Abstract
The first pathologists, oncologists, and medical physicists were aware that tumors were populated by an aberrant vasculature. The classic observations of Thomlinson and Gray in the 1950’s established that O2 diffusion distances caused tumor to grow in cords. Tumor necrosis was observed surrounding a Krogh cylinder of viable tumor. That work helped explain earlier work by Warburg, who demonstrated a predisposition for tumors to favor anaerobic respiration, and it became the basis for 5 decades of subsequent research aimed at improving tumor oxygenation at the time of radiation. The role of O2 in modifying radiation response was attributed exclusively to the reactive free radicals that can be formed when O2 is present. These radicals produce approximately three-fold more irreparable double strand breaks in DNA.
Subsequently it became clear that tumor had nutritional insufficiencies in addition to hypoxia. Ischemic regions are hypoglycemic, acidotic, have poor penetration of drugs, increased interstitial pressure, and altered immunological states. Ischemic regions can have intermittent reflow and associated redox stress. The relative impact of O2 compared to these associated phenomenon, and the degree to which hypoxia causes or follows these associated physiologic stresses, have been studied in detail. ISOTT scientists are responsible for much of the elucidation of the specific effects of O2, ADP/ATP ratios, hypoglycemia, and acidosis on tumor responses to radiation and hyperthermia. Many questions still remain.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
R. H. Thomlinson, Changes of oxygenation in tumors in relation to irradiation, Front. Radiat. Ther. Oncol. 3, 109–112 (1968).
K. Groebe, and P. Vaupel, Evaluation of oxygen diffusion distances in human breast cancer xenografts using tumor-specific in vivo data: Role of various mechanisms in the development of tumor hypoxia, Int. J. Radiat. Oncol. Biol. Phys. 15(3), 691–697 (1988).
O. Warburg, Uber den Stoffwechsel der Carcinomzellen, Klin. Wschr. 4, 534–536 (1925).
J. P. Freyer, K. Jarrett, S. Carpenter, and M. R. Raju, Oxygen enhancement ratio as a function of dose and cell cycle phase for radiation-resistant and sensitive CHO cells, Radiat. Res. 127, 297–307 (1991).
E. K. Rofstad, P. DeMuth, B. M. Fenton, and R. M. Sutherland, 31P nuclear magnetic resonance spectroscopy studies of tumor energy metabolism and its relationship to intracapillary oxyhemoglobin saturation status and tumor hypoxia, Cancer Res. 48, 5440–5446 (1988).
P. Vaupel, C. Schaefer, and P. Okunieff, Intracellular acidosis in murine fibrosarcomas coincides with ATP depletion, hypoxia, and high levels of lactate and total Pi, NMR Biomed. 7, 128–136 (1994).
P. Vaupel, H. P. Fortmeyer, S. Runkel, and F. Kallinowski, Blood flow, oxygen consumption, and tissue oxygenation of human breast cancer xenografts in nude rats, Cancer Res. 47, 3496–3503 (1987).
P. Vaupel, F. Kallinowski, and P. Okunieff, Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review, Cancer Res. 49, 6449–6465 (1989).
B. A. Teicher, Hypoxia and drug resistance, Cancer Metastasis Rev. 13(2), 139–168 (1994).
I. Lee, Y. Boucher, T. J. Demhartner, and R. K. Jain, Changes in tumour blood flow, oxygenation and interstitial fluid pressure induced by pentoxifylline, Br. J. Cancer 69, 492–496 (1994).
J. Biaglow, M. Dewirst, D. Leeper, R. Burd, and S. Tuttle, Factors controlling oxygen utilization, Adv. Exp. Med. Biol. 317–324 (2005).
P. Vaupel, A. Mayer, S. Briest, and M. Höckel, Hypoxia in breast cancer: role of blood flow, oxygen diffusion distances, and anemia in the development of oxygen depletion, Adv. Exp. Med. Biol. 333–342 (2005).
P. Vaupel, P. Okunieff, and L. J. Neuringer, Blood flow, tissue oxygenation, pH distribution, and energy metabolism of murine mammary adenocarcinomas during growth, Adv. Exp. Med. Biol. 248, 835–846 (1989).
P. Vaupel, K. Schlenger, and M. Höckel, Blood flow and tissue oxygenation of human tumors: an update, Adv. Exp. Med. Biol. 317, 139–152 (1992).
M. Tamura, O. Hazeki, S. Nioka, B. Chance, and D. S. Smith, The simultaneous measurements of tissue oxygen concentration and energy state by near-infrared and nuclear magnetic resonance spectroscopy, Adv. Exp. Med. Biol. 222, 359–363 (1988).
K. Erickson, R. D. Braun, D. Yu, J. Lanzen, D. Wilson, D. M. Brizel, T. W. Secomb, J. E. Biaglow, and M. W. Dewhirst, Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation, Cancer Res. 63(15), 4705–4712 (2003).
S. Nioka, D. S. Smith, B. Chance, H. V. Subramanian, S. Butler, and M. Katzenberg, Oxidative phosphorylation system during steady-state hypoxia in the dog brain, J. Appl. Physiol. 68(6), 2527–2535 (1990).
J. T. Erler, C. J. Cawthorne, K. J. Williams, M. Koritzinsky, B. G. Wouters, C. Wilson, C. Miller, C. Demonacos, I. J. Stratford, and C. Dive, Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor l-dependent and-independent mechanisms and contributes to drug resistance, Mol. Cell. Biol. 24(7), 2875–2889 (2004).
B. Chance, S. Nioka, W. Warren, and G. Yurtsever, Mitochondrial NADH as the bellwether of tissue O2 delivery, Adv. Exp. Med. Biol. 17–22 (2005).
P. Okunieff, E. P. Dunphy, M. Höckel, D. J. Terris, and P. Vaupel, The role of oxygen tension distribution on the radiation response of human breast carcinoma, Adv. Exp. Med. Biol. 345, 485–492 (1994).
P. Okunieff, M. Höckel, E. P. Dunphy, K. Schlenger, C. Knoop, and P. Vaupel, Oxygen tension distributors are sufficient to explain the local response of human breast tumors treated with radiation alone, Int. J. Radial. Oncol. Biol. Phys. 26, 631–636 (1993).
S. Istrail, G. G. Sutton, L. Florea, A. L. Halpern, C. M. Mobarry, R. Lippert, et al., Whole-genome shotgun assembly and comparison of human genome assemblies, Proc. Natl. Acad. Sci. USA, 101(7), 1916–1921 (2004).
J. C. Venter, M. D. Adams, E. W. Myers, P. W. Li, R. J. Mural, G. G. Sutton, et al., The sequence of the human genome, Science 291(5507), 1304–1351 (2001).
G. Taucher-Scholz, J. A. Stanton, M. Schneider, and G. Kraft, Induction of DNA breaks in SV40 by heavy ions, Adv. Space Res. 12(2–3), 73–80 (1992).
J. T. Hwang, M. M. Greenberg, T. Fuchs, and K. S. Gates, Reaction of the hypoxia-selective antitumor agent tirapazamine with a Cl’-radical in single-stranded and double-stranded DNA: the drug and its metabolites can serve as surrogates for molecular oxygen in radical-mediated DNA damage reactions, Biochemistry 38(43), 14248–14255 (1999).
H. Cangul, Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers, BMC Genet. 5(1), 27 (2004).
H. Swartz, and J. Dunn, The difficulties in comparing in vivo oxygen measurements: turning the problems into virtues! Adv. Exp. Med. Biol. 295–302 (2005).
D. M. Brizel, G. S. Sibley, L. R. Prosnitz, R. L. Scher, and M. W. Dewhirst, Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck, Int. J. Radial. Oncol. Biol. Phys. 38, 285–289 (1997).
P. Okunieff, J. de Bie, E. P. Dunphy, D. J. Terris, and M. Höckel, Oxygen distributions partly explain the radiation response of human squamous cell carcinomas, Br. J. Cancer 27, S185–S190 (1996).
R. Rampling, G. Cruickshank, A. Lewis, S. A. Fitzsimmons, and P. Workman, Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors, Int. J. Radiat. Oncol. Biol. Phys. 29, 427–431 (1994).
D. M. Brizel, S. P. Scully, J. M. Harrelson, L. J. Layfield, J. M. Bean, L. R. Prosnitz, and M. W. Dewhirst, Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma, Cancer Res. 56, 941–943 (1996).
D. M. Brizel, G. L. Rosner, L. R. Prosnitz, and M. W. Dewhirst, Patterns of variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases, Int. J. Radiat. Oncol. Biol. Phys. 32, 1121–11251 (1995).
M. Höckel, K. Schlenger, B. Aral, M. Mitze, U. Shaffer, and P. Vaupel, Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix, Cancer Res. 56 4509–4515 (1996).
M. Höckel, C. Knoop, B. Vorndran, E. Baussmann, M. Mitze, P. G. Knapstein, and P. Vaupel, Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix, Radiother. Oncol. 26, 45–50 (1993).
P. Okunieff, I. Ding, P. Vaupel, and M. Höckel, Evidence for and against hypoxia as the primary cause of tumor aggressiveness, Adv. Exp. Med. Biol. 510, 69–75 (2003).
B. M. Seddon, D. J. Honess, B. Vojnovic, G. M. Tozer, and P. Workman, Measurement of tumor oxygenation: in vivo comparison of a luminescence fiber-optic sensor and a polarographic electrode in the p22 tumor, Radiat. Res. 155(6), 837–846 (2001).
G. Ilangovan, A. Bratasz, and P. Kuppusamy, Non-invasive measurement of tumor oxygenation using embedded microparticulate EPR spin probe, Adv. Exp. Med. Biol. 67–74 (2005).
Y. S. Sakata, O. Y. Grinberg, S. Grinberg, R. Springett, and H. M. Swartz, Simultaneous NIR-EPR spectroscopy of rat brain oxygenation, Adv. Exp. Med. Biol. 357–362 (2005).
N. Khan, H. Hou, P. Hein, R. J. Comi, J. C. Buckey, O. Grinberg, I. Salikhov, S. Y. Lu, H. Wallach, and H. M. Swartz, Black magic and EPR oximetry: from lab to clinical trials, Adv. Exp. Med. Biol. 119–126 (2005).
H. Hou, O. Y. Grinberg, S. A. Grinberg, N. Khan, J. F. Dunn, and H. M. Swartz, Cerebral PtO2 acute hypoxia, and volatile anesthetics in the rat brain, Adv. Exp. Med. Biol. 179–186 (2005).
R. D. Shonat, and A. S. Norige, Developing strategies for three-dimensional imaging of oxygen tension in the rodent retina, Adv. Exp. Med. Biol. 173–178 (2005).
G. Schears, J. Creed, T. Zaitseva, S. Schultz, D. F. Wilson, and A. Pastuszko, Cerebral oxygenation during repetitive apnea in newborn piglets, Adv. Exp. Med. Biol. 1–8 (2005).
E. Takahashi, T. Takano, A. Numata, N. Hayashi, S. Okano, O. Nakajima, Y. Nomura, and M. Sato, Genetic oxygen sensor: GFP as an indicator of intracellular oxygenation, Adv. Exp. Med. Biol. 39–44 (2005).
Y. Song, K. L. Worden, X. Jiang, D. Zhao, A. Constantinescu, H. Liu, and R. P. Mason, Tumor oxygen dynamics: comparison of 19F MR EPI and frequency domain NIR spectroscopy, Adv. Exp. Med. Biol. 530, 225–236 (2003).
L. Bentzen, S. Keiding, M. Nordsmark, L. Falborg, S. B. Hansen, J. Keller, O. S. Nielsen, and J. Overgaard, Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours, Radiother. Oncol. 67(3), 339–344 (2003).
J. S. Rasey, W. J. Koh, M. L. Evans, L. M. Peterson, T. K. Lewellen, M. M. Graham, and K. A. Krohn, Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients, Int. J. Radiat. Oncol. Biol. Phys. 36(2), 417–428 (1996).
P. Okunieff, T. Tokuhiro, P. Vaupel, and L. J. Neuringer, Interaction of oxygen partial pressure and energy metabolism with the relaxation rate of inorganic phosphate: a 31P NMR study, Adv. Exp. Med. Biol. 277, 95–105 (1990).
F. Kallinowski, K. H. Schlenger, S. Runkel, M. Kloes, M. Stohrer, P. Okunieff, and P. Vaupel, Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts, Cancer Res. 49(14), 3759–3764 (1989).
P. B. Benni, B. Chen, F. D. Dykes, S. F. Wagoner, M. Heard, A. J. Tanner, T. L. Young, K. Rais-Bahrami, O. Rivera, and B. Short, Validation of the CAS neonatal NIRS system by monitoring VV-EMCO patients, Adv. Exp. Med. Biol. 195–202 (2005).
C. E. Elwell, J. R. Henty, T. S. Leung, T. Austin, J. H. Meek, D. T. Delphy, and J. S. Wyatt, Measurement of CMRO2 in neonates undergoing intensive care using near infrared spectroscopy, Adv. Exp. Med. Biol. 263–268 (2005).
F. A. Howe, J. P. Connelly, S. P. Robinson, R. Springett, and J. R. Griffiths, The effects of tumor blood flow and oxygenation modifiers on subcutaneous tumours as determined by NIRS, Adv. Exp. Med. Biol. 75–82 (2005).
K. von Siebenthal, M. Keel, J.-C. Fauchère, V. Dietz, D. Haensse, U. Wolf, U. Helfenstein, O. Bänziger, H. U. Bucher, and M. Wolf, Variability of cerebral hemoglobin concentration in very preterm infants during the first 6 hours of life, Adv. Exp. Med. Biol. 91–98 (2005).
M. Urano, Y. Chen, J. Humm, J. A. Koutcher, P. Zanzonico, and C. Ling, Measurements of tumor tissue oxygen tension using a time-resolved luminescence-based optical oxylite probe: comparison with a paired survival assay, Radiat. Res. 158(2), 167–173 (2002).
T. Jarm, G. Sersa, and D. Miklavcic, Oxygenation and blood flow in tumors treated with hydralazine: evaluation with a novel luminescence-based fiber-optic sensor, Technol. Health Care 10(5), 363–380 (2002).
B. M. Fenton, S. F. Paoni, B. Grimwood, and I. Ding, Varied response of spontaneous tumors to antiangiogenic agents, Adv. Exp. Med. Biol. 59–66 (2005)
I. Ding, P. Okunieff, K. Salnikow, W. Liu, and B. Fenton, A new intrinsic hypoxia marker in esophageal cancer, Adv. Exp. Med. Biol. 540, 227–233 (2003).
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer Science+Business Media, Inc.
About this paper
Cite this paper
Okunieff, P., Fenton, B., Chen, Y. (2005). Past, Present, and Future of Oxygen in Cancer Research. In: Okunieff, P., Williams, J., Chen, Y. (eds) Oxygen Transport to Tissue XXVI. Advances in Experimental Medicine and Biology, vol 566. Springer, Boston, MA. https://doi.org/10.1007/0-387-26206-7_29
Download citation
DOI: https://doi.org/10.1007/0-387-26206-7_29
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-387-25062-5
Online ISBN: 978-0-387-26206-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)