods Enzymol 2007;435:421–46.
   PubMed Web of Science ®Google Scholar
• Bonello S, Zähringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, et al. Reactive oxygen species activate the HIF-1α promoter via a functional NFκB site. Arterioscler Thromb Vasc Biol 2007;27:755–61.
   PubMed Web of Science ®Google Scholar
• BelAiba RS, Bonello S, Schmidt S, Diemer K, Kietzmann T, Hess J, et al. Hypoxia-induced HIF-1α mRNA level is mediated by NFκB via PI3K/AKT pathway activation in pulmonary artery smooth muscle cells. Mol Biol Cell 2007;18:4691–7.
   PubMed Web of Science ®Google Scholar
• Lambeth JD. NOX enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med 2007;43:332–47.
   PubMed Web of Science ®Google Scholar
• Rokutan K, Kawahara T, Kuwano Y, Tominaga K, Sekiyama A, Teshima-Kondo S. NADPH oxidases in the gastrointestinal tract: a potential role of Nox1 in innate immune response and carcinogenesis. Antioxid Redox Signal 2006;8(9–10):1573–82.
   Google Scholar
• Ushio-Fukai M. Redox signaling in angiogenesis: role of NADPH oxidase. Cardiovasc Res 2006;71:226–35.
   PubMed Web of Science ®Google Scholar
• Otani H. Reactive oxygen species as mediators of signal transduction in ischemic preconditioning. Antioxid Redox Signal 2004;6:449–69.
   PubMed Web of Science ®Google Scholar
• Lambeth JD, Krause KH, Clark RA. NOX enzymes as novel targets for drug development. Semin Immunopathol 2008;30:339–63.
   PubMedGoogle Scholar
• Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 2008; 8:425–37.
   PubMed Web of Science ®Google Scholar
• Robinson JM. Reactive oxygen species in phagocytic leukocytes. Histochem Cell Biol 2008;130:281–97.
   PubMed Web of Science ®Google Scholar
• Ono M. Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Sci 2008;99:1501–6.
   PubMed Web of Science ®Google Scholar
• BelAiba RS, Djordjevic T, Bonello S, Flügel D, Hess J, Kietzmann T, et al. Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells. Biol Chem 2004;385:249–57.
   PubMed Web of Science ®Google Scholar
• BelAiba RS, Djordjevic T, Petry A, Diemer K, Bonello S, Banfi B, et al. NOX5 variants are functionally active in endothelial cells. Free Rad Biol Med 2007;42:446–59.
   PubMed Web of Science ®Google Scholar
• Brahimi-Horn MC, Pouysségur J. Hypoxia in cancer cell metabolism and pH regulation. Essays Biochem 2007;43:165–78.
   PubMed Web of Science ®Google Scholar
• Walenta S, Mueller-Klieser WF. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol 2004;14:267–74.
   PubMed Web of Science ®Google Scholar
• Helmlinger G, Sckell A, Dellian M, Forbes NS, Jain RK. Acid production in glycolysis-impaired tumors provides new insights into tumor metabolism. Clin Cancer Res 2002;8:1284–91.
   PubMed Web of Science ®Google Scholar
• Stubbs M, McSheehy PMJ, Griffiths JR, Bashford CL. Causes and consequences of tumor acidity and implications for treatment. Mol Med Today 2000;6:15–19.
   PubMedGoogle Scholar
• Raghunand N, Gatenby RA, Gillies RJ. Microenvironmental and cellular consequences of altered blood flow in tumors. Br J Radiol 2003;76:S11–22.
   PubMed Web of Science ®Google Scholar
• Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 2000;60:7075–83.
   PubMed Web of Science ®Google Scholar
• Pastorekova S, Casini A, Scozzafava A, Vullo D, Pastorek J, Supuran CT. Carbonic anhydrase inhibitors: the first selective, membrane-impermeant inhibitors targeting the tumor-associated isozyme IX. Bioorg Med Chem Lett 2004;14:869–73.
   PubMed Web of Science ®Google Scholar
• Potter CP, Harris AL. Diagnostic, prognostic and therapeutic implications of carbonic anhydrases in cancer. Br J Cancer 2003;89:2–7.
   PubMed Web of Science ®Google Scholar
• Pastorek J, Pastorekova S, Callebaut I, Mornon JP, Zelnik V, Opavsky R, et al. Cloning and characterisation of MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and putative helix-loop-helix DNA binding segment. Oncogene 1994;9:2877–88.
   PubMed Web of Science ®Google Scholar
• Pastorekova S, Ratcliffe PJ, Pastorek J. Molecular mechanisms of carbonic anhydrase IX-mediated pH regulation under hypoxia. BJU Int 2008;101(Suppl 4):8–15.
   Google Scholar
• Svastova E, Hulikova A, Rafajova M, Zatovicova M, Gibadulinova A, Casini A, et al. Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett 2004;577:439–45.
   PubMed Web of Science ®Google Scholar
• Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 2007; 26:299–310.
   PubMed Web of Science ®Google Scholar
• Swietach P, Wigfield S, Cobden P, Supuran CT, Harris AL, Vaughan-Jones RD. Tumor-associated carbonic anhydrase 9 spatially coordinates intracellular pH in three-dimensional multicellular growths. J Biol Chem 2008;283:20473–83.
   PubMed Web of Science ®Google Scholar
• Dubois L, Douma K, Supuran CT, Chiu RK, van Zandvoort MA, Pastoreková S, et al. Imaging the hypoxia surrogate marker CA IX requires expression and catalytic activity for binding fluorescent sulfonamide inhibitors. Radiother Oncol 2007;83:367–73.
   PubMed Web of Science ®Google Scholar
• Rafajova M, Zatovicova M, Kettmann R, Pastorek J, Pastorekova S. Induction by hypoxia combined with low glucose or low bicarbonate and high posttranslational stability upon reoxygenation contribute to carbonic anhydrase IX expression in cancer cells. Int J Oncol 2004;24:995–1004.
   PubMed Web of Science ®Google Scholar
• Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1α. Genes Dev 1998;12:149–62.
   PubMed Web of Science ®Google Scholar
• Pastorekova S, Zatovicova M, Pastorek J. Cancer-associated carbonic anhydrases and their inhibition. Curr Pharm Des 2008;14: 685–98.
   PubMed Web of Science ®Google Scholar
• Görlach A, Camenisch G, Kvietikova I, Vogt L, Wenger RH, Gassmann M. Efficient translation of mouse hypoxia-inducible factor-1α under normoxic and hypoxic conditions. Biochim Biophys Acta 2000;1493:125–34.
   PubMedGoogle Scholar
• Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 2007;129:111–22.
   PubMed Web of Science ®Google Scholar
• Wenger RH. Mitochondria: oxygen sinks rather than sensors? Med Hypoth 2006;66:380–3.
   PubMedGoogle Scholar
• Stiehl DP, Wirthner R, Köditz J, Spielmann P, Camenisch G, Wenger RH. Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels.Evidence for an autoregulatory oxygen-sensing system. J Biol Chem 2006;281:23482–91.
   PubMed Web of Science ®Google Scholar
• Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006;3:177–85.
   PubMed Web of Science ®Google Scholar
• Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006;3:187–97.
   PubMed Web of Science ®Google Scholar
• Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell 2007;11:407–20.
   PubMed Web of Science ®Google Scholar
• Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008;283:10892–903.
   PubMed Web of Science ®Google Scholar
• Blais JD, Filipenko V, Bi M, Harding HP, Ron D, Koumenis C, et al. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 2004;24:7469–82.
   PubMed Web of Science ®Google Scholar
• Köditz J, Nesper J, Wottawa M, Stiehl DP, Camenisch G, Franke C, et al. Oxygen-dependent ATF-4 stability is mediated by the PHD3 oxygen sensor. Blood 2007;110:3610–17.
   PubMed Web of Science ®Google Scholar
• Pettersen EO, Lindmo T. Inhibition of cell-cycle progression by acute treatment with various degrees of hypoxia: modifications induced by low concentrations of misonidazole present during hypoxia. Br J Cancer 1983;48:809–17.
   PubMed Web of Science ®Google Scholar
• åmellem O, Stokke T, Sandvik JA, Pettersen EO. The retinoblastoma gene product is reversibly dephosphorylated and bound in the nucleus in S and G2 phase during hypoxic stress. Exp Cell Res 1996;227:106–15.
   PubMed Web of Science ®Google Scholar
• åmellem O, Stokke T, Sandvik JA, Karlsen F, Pettersen EO. The retinoblastoma protein-associated cell cycle arrest in S-phase under moderate hypoxia is disrupted in cells expressing HPV18 E7 oncoprotein. Br J Cancer 1998;77:862–72.
   PubMed Web of Science ®Google Scholar
• Gardner LB, Li Q, Park MS, Flanagan WM, Semenza GL, Dang CV. Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem. 2001 Mar 16;276(11):7919–26.
   Google Scholar
• Krtolica A, Krucher NA, Ludlow JW. Hypoxia-induced pRB hypophosphorylation results from downregulation of CDK and upregulation of PP1 activities. Oncogene 1998;17:2295–304.
   PubMedGoogle Scholar
• Goda N, Ryan HE, Khadivi B, McNulty W, Rickert RC, Johnson RS. Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol 2003;23:359–69.
   PubMed Web of Science ®Google Scholar
• Graff P, Seim J, Amellem Ø, Arakawa H, Nakamura Y, Andersson KK, Stokke T, Pettersen EO. Counteraction of pRb-dependent protection after extreme hypoxia by elevated ribonucleotide reductase. Cell Prolif. 2004 Oct;37(5):367–83.
   Google Scholar
• Green SL, Freiberg RA, Giaccia AJ. p21(Cip1) and p27(Kip1) regulate cell cycle reentry after hypoxic stress but are not necessary for hypoxia-induced arrest. Mol Cell Biol 2001;21:1196–206.
   PubMed Web of Science ®Google Scholar
• Graeber TG, Peterson JF, Tsai M, Monica K, Fornace AJ Jr, Giaccia AJ. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol Cell Biol 1994;14:6264–77.
   PubMed Web of Science ®Google Scholar
• Pettersen EO, Lindmo T. Inhibition of cell-cycle progression by acute treatment with various degrees of hypoxia: modifications induced by low concentrations of misonidazole present during hypoxia. Br J Cancer. 1983 Dec;48(6):809–17.
   Google Scholar
• åmellem O, Pettersen EO. The role of protein accumulation on the kinetics of entry into S phase following extreme hypoxia. Anticancer Res 1991;11:1083–7.
   Google Scholar
• åmellem O, Pettersen EO. Cell inactivation and cell cycle inhibition as induced by extreme hypoxia: the possible role of cell cycle arrest as a protection against hypoxia-induced lethal damage. Cell Prolif 1991;24:127–41.
   PubMed Web of Science ®Google Scholar
• åmellem O, Löffler M, Pettersen EO. Regulation of cell proliferation under extreme and moderate hypoxia: the role of pyrimidine (deoxy)nucleotides. Br J Cancer 1994;70:857–66.
   PubMedGoogle Scholar
• Ohtani K, DeGregori J, Nevins JR. Regulation of the cyclin E gene by transcription factor E2F1. Proc Natl Acad Sci USA 1995;92:12146–50.
   PubMed Web of Science ®Google Scholar
• Probst G, Riedinger HJ, Martin P, Engelcke M, Probst H. Fast control of DNA replication in response to hypoxia and to inhibited protein synthesis in CCRF-CEM and HeLa cells. Biol Chem 1999;380:1371–82.
   PubMedGoogle Scholar
• Ludlow JW, Howell RL, Smith HC. Hypoxic stress induces reversible hypophosphorylation of pRb and reduction in cyclin A abundance independent of cell-cycle progression. Oncogene 1993;8:331–9.
   PubMedGoogle Scholar
• Krtolica A, Ludlow JW. Hypoxia arrests ovarian carcinoma cell cycle progression, but invasion is unaffected. Cancer Res 1996;56:1168–73.
   PubMed Web of Science ®Google Scholar
• Graff P, åmellem ø, Andersson KK, Pettersen EO. Role of ribonucleotide reductase in regulation of cell cycle progression during and after exposure to moderate hypoxia. Anticancer Res 2002;22:59–68.
   Google Scholar
• Thelander L, Reichard P. Reduction of ribonucleotides. Annu Rev Biochem 1979;48:133–58.
   PubMed Web of Science ®Google Scholar
• Eklund H, Uhlin U, Färnegårdh M, Logan DT, Nordlund P. Structure and function of the radical enzyme ribonucleotide reductase. Prog Biophys Mol Biol 2001;77:177–268.
   PubMed Web of Science ®Google Scholar
• Bianchi V, Borella S, Calderazzo F, Ferraro P, Chieco BL, Reichard P. Inhibition of ribonucleotide reductase by 2’-substituted deoxycytidine analogs: possible application in AIDS treatment. Proc Natl Acad Sci USA 1994;91:8403–7.
   PubMed Web of Science ®Google Scholar
• Nocentini G. Ribonucleotide reductase inhibitors: new strategies for cancer chemotherapy. Crit Rev Oncol Hematol 1996;22:89–126.
   PubMed Web of Science ®Google Scholar
• Holland KP, Elford HL, Bracchi V, Annis CG, Schuster SM, Chakrabarti D. Antimalarial activities of polyhydroxyphenyl and hydroxamic acid derivatives. Antimicrob Agents Chemother 1998;42:2456–8.
   PubMed Web of Science ®Google Scholar
• Guppy M, Withers P. Metabolic depression in animals: physiological perspectives and biochemical generalizations. Biol Rev Camb Philos Soc 1999;74:1–40.
   PubMed Web of Science ®Google Scholar
• Gorr TA, Gassmann M, Wappner P. Sensing and responding to hypoxia via HIF in model invertebrates. J Insect Physiol 2006;52:349–64.
   Google Scholar
• Hochachka PW, Buck LT, Doll CJ, Land SC. Unifying theory of hypoxia tolerance: molecular/metabolic defense and rescue mechanisms for surviving oxygen lack. Proc Natl Acad Sci USA 1996;93:9493–8.
   PubMed Web of Science ®Google Scholar
• Boutilier RG. Mechanisms of cell survival in hypoxia and hypothermia. J Exp Biol 2001;204:3171–81.
   PubMed Web of Science ®Google Scholar
• Boutilier RG, Donohoe PH, Tattersall GJ, West TG. Hypometabolic homeostasis in overwintering aquatic amphibians. J Exp Biol. 1997 Jan;200(Pt 2):387–400.
   Google Scholar
• Rolfe DF, Brown GC. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 1997;77:731–58.
   PubMed Web of Science ®Google Scholar
• Land SC, Buck LT, Hochachka PW. Response of protein synthesis to anoxia and recovery in anoxia-tolerant hepatocytes. Am J Physiol 1993;265:R41–8.
   Google Scholar
• Land SC, Hochachka PW. Protein turnover during metabolic arrest in turtle hepatocytes: role and energy dependence of proteolysis. Am J Physiol 1994;266:C1028–36.
   Google Scholar
• Buck LT, Hochachka PW. Anoxic suppression of Na(+)-K(+)-ATPase and constant membrane potential in hepatocytes: support for channel arrest. Am J Physiol 1993;265:R1020–5.
   Google Scholar
• Krumschnabel G, Schwarzbaum PJ, Lisch J, Biasi C, Wieser W. Oxygen-dependent energetics of anoxia-tolerant and anoxia-intolerant hepatocytes. J Exp Biol 2000;203:951–9.
   Google Scholar
• Storey K. A re-evaluation of the Pasteur effect: new mechanisms in anaerobic metabolism. Mol Physiol 1985;8:439–61.
   Google Scholar
• Schmidt H, Kamp G. The Pasteur effect in facultative anaerobic metazoa. Experientia 1996;52:440–8.
   PubMedGoogle Scholar
• Padilla PA, Roth MB. Oxygen deprivation causes suspended animation in the zebrafish embryo. Proc Natl Acad Sci USA 2001;98:7331–5.
   PubMedGoogle Scholar
• Padilla PA, Nystul TG, Zager RA, Johnson AC, Roth MB. Dephosphorylation of cell cycle-regulated proteins correlates with anoxia-induced suspended animation in Caenorhabditis elegans. Mol Biol Cell 2002;13:1473–83.
   Google Scholar
• Froese G. The respiration of ascites tumor cells at low oxygen concentrations. Biochim Biophys Acta 1962;57:509–19.
   PubMedGoogle Scholar
• Freyer JP. Rates of oxygen consumption for proliferating and quiescent cells isolated from multicellular tumor spheroids. Adv Exp Med Biol 1994;345:335–42.
   Google Scholar
• Pettersen EO, Lindmo T. Inhibition of cell-cycle progression by acute treatment with various degrees of hypoxia: modifications induced by low concentrations of misonidazole present during hypoxia. Br J Cancer. 1983;48:809–817.
   PubMed Web of Science ®Google Scholar
• Probst H, Schiffer H, Gekeler V, et al. Oxygen dependent regulation of DNA synthesis and growth of Ehrlich ascites tumor cells in vitro and in vivo. Cancer Res 1988;48:2053–60.
   PubMedGoogle Scholar
• Pettersen EO, Juul NO, Ronning OW. Regulation of protein metabolism of human cells during and after acute hypoxia. Cancer Res 1986;46:4346–51.
   PubMed Web of Science ®Google Scholar
• Kraggerud SM, Sandvik JA, Pettersen EO. Regulation of protein synthesis in human cells exposed to extreme hypoxia. Anticancer Res 1995;15:683–6.
   PubMedGoogle Scholar
• Guppy M, Brunner S, Buchanan M. Metabolic depression: a response of cancer cells to hypoxia? Comp Biochem Physiol B Biochem Mol Biol 2005;140:233–9.
   Google Scholar
• Giaccia AJ. Hypoxic stress proteins: survival of the fittest. Semin Radiat Oncol 1996;6:46–58.
   PubMed Web of Science ®Google Scholar
• Freyer JP, Sutherland RM. A reduction in the in situ rates of oxygen and glucose consumption of cells in EMT6/Ro spheroids during growth. J Cell Physiol 1985;124:516–24.
   Google Scholar
• Eskey CJ, Koretsky AP, Domach MM, Jain RK. Role of oxygen vs.glucose in energy metabolism in a mammary carcinoma perfused ex vivo: direct measurement by 31P NMR. Proc Natl Acad Sci USA 1993;90:2646–50.
   PubMed Web of Science ®Google Scholar
• Walenta S, Doetsch J, Mueller-Klieser W, Kunz-Schughart LA. Metabolic imaging in multicellular spheroids of oncogene-transfected fibroblasts. J Histochem Cytochem 2000;48:509–22.
   PubMed Web of Science ®Google Scholar
• Kunz-Schughart LA, Freyer JP. Phosphorous metabolites and steady-state energetics of transformed fibroblasts during three-dimensional growth. Am J Physiol Cell Physiol 2002;283:C1287–97.
   PubMed Web of Science ®Google Scholar
• Zölzer F, Stüben G, Knühmann K, Streffer C, Sack H. Quiescent S-phase cells as indicators of extreme physiological conditions in human tumor xenografts. Int J Radiat Oncol Biol Phys 1999;45:1019–24.
   Google Scholar
• Masunaga S, Ono K, Takahashi A, Ohnishi T, Kinashi Y, Takagaki M. Radiobiological characteristics of solid tumors depending on the p53 status of the tumor cells, with emphasis on the response of intratumor quiescent cells. Eur J Cancer 2002;38:718–27.
   PubMed Web of Science ®Google Scholar
• Masunaga S, Uto Y, Nagasawa H, Hori H, Nagata K, Suzuki M, et al. Evaluation of hypoxic cell radio-sensitizers in terms of radio-sensitizing and repair-inhibiting potential. Dependency on p53 status of tumor cells and the effects on intratumor quiescent cells. Anticancer Res 2006;26:1261–70.
   Google Scholar
• Dubois L, Magagnin MG, Cleven AH, Weppler SA, Grenacher B, Landuyt W, Lieuwes N, Lambin P, Gorr TA, Koritzinsky M, Wouters BG. Inhibition of 4E-BP1 Sensitizes U87 Glioblastoma Xenograft Tumors to Irradiation by Decreasing Hypoxia Tolerance. Int J Radiat Oncol Biol Phys. 2009 Mar 15;73(4):1219–27.
   Google Scholar
• Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2002;2(1):38–47.
   PubMed Web of Science ®Google Scholar
• Beasley NJ, Wykoff CC, Watson PH, 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. Cancer Res 2001;61(13):5262–7.
   Google Scholar
• Semenza GL. Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med 2001;7(8):345–50.
   Google Scholar
• Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 1995;92(12):5510–4.
   PubMed Web of Science ®Google Scholar
• Gustafsson MV, Zheng X, Pereira T, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 2005;9(5):617–28.
   PubMed Web of Science ®Google Scholar
• Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL. Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 2005;65(19):8690–7.
   Google Scholar
• Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10(8):789–99.
   PubMed Web of Science ®Google Scholar
• Huang LE, Bindra RS, Glazer PM, Harris AL. Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression. J Mol Med 2007;85(2):139–48.
   Google Scholar
• Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes & development 2004;18(17):2095–107.
   Google Scholar
• Graeber TG, Osmanian C, Jacks T, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 1996;379(6560):88–91.
   Google Scholar
• Chan DA, Giaccia AJ. Hypoxia, gene expression, and metastasis. Cancer metastasis reviews 2007;26(2):333–9.
   PubMed Web of Science ®Google Scholar
• Gort EH, Groot AJ, van der Wall E, van Diest PJ, Vooijs MA. Hypoxic regulation of metastasis via hypoxia-inducible factors. Current molecular medicine 2008;8(1):60–7.
   Google Scholar
• Cosse JP, Michiels C. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med Chem 2008;8(7):790–7.
   Google Scholar
• Charlesworth PJ, Harris AL. Mechanisms of disease: angiogenesis in urologic malignancies. Nature clinical practice 2006;3(3):157–69.
   Google Scholar
• Koukourakis MI, Bentzen SM, Giatromanolaki A, et al. Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol 2006;24(5):727–35.
   Google Scholar
• Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. British journal of cancer 2003;89(5):877–85.
   Google Scholar
• Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Harris AL. Lactate dehydrogenase 5 expression in operable colorectal cancer: strong association with survival and activated vascular endothelial growth factor pathway—a report of the Tumour Angiogenesis Research Group. J Clin Oncol 2006;24(26):4301–8.
   Google Scholar
• Marignol L, Coffey M, Lawler M, Hollywood D. Hypoxia in prostate cancer: a powerful shield against tumour destruction? Cancer Treat Rev 2008;34(4):313–27.
   PubMedGoogle Scholar
• Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, et al. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 2003;22(21):3213–20.
   Google Scholar
• Song X, Liu X, Chi W, et al. Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer chemotherapy and pharmacology 2006;58(6):776–84.
   Google Scholar
• Sermeus A, Cosse JP, Crespin M, et al. Hypoxia induces protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor activity. Mol Cancer 2008;7:27.
   Google Scholar
• Moeller BJ, Dewhirst MW. HIF-1 and tumor radiosensitivity. Br J Cancer 2006;95(1):1–5.
   Google Scholar
• Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005;8(2):99–110.
   Google Scholar
• Harada H, Kizaka-Kondoh S, Li G, Itasaka S, Shibuya K, Inoue M, et al. Significance of HIF-1-active cells in angiogenesis and radioresistance. Oncogene 2007;26(54):7508–16.
   Google Scholar
• Williams KJ, Telfer BA, Xenaki D, et al. Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiother Oncol 2005;75(1):89–98.
   Google Scholar
• Wouters BG, Weppler SA, Koritzinsky M, Landuyt W, Nuyts S, Theys J, et al. Hypoxia as a target for combined modality treatments. Eur J Cancer 2002;38:240–57.
   PubMed Web of Science ®Google Scholar
• Adam MF, Gabalski EC, Bloch DA, Oehlert JW, Brown JM, Elsaid AA, et al. Tissue oxygen distribution in head and neck cancer patients. Head Neck 1999;21(2):146–53.
   Google Scholar
• Stadler P, Becker A, Feldmann HJ, Hansgen G, Dunst J, Wurschmidt F, et al. Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys 1999;44(4):749–54.
   Google Scholar
• Raleigh JA, Chou SC, Calkins-Adams DP, Ballenger CA, Novotny DB, Varia MA. A clinical study of hypoxia and metallothionein protein expression in squamous cell carcinomas. Clin Cancer Res 2000;6(3):855–62.
   Google Scholar
• Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van den Hoogen JA, et al. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res 2002;62:7066–74.
   PubMed Web of Science ®Google Scholar
• Gross MW, Karbach U, Groebe K, Franko AJ, Mueller-Klieser W. Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids. Int J Cancer 1995;61(4):567–73.
   Google Scholar
• Nordsmark M, Loncaster J, Aquino-Parsons C, Chou SC, Ladekarl M, Havsteen H, et al. Measurements of hypoxia using pimonidazole and polarographic oxygen-sensitive electrodes in human cervix carcinomas. Radiother Oncol 2003;67(1):35–44.
   Google Scholar
• Beasley NJ, Wykoff CC, Watson PH, Leek R, Turley H, Gatter K, 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. Cancer Res 2001;61(13):5262–7.
   Google Scholar
• Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, et al. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2000;157(2):411–21.
   Google Scholar
• Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res 1999;59(22):5830–5.
   PubMedGoogle Scholar
• Lidgren A, Hedberg Y, Grankvist K, Rasmuson T, Vasko J, Ljungberg B. The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma. Clin Cancer Res 2005;11(3):1129–35.
   Google Scholar
• Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos K, Pastorek J, Wykoff CC, et al. Hypoxia-regulated carbonic anhydrase-9 (CA IX) relates to poor vascularization and resistance of squamous cell head and neck cancer to chemoradiotherapy. Clin Cancer Res 2001;7(11):3399–403.
   Google Scholar
• Giatromanolaki A, Koukourakis MI, Sivridis E, Pastorek J, Wykoff CC, Gatter KC, et al. Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 2001;61(21):7992–8.
   Google Scholar
• Swinson DE, Jones JL, Richardson D, Wykoff C, Turley H, Pastorek J, et al. Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol 2003;21(3):473–82.
   Google Scholar
• Loncaster JA, Harris AL, Davidson SE, Loque JP, Hunter RD, Wykoff CC, 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. Cancer Res 2001;61(17):6394–9.
   Google Scholar
• Chia SK, Wykoff CC, Watson PH, Han C, Leek RD, Pastorek J, et al. Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. J Clin Oncol 2001;19(16):3660–8.
   Google Scholar
• Hutchison GJ, Valentine HR, Loncaster JA, Davidson SE, Hunter RD, Roberts SA, et al. Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix. Clin Cancer Res 2004;10(24):8405–12.
   Google Scholar
• Mayer A, Hockel M, Vaupel P. Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix. Clin Cancer Res 2005;11(20):7220–5.
   Google Scholar
• Mayer A, Wree A, Hockel M, Leo C, Pilch H, Vaupel P. Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix. Cancer Res 2004;64(16):5876–81.
   Google Scholar
• Olive PL, Aquino-Parsons C, MacPhail SH, Liao SY, Raleigh JA, Lerman MI, et al. Carbonic anhydrase 9 as an endogenous marker for hypoxic cells in cervical cancer. Cancer Res 2001;61(24):8924–9.
   Google Scholar
• Janssen HL, Haustermans KM, Sprong D, Blommestijn G, Hofland I, Hoebers FJ, et al. HIF-1A, pimonidazole, and iododeoxyuridine to estimate hypoxia and perfusion in human head-and-neck tumors. Int J Radiat Oncol Biol Phys 2002;54(5):1537–49.
   Google Scholar
• Le QT, Sutphin PD, Raychaudhuri S, Yu SC, Terris DJ, Lin HS, et al. Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res 2003;9(1):59–67.
   Google Scholar
• Overgaard J, Eriksen JG, Nordsmark M, Alsner J, 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 2005;6(10):757–64.
   Google Scholar
• Krause BJ, Beck R, Souvatzoglou M, Piert M. PET and PET/CT studies of tumor tissue oxygenation. Q J Nucl Med Mol Imaging 2006;50(1):28–43.
   Google Scholar
• Bucca G, Carruba G, Saetta A, Muti P, Castagnetta L, Smith CP. Gene expression profiling of human cancers. Ann NY Acad Sci 2004;1028:28–37.
   PubMedGoogle Scholar
• Choi P, Chen C. Genetic expression profiles and biologic pathway alterations in head and neck squamous cell carcinoma. Cancer 2005;104(6):1113–28.
   Google Scholar
• Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, et al. Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet 2001;29(4):365–71.
   Google Scholar
• Akervall J. Gene profiling in squamous cell carcinoma of the head and neck. Cancer Metastasis Rev 2005;24(1):87–94.
   Google Scholar
• Chung CH, Parker JS, Karaca G, Wu J, Funkhouser WK, Moore D, et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 2004;5(5):489–500.
   Google Scholar
• Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T, et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA 2005;102(10):3738–43.
   PubMed Web of Science ®Google Scholar
• Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, et al. Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 2006;3(3):e47.
   Google Scholar
• Nuyten DS, Kreike B, Hart AA, Chi JT, Sneddon JB, Wessels LF, et al. Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Breast Cancer Res 2006;8(5):R62.
   Google Scholar
• Francis P, Namlos HM, Muller C, Eden P, Fernebro J, Berner JM, et al. Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential. BMC Genomics 2007;8:73.
   PubMed Web of Science ®Google Scholar
• Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, et al. hsa-miR-210 is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res 2008;14(5):1340–8.
   Google Scholar
• Mandriota SJ, Turner KJ, Davies DR, Murray PG, Morgan NV, Sowter HM, et al. HIF activation identifies early lesions in VHL kidneys.Evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 2002;1:459–68.
   PubMed Web of Science ®Google Scholar
• Rosenberger C, Mandriota S, Jurgensen JS, Wiesener MS, Horstrup JH, Frei U, et al. Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys. J Am Soc Nephrol 2002;13:1721–32.
   PubMed Web of Science ®Google Scholar
• Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li JL, et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 2005;25:5675–86.
   PubMed Web of Science ®Google Scholar
• Esteban MA, Harten SK, Tran MG, Maxwell PH. Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. J Am Soc Nephrol 2006;17:1801–6.
   PubMedGoogle Scholar
• Harten SK, Shukla D, Barod R, Hergovich A, Balda MS, Matter K, et al. Repression of occludin and claudin 1 contributes to tight junction abnormalities in von Hippel-Lindau defective renal cancer cells. Mol Biol Cell 2009;20:1089–101.
   PubMedGoogle Scholar
• Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998;58:1408–16.
   PubMed Web of Science ®Google Scholar
• Sutherland RM, Ausserer WA, Murphy BJ, Laderoute KR. Tumor hypoxia and heterogeneity: challenges and opportunities for the future. Semin Radiat Oncol 1996;6:59–70.
   PubMedGoogle Scholar
• Koch CJ. Oxygen effects in radiobiology. Adv Exp Med Biol 1982;157:123–44.
   PubMedGoogle Scholar
• Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997;38:285–9.
   PubMed Web of Science ®Google Scholar
• Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996;56:4509–15.
   PubMed Web of Science ®Google Scholar
• Nordsmark M, Alsner J, Keller J, Nielsen OS, Jensen OM, Horsman MR, et al. Hypoxia in human soft tissue sarcomas: adverse impact on survival and no association with p53 mutations. Br J Cancer 2001;84:1070–5.
   PubMed Web of Science ®Google Scholar
• Vaupel P, Thews O, Kelleher DK, Hoeckel M. Oxygenation of human tumors: the Mainz experience. Strahlenther Onkol 1998;174 (Suppl 4):6–12.
   Google Scholar
• Magagnin MG, Koritzinsky M, Wouters BG. Patterns of tumor oxygenation and their influence on the cellular hypoxic response and hypoxia-directed therapies. Drug Resist Updat. 2006 Aug–Oct;9(4–5):185–97.
   Google Scholar
• Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KS, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 2006;82:699–757.
   PubMed Web of Science ®Google Scholar
• Bussink J, Kaanders JH, Strik AM, Vojnovic B, van der Kogel AJ. Optical sensor-based oxygen tension measurements correspond with hypoxia marker binding in three human tumor xenograft lines. Radiat Res 2000;154:547–55.
   Google Scholar
• Vaupel P, Schlenger K, Knoop C, Hockel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 1991;51:3316–22.
   PubMed Web of Science ®Google Scholar
• Koch CJ. Measurement of absolute oxygen levels in cells and tissues using oxygen sensors and 2-nitroimidazole EF5. Methods Enzymol 2002;352:3–31.
   PubMed Web of Science ®Google Scholar
• Raleigh JA, Chou SC, Bono EL, Thrall DE, Varia MA. Semiquantitative immunohistochemical analysis for hypoxia in human tumors. Int J Radiat Oncol Biol Phys 2001;49:569–74.
   PubMedGoogle Scholar
• van Baardwijk A, Dooms C, van Suylen RJ, Verbeken E, Hochstenbag M, Dehing-Oberije C, et al. The maximum uptake of (18)F-deoxyglucose on positron emission tomography scan correlates with survival, hypoxia inducible factor-1alpha and GLUT-1 in non-small cell lung cancer. Eur J Cancer 2007;43:1392–8.
   Google Scholar
• Seigneuric R, Starmans MH, Fung G, Krishnapuram B, Nuyten DS, van Erk A, et al. Impact of supervised gene signatures of early hypoxia on patient survival. Radiother Oncol 2007;83:374–82.
   PubMed Web of Science ®Google Scholar
• Chapman JD, Bradley JD, Eary JF, Haubner R, Larson SM, Michalski JM, et al. Molecular (functional) imaging for radiotherapy applications: an RTOG symposium. Int J Radiat Oncol Biol Phys 2003;55:294–301.
   PubMedGoogle Scholar
• Rajendran JG, Mankoff DA. Beyond detection: novel applications for PET imaging to guide cancer therapy. J Nucl Med 2007;48:855–6.
   PubMed Web of Science ®Google Scholar
• Rasey JS, Grunbaum Z, Magee S, Nelson NJ, Olive PL, Durand RE, et al. Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res 1987;111:292–304.
   PubMed Web of Science ®Google Scholar
• Bentzen L, Keiding S, Horsman MR, Gronroos T, Hansen SB, Overgaard J. Assessment of hypoxia in experimental mice tumors by [18F]fluoromisonidazole PET and pO2 electrode measurements. Influence of tumor volume and carbogen breathing. Acta Oncol 2002;41:304–12.
   PubMed Web of Science ®Google Scholar
• Dubois L, Landuyt W, Haustermans K, Dupont P, Bormans G, Vermaelen P, et al. Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer 2004;91:1947–54.
   PubMed Web of Science ®Google Scholar
• Gagel B, Reinartz P, Demirel C, Kaiser HJ, Zimny M, Piroth M, et al. [18F] fluoromisonidazole and [18F] fluorodeoxyglucose positron emission tomography in response evaluation after chemo-/radiotherapy of non-small-cell lung cancer: a feasibility study. BMC Cancer 2006;6:51.
   PubMed Web of Science ®Google Scholar
• Rajendran JG, Schwartz DL, O’Sullivan J, Peterson ML, Ng P, Scharnhorst J, et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res 2006;12:5435–41.
   PubMed Web of Science ®Google Scholar
• Dubois L, Landuyt W, Haustermans K, et al. Evaluation of hypoxia in an experimental rat tumour model by [(18)F]fluoromisonidazole PET and immunohistochemistry. Br J Cancer 2004;91:1947–1954.
   PubMed Web of Science ®Google Scholar
• Troost EG, Bussink J, Kaanders JH, van Eerd J, Peters JP, Rijken PF, et al. Comparison of different methods of CAIX quantification in relation to hypoxia in three human head and neck tumor lines. Radiother Oncol 2005;76:194–9.
   PubMed Web of Science ®Google Scholar
• Rajendran JG, Mankoff DA, O’Sullivan F, Peterson ML, Schwartz DL, Conrad EU, et al. Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res 2004; 10:2245–52.
   PubMed Web of Science ®Google Scholar
• Eschmann SM, Paulsen F, Bedeshem C, Machulla HJ, Hehr T, Bamberg M, et al. Hypoxia-imaging with (18)F-misonidazole and PET: changes of kinetics during radiotherapy of head-and-neck cancer. Radiother Oncol 2007;83:406–10.
   PubMed Web of Science ®Google Scholar
• Lucignani G. PET imaging with hypoxia tracers: a must in radiation therapy. Eur J Nucl Med Mol Imaging 2008;35:838–42.
   Google Scholar
• Thorwarth D, Eschmann SM, Paulsen F, Alber M. A model of reoxygenation dynamics of head-and-neck tumors based on serial 18F-fluoromisonidazole positron emission tomography investigations. Int J Radiat Oncol Biol Phys 2007;68:515–21.
   PubMed Web of Science ®Google Scholar
• Serganova I, Humm J, Ling C, Blasberg R. Tumor hypoxia imaging. Clin Cancer Res 2006;12:5260–4.
   PubMed Web of Science ®Google Scholar
• Dubois L, Landuyt W, Cloetens L, Bol A, Bormans G, Haustermans K, et al. [(18)F]EF3 is not superior to [(18)F]FMISO for PET-based hypoxia evaluation as measured in a rat rhabdomyosarcoma tumour model. Eur J Nucl Med Mol Imaging 2009;36:209–18.
   PubMed Web of Science ®Google Scholar
• Graham MA, Senan S, Robin H Jr, Eckhardt M, Lendrem D, Hincks J, et al. Pharmacokinetics of the hypoxic cell cytotoxic agent tirapazamine and its major bioreductive metabolites in mice and humans: retrospective analysis of a pharmacokinetically guided dose-escalation strategy in a phase I trial. Cancer Chemother Pharmacol 1997;40:1–10.
   PubMed Web of Science ®Google Scholar
• Davda S, Bezabeh T. Advances in methods for assessing tumor hypoxia in vivo: implications for treatment planning. Cancer Metastasis Rev 2006;25:469–80.
   PubMed Web of Science ®Google Scholar
• Pastorekova S, Parkkila S, Zavada J. Tumor-associated carbonic anhydrases and their clinical significance. Adv Clin Chem 2006;42:167–216.
   PubMed Web of Science ®Google Scholar
• Svastova E, Zilka N, Zat’ovicova M, Gibadulinova A, Ciampor F, Pastorek J, et al. Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. Exp Cell Res 2003;290:332–45.
   PubMed Web of Science ®Google Scholar
• Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 2008;7:168–81.
   PubMed Web of Science ®Google Scholar
• Supuran CT. Development of small molecule carbonic anhydrase IX inhibitors. BJU Int. 2008 Jun;101 Suppl 4:39–40.
   Google Scholar
• Cecchi A, Hulikova A, Pastorek J, Pastorekova S, Scozzafava A, Winum JY, et al. Carbonic anhydrase inhibitors. Design of fluorescent sulfonamides as probes of tumor-associated carbonic anhydrase IX that inhibit isozyme IX-mediated acidification of hypoxic tumors. J Med Chem 2005;48:4834–41.
   PubMed Web of Science ®Google Scholar
• Chrastina A, Zavada J, Parkkila S, Kaluz S, Kaluzova M, Rajcani J, et al. Biodistribution and pharmacokinetics of 125I-labeled monoclonal antibody M75 specific for carbonic anhydrase IX, an intrinsic marker of hypoxia, in nude mice xenografted with human colorectal carcinoma. Int J Cancer 2003;105:873–81.
   PubMed Web of Science ®Google Scholar
• Divgi CR, Pandit-Taskar N, Jungbluth AA, Reuter VE, Gonen M, Ruan S, et al. Preoperative characterisation of clear-cell renal carcinoma using iodine-124-labelled antibody chimeric G250 (124I-cG250) and PET in patients with renal masses: a phase I trial. Lancet Oncol 2007;8:304–10.
   PubMed Web of Science ®Google Scholar
• Lin AJ, Cosby LA, Shansky CW, Sartorelli AC. Potential bioreductive alkylating agents. 1.Benzoquinone derivatives. J Med Chem 1973;15:1247–52.
   Google Scholar
• Kennedy KA, Teicher BA, Rockwell S, Sartorelli AC. The hypoxic tumor cell: a target for selective cancer chemotherapy. Biochem Pharmacol 1980;29:1–8.
   PubMed Web of Science ®Google Scholar
• Rockwell S. Effect of some proliferative and environmental factors on the toxicity of mitomycin C to tumor cells in vitro. Int J Cancer 1986;38:229–35.
   Google Scholar
• Stratford IJ, Adams GE, Godden J, Howells N. Induction of tumor hypoxia post-irradiation: a method for increasing the sensitizing efficiency of misonidazole and RSU 1069 in vivo. Int J Radiat Biol 1989;55:411–22.
   PubMed Web of Science ®Google Scholar
• Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV, Ross D, et al. NAD(P)H:quinine oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Res 1992;52:797–802.
   PubMed Web of Science ®Google Scholar
• Gan Y, Mo Y, Kalns JE, Lu J, Danenberg K, Danenberg P, et al. Expression of DT-diaphorase and cytochrome P450 reductase correlates with mitomycin C activity in human bladder tumors. Clin Cancer Res 2001;7:1313–19.
   PubMed Web of Science ®Google Scholar
• Cowen RL, Patterson AV, Telfer BA, Airley RE, Hobbs S, Phillips RM, et al. Viral delivery of P450 reductase recapitulates the ability of constitutive overexpression of reductase enzymes to potentiate the activity of mitomycin C in human breast cancer xenografts. Mol Cancer Ther 2003;2:901–9.
   Google Scholar
• Fracasso PM, Sartorelli AC. Cytotoxicity and DNA lesions produced by mitomycin C and porfiromycin in hypoxic and aerobic EMT6 and Chinese hamster ovary cells. Cancer Res 1986;46:3939–44.
   PubMed Web of Science ®Google Scholar
• Keyes SR, Rockwell S, Sartorelli AC. Correlation between drug uptake and selective toxicity of porfiromycin to hypoxic EMT6 cells. Cancer Res 1987;47:5654–7.
   Google Scholar
• Rockwell S, Keyes SR, Sartorelli AC. Preclinical studies of porfiromycin as an adjunct to radiotherapy. Radiat Res 1988;116:100–13.
   Google Scholar
• Haffty BG, Wilson LD, Son YH, Cho EI, Papac RJ, Fischer DB, et al. Concurrent chemoradiotherapy with mitomycin C compared with porfiromycin in squamous cell cancer of the head and neck: final results of a randomized clinical trial. Int J Radiat Oncol Biol Phys 2005;61:119–28.
   PubMedGoogle Scholar
• Walton MI, Smith PJ, Workman P. The role of NAD(P)H: quinone reductase (EC1.6.99.2, DT-diaphorase) in the reductive bioactivation of the novel indoloquinone antitumor agent EO9. Cancer Commun 1991;3:199–206.
   PubMed Web of Science ®Google Scholar
• Robertson N, Haigh A, Adams GE, Stratford IJ. Factors affecting sensitivity to EO9 in rodent and human tumor cells in vitro: DT-diaphorase activity and hypoxia. Eur J Cancer 1994;30A:1013–19.
   PubMed Web of Science ®Google Scholar
• Saunders MP, Jaffar M, Patterson AV, Nolan J, Naylor MA, Phillips RM, et al. The relative importance of NADPH: cytochrome c (P450) reductase for determining the sensitivity of human tumor cells to the indolequinone EO9 and related analogues lacking functionality at the C-2 and C-3 positions. Biochem Pharmacol 2000;59:993–6.
   PubMed Web of Science ®Google Scholar
• Loadman PM, Bibby MC, Phillips RM. Pharmacological approach towards the development of indolequinone bioreductive drugs based on the clinically inactive agent EO9. Br J Pharmacol 2002;137:701–9.
   PubMed Web of Science ®Google Scholar
• Puri R, Palit V, Loadman PM, Flannigan M, Shah T, Choudry GA, et al. Phase I/II pilot study of intravesical apaziquone (EO9) for superficial bladder cancer. J Urol 2006;176:1344–8.
   PubMed Web of Science ®Google Scholar
• Hendricksen K, Gleason D, Young JM, Saltzstein D, Gershman A, Lerner S, et al. Safety and side effects of immediate instillation of apaziquone following transurethral resection in patients with nonmuscle invasive bladder cancer. J Urol 2008;180:116–20.
   PubMed Web of Science ®Google Scholar
• Stratford IJ, O’Neill P, Sheldon PW, Silver AR, Walling JM, Adams GE. RSU 1069, a nitroimidazole containing an aziridine group.Bioreduction greatly increases cytotoxicity under hypoxic conditions. Biochem Pharmacol 1986;35:105–9.
   PubMed Web of Science ®Google Scholar
• Stratford IJ, Stephens MA. The differential hypoxic cytotoxicity of bioreductive agents determined in vitro by the MTT assay. Int J Radiat Oncol Biol Phys 1989;16:973–6.
   PubMedGoogle Scholar
• Stratford IJ, Williams KJ, Cowen RL, Jaffar M. Combining bioreductive drugs and radiation for the treatment of solid tumors. Semin Radiat Oncol 2003;13:42–52.
   Google Scholar
• Patterson AV, Saunders MP, Chinje EC, Talbot DC, Harris AL, Strafford IJ. Overexpression of human NADPH:cytochrome c (P450) reductase confers enhanced sensitivity to both tirapazamine (SR 4233) and RSU 1069. Br J Cancer 1997;76:1338–47.
   PubMed Web of Science ®Google Scholar
• Patterson AV, Williams KJ, Cowen RL, Jaffar M, Telfer BA, Saunders M, et al. Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiationresistant solid tumors. Gene Ther 2002;9:946–54.
   PubMed Web of Science ®Google Scholar
• Horwich A, Holliday SB, Deacon JM, Peckham MJ. A toxicity and pharmacokinetic study in man of the hypoxic-cell radiosensitiser RSU-1069. Br J Radiol 1986;59:1238–40.
   PubMedGoogle Scholar
• Bremner JC. Assessing the bioreductive effectiveness of the nitroimidazole RSU1069 and its prodrug RB6145: with particular reference to in vivo methods of evaluation. Cancer Metastasis Rev 1993;12:177–93.
   PubMedGoogle Scholar
• Breider MA, Pilcher GD, Graziano MJ, Gough AW. Retinal degeneration in rats induced by Cl-1010, a 2-nitroimidazole radiosensitizer. Toxicol Pathol 1998;26:234–9.
   PubMed Web of Science ®Google Scholar
• Brown JM. Tumor microenvironment and the response to anticancer therapy. Cancer Biol Ther 2002;1:453–8.
   PubMed Web of Science ®Google Scholar
• Lunt SJ, Telfer BA, Fitzmaurice RJ, Stratford IJ, Williams KJ. Selective killing of hypoxic cells in primary tumors using tirapazamine reduces metastatic dissemination. Clin Cancer Res 2005;11:4212–16.
   PubMed Web of Science ®Google Scholar
• Cowen RL, Williams KJ, Chinje EC, Jaffar M, Sheppard FC, Telfer BA, et al. Hypoxia targeted gene therapy to increase the efficacy of tirapazamine as an adjuvant to radiotherapy: reversing tumor radioresistance and effecting cure. Cancer Res 2004;64:1396–402.
   PubMed Web of Science ®Google Scholar
• McKeown SR, Cowen RL, Williams KJ. Bioreductive drugs: from concept to clinic. Clin Oncol 2007;19:427–42.
   PubMed Web of Science ®Google Scholar
• Raleigh SM, Wanogho E, Burke MD, Patterson LH. Rat cytochromes P450 (CYP) specifically contribute to the reductive bioactivation of AQ4N, an alkylaminoanthraquinone-di-N-oxide anticancer prodrug. Xenobiotica. 1999 Nov;29(11):1115–22.
   Google Scholar
• Fitzpatrick B, Mehibel M, Cowen RL, Stratford IJ. iNOS as a therapeutic target for treatment of human tumors. Nitric Oxide 2008;19:217–24.
   PubMed Web of Science ®Google Scholar
• Nishida CR, Ortiz de Montellano PR. Reductive heme-dependent activation of the n-oxide prodrug AQ4N by nitric oxide synthase. J Med Chem 2008;5:5118–20.
   Google Scholar
• McKeown SR, Hejmadi MV, McIntyre IA, McAleer JJ, Patterson LH. AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer 1995;72:76–81.
   PubMed Web of Science ®Google Scholar
• McKeown SR, Friery OP, McIntyre IA, Hejmadi MV, Patterson LH, Hirst DG. Evidence for a therapeutic gain when AQ4N or tirapazamine is combined with radiation. Br J Cancer 1996;74:S39–42.
   Google Scholar
• Patterson LH, McKeown SR, Ruparelia K, Double JA, Bibby MC, Cole S, et al. Enhancement of chemotherapy and radiotherapy of murine tumors by AQ4N, a bioreductively activated anti-tumor agent. Br J Cancer 2000;82:1984–90.
   PubMed Web of Science ®Google Scholar
• Friery OP, Gallagher R, Murray MM, Hughes CM, Galligan ES, McIntyre IA, et al. Enhancement of the anti-tumor effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br J Cancer 2000;82:1469–73.
   PubMed Web of Science ®Google Scholar
• Gallagher R, Hughes CM, Murray MM, Friery OP, Patterson LH, Hirst DG, et al. The chemopotentiation of cisplatin by the novel bioreductive drug AQ4N. Br J Cancer 2001;85:625–9.
   PubMed Web of Science ®Google Scholar
• Albertella MR, Loadman PM, Jones PH, Phillips RM, Rampling R, Burnet M, et al. Hypoxia-selective targeting by the bioreductive prodrug AQ4N in patients with solid tumors: results of a phase I study. Clin Cancer Res 2008;14:1096–104.
   PubMed Web of Science ®Google Scholar
• Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group study 98.02. J Clin Oncol 2006;24:2098–104.
   PubMed Web of Science ®Google Scholar
• Papadopoulou MV, Bloomer WD. NLCQ-1 (NSC 709257): exploiting hypoxia with a weak DNA-intercalating bioreductive drug. Clin Cancer Res 2003;9:5714–20.
   PubMedGoogle Scholar
• Papadopoulou MV, Ji M, Rao MK, Bloomer WD. Reductive metabolism of the nitroimidazole-based hypoxia-selective cytotoxin NLCQ-1 (NSC 709257). Oncol Res 2003;14:21–9.
   PubMed Web of Science ®Google Scholar
• Papadopoulou MV, Ji M, Bloomer WD. Schedule-dependent potentiation of chemotherapeutic drugs by the bioreductive compounds NLCQ-1 and tirapazamine against EMT6 tumors in mice. Cancer Chemother Pharmacol 2001;48:160–8.
   Google Scholar
• Papadopoulou MV, Ji M, Rao MK, Bloomer WD. 4-[3-(2-Nitro-1- imidazolyl)propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a novel bioreductive agent as radiosensitizer in vitro and in vivo: comparison with tirapazamine. Oncol Res 2001;12:325–33.
   Google Scholar
• Papadopoulou MV, Ji M, Bloomer WD. Synergistic enhancement of the antitumor effect of taxol by the bioreductive compound NLCQ-1, in vivo: comparison with tirapazamine. Oncol Res 2002;13:47–54.
   Google Scholar
• Papadopoulou MV, Ji M, Ji X, Bloomer WD. Therapeutic advantage from combining 5-fluorouracil with the hypoxia-selective cytotoxin NLCQ-1 in vivo; comparison with tirapazamine. Cancer Chemother Pharmacol 2002;50: 291–8.
   Google Scholar
• Papadopoulou MV, Ji X, Bloomer WD. Potentiation of alkylating agents by NLCQ-1 or TPZ in vitro and in vivo. J Exp Ther Oncol 2006;5:261–72.
   Google Scholar
• Wilson WR, Pullen SM, Degenkolbe A, Ferry DM, Helsby NA, Hicks KO, Atwell GJ, Yang S, Denny WA, Patterson AV. Water-soluble dinitrobenzamide mustard phosphate pre-prodrugs as hypoxic cytotoxins. Eur J Cancer. 2004;Suppl. 2(8):151.
   Google Scholar
• Patterson AV, Ferry DM, Edmunds SJ, Gu Y, Singleton RS, Patel K, et al. Mechanism of action and preclinical antitumor activity of the novel hypoxia-activated DNA cross-linking agent PR-104. Clin Cancer Res 2007;13:3922–32.
   PubMed Web of Science ®Google Scholar
• Danson S, Johnson P, Ward T, Dawson M, Denneny O, Watson A. et al. Final results of a phase I clinical trial of the bioreductive drug RH1. J Clin Oncol 2007;25(18S):2514.
   Google Scholar
• Yan C, Kepa JK, Siegel D, Stratford IJ, Ross D. Dissecting the role of multiple reductases in bioactivation and cytotoxicity of the antitumor agent 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1). Mol Pharmacol. 2008 Dec;74(6):1657–65. Epub 2008 Sep 15.
   Google Scholar
• Loadman PM, Phillips RM, Lim LE, Bibby MC. Pharmacological properties of a new aziridinylbenzoquinone, RH1 (2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone), in mice. Biochem Pharmacol 2000;59:831–7.
   PubMed Web of Science ®Google Scholar
• Supuran CT, Scozzafava A, Casini A. Carbonic anhydrase inhibitors. Med Res Rev 2003;23:146–89.
   PubMed Web of Science ®Google Scholar
• Pastorekova S, Pastorek, J. Cancer-related carbonic anhydrase isozymes. In: Supuran CT, Scozzafava A, Conway J, eds. Carbonic Anhydrase—Its Inhibitors and Activators. Boca Raton, FL: CRC Press, 2004: 253–80.
   Google Scholar
• Hilvo M, Monti SM, De Simone G, Supuran CT, Parkkila S. Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 2008;283:27799–809.
   PubMed Web of Science ®Google Scholar
• Winum JY, Rami M, Scozzafava A, Montero JL, Supuran C. Carbonic anhydrase IX: a new druggable target for the design of antitumor agents. Med Res Rev 2008;28:445–63.
   PubMed Web of Science ®Google Scholar
• Thiry A, Supuran CT, Masereel B, Dogné JM. Recent developments of carbonic anhydrase inhibitors as potential anticancer drugs. J Med Chem 2008;51:3051–6.
   PubMed Web of Science ®Google Scholar
• Cecchi A, Supuran CT. Fluorescence- and spin-labeled carbonic anhydrase inhibitors. Curr Pharm Des 2008;14:699–707.
   PubMed Web of Science ®Google Scholar
• Pastorekova S, Parkkila S, Pastorek J, Supuran CT. Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J Enzyme Inhib Med Chem 2004;19:199–229.
   PubMed Web of Science ®Google Scholar
• Menchise V, De Simone G, Alterio V, Di Fiore A, Pedone C, Scozzafava A, et al. Carbonic anhydrase inhibitors: stacking with Phe131 determines active site binding region of inhibitors as exemplified by the X-ray crystal structure of a membrane-impermeant antitumor sulfonamide complexed with isozyme II. J Med Chem 2005;48:5721–7.
   PubMed Web of Science ®Google Scholar
• Alterio V, Vitale RM, Monti SM, Pedone C, Scozzafava A, Cecchi A, et al. Carbonic anhydrase inhibitors: X-ray and molecular modeling study for the interaction of a fluorescent antitumor sulfonamide with isozyme II and IX. J Am Chem Soc 2006;128:8329–35.
   PubMed Web of Science ®Google Scholar
• Abbate F, Casini A, Owa T, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors: E7070, a sulfonamide anticancer agent, potently inhibits cytosolic isozymes I and II, and transmembrane, tumor-associated isozyme IX. Bioorg Med Chem Lett 2004;14:217–23.
   PubMed Web of Science ®Google Scholar
• Garaj V, Pucetti L, Fasolis G, Winum J-Y, Montero J-L, Scozzafava A, et al. Carbonic anhydrase inhibitors: synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating 1,2,4-triazine moieties. Bioorg Med Chem Lett 2004;14:5427–33.
   PubMed Web of Science ®Google Scholar
• De Simone G, Vitale RM, Di Fiore A, Pedone C, Scozzafava A, Montero JL, et al. Carbonic anhydrase inhibitors: hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX. J Med Chem 2006;49:5544–51.
   Google Scholar
• Robertson N, Potter C, Harris AL. Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res 2004;64:6160–5.
   PubMed Web of Science ®Google Scholar
• Oosterwijk E. Carbonic anhydrase IX: historical and future perspectives. BJU Int 2008;101(Suppl 4):2–7.
   Google Scholar
• Lam JS, Pantuck AJ, Belldegrun AS, Figlin RA. G250: a carbonic anhydrase IX monoclonal antibody. Curr Oncol Rep 2005;7:109–15.
   PubMedGoogle Scholar
• Görlach A, Kietzmann T. Superoxide and derived reactive oxygen species in the regulation of hypoxia-inducible factors. Methods in Enzymology. 2007;435:421–46.
   PubMed Web of Science ®Google Scholar
• Kietzmann T, Görlach A. Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression, Semin Cell Dev Biol. 2005;16:474–86.
   Google Scholar
• Toffoli S, Michiels C. <http://www.ncbi.nlm.nih.gov/pubmed/18445039?ordinalpos=10&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours. FEBS J. 2008;275:2991–3002.
   PubMed Web of Science ®Google Scholar
• Dewhirst MW, Cao Y, Moeller B. <http://www.ncbi.nlm.nih.gov/pubmed/18500244?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer. 2008;8:425–37.
   PubMed Web of Science ®Google Scholar
• Nanduri J, Yuan G, Kumar GK, Semenza GL, Prabhakar NR. <http://www.ncbi.nlm.nih.gov/pubmed/18692603?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Transcriptional responses to intermittent hypoxia. Respir Physiol Neurobiol. 2008 164:277–81.
   PubMedGoogle Scholar
• Dewhirst MW. <http://www.ncbi.nlm.nih.gov/pubmed/17283112?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res. 2007;67:854–5.
   PubMed Web of Science ®Google Scholar
• Martínez-Sánchez G, Giuliani A. <http://www.ncbi.nlm.nih.gov/pubmed/17550131?ordinalpos=39&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Cellular redox status regulates hypoxia inducible factor-1 activity. Role in tumour development. J Exp Clin Cancer Res. 2007;26:39–50.
   PubMed Web of Science ®Google Scholar
• Bell EL, Chandel NS. <http://www.ncbi.nlm.nih.gov/pubmed/17705790?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Mitochondrial oxygen sensing: regulation of hypoxia-inducible factor by mitochondrial generated reactive oxygen species. Essays Biochem. 2007;43:17–27.
   PubMed Web of Science ®Google Scholar
• Cash TP, Pan Y, Simon MC. <http://www.ncbi.nlm.nih.gov/pubmed/17893032?ordinalpos=23&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Reactive oxygen species and cellular oxygen sensing. Free Radic Biol Med. 2007;43:1219–25.
   PubMed Web of Science ®Google Scholar
• Guzy RD, Schumacker PT. <http://www.ncbi.nlm.nih.gov/pubmed/16857720?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol. 2006;91:807–19.
   PubMed Web of Science ®Google Scholar
• Wang J, Yi J. <http://www.ncbi.nlm.nih.gov/pubmed/18981733?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Cancer cell killing via ROS: To increase or decrease, that is a question. Cancer Biol Ther. 2008;7:1875–84.
   PubMed Web of Science ®Google Scholar
• Matsumoto K, Subramanian S, Murugesan R, Mitchell JB, Krishna MC. <http://www.ncbi.nlm.nih.gov/pubmed/17571957?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum> Spatially resolved biologic information from in vivo EPRI, OMRI, and MRI. Antioxid Redox Signal. 2007;9:1125–41.
   PubMed Web of Science ®Google Scholar