Oxygenation of Solid Tumors in Animals and Patients

  • Eric Lartigau
  • Marcelle Guichard
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The biological effectiveness of low energy transfer (LET) ionizing radiation is in part related to the amount of oxygen present at the time of the energy deposit. This dose modifying role of oxygen (oxygen enhancement ratio) is principally caused by the indirect effect ofradiation on DNA (1,2). Hypoxic cells are present in rodent and xenografted human tumors, and it has been known for a long time that the absence ofoxygen in tumors is a factor ofresistance against ionizing radiation (3–5). More recently, it has been shown that the decrease in tumor oxygen tension could also be a factor ofresistance for treatment with some cytotoxic drugs (6–8), not only directly through the low-oxygen partial pressures, but indirectly through modifications in some gene expression by O2 and other environmental factors (vascularization, pH, metabolism, angiogenic factors, and so on) (9,10). In patients, tumors are known to contain hypoxic areas (11–14), and the local control of human solid tumors could be improved if a clinically relevant test was able to identify tumors that would benefit from radiosensitization (5). Oxygen availability is dependent on oxygen supply, which depends on many parameters: microvasculature, blood flow, tissue temperature, and pH (15,16). Tissue oxygenation will result directly from 02 availability, and from the respiration rate ofthe cells. For normal tissues, changes in oxygenation reflect variations in blood flow, and partial oxygen pressure (pO2) distribution has been evaluated as a function of hemoglobin concentration, temperature, pH, and so on (15). In tumors, tissue vascularization is qualitatively poor with shunts, vessel collapses, and high interstitial pressure. All these parameters may represent a potential therapeutic target (16–18).


Partial Oxygen Pressure Oxygen Tension Comet Assay Tissue Oxygenation Neck Tumor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kellerer, A. M. and Rossi, H. H. (1971) RBE and the primary mechanism of radiation action. Radiat. Res. 47, 15–34.Google Scholar
  2. 2.
    Biaglow, J. E. (1981) Effects of ionizing radiation on mammalian cells. J. Chem. Educ. 58, 144–156.CrossRefGoogle Scholar
  3. 3.
    Thomlinson, R. H. and Gray, L. H. (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549.PubMedCrossRefGoogle Scholar
  4. 4.
    Bush, R. S., Jenkin, R. D. T., Allt, W. E. C., Beale, F. A., Bean, H., Dembo, A. J., and Pringle, J. F. (1978) Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br. J. Cancer 37(Suppl. III), 302–306.Google Scholar
  5. 5.
    Overgaard, J. (1991) Importance of tumor hypoxia in radiotherapy. A meta-analysis of controlled clinical trials. Radiother. Oncol. 24, S64.Google Scholar
  6. 6.
    Teicher, B. A., Lazo, J. S., and Sartorelli, A. C. (1981) Classification of antineoplasic agents by their selective toxicities towards oxygenated and hypoxic tumor cell. Cancer Res. 41, 73–81.PubMedGoogle Scholar
  7. 7.
    Kennedy, K. A. (1987) Hypoxic cells as specific drug targets for chemotherapy. Anticancer Drug Res. 2, 181–194.Google Scholar
  8. 8.
    Sakata, K., Tak Kwok, T., Murphy, B. J., Laderoute, K. R., Gordon, G. R., and Sutherland, R. M. (1991) Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance. Br. J. Cancer 64, 809–814.PubMedCrossRefGoogle Scholar
  9. 9.
    Sutherland, R. M., Ausserer, W. A., Murphy, B. J., and Laderoute, K. R. (1996) Tumour hypoxia and heterogeneity: challenges and opportunities for the future. Sem. Radiat. Oncol. 6, 59–70.CrossRefGoogle Scholar
  10. 10.
    Giaccia, A. J. (1996) Hypoxic stress proteins: survival of the fittest. Sem. Radiat. Oncol. 6, 46–58.CrossRefGoogle Scholar
  11. 11.
    Guichard, M. (1990) Comparison of the radiobiological properties of human tumor xenografts and rodent tumors. Int. J. Radiat. Biol. 56, 583–586.CrossRefGoogle Scholar
  12. 12.
    Rockwell, S. and Moulder, J. E. (1990) Hypoxic fractions of human tumors xenografted into mice: a review. Int. J. Radiat. Oncol. Biol. Phys. 19, 197–202.PubMedCrossRefGoogle Scholar
  13. 13.
    Chapman, J. D. (1991) Measurement of tumor hypoxia by invasive and noninvasive procedures: a review of recent clinical studies. Radiother. Oncol. 20, 13–19.PubMedCrossRefGoogle Scholar
  14. 14.
    Coleman, C. N. (1988) Hypoxia in tumors: aparadigm for the approach to biochemical and physiological heterogeneity. J. Natl. Cancer. Inst. 80, 310–316.PubMedCrossRefGoogle Scholar
  15. 15.
    Vaupel, P., Kallinowski, F., and Okunieff, P. (1989) Blood flow, oxygen and nutrient supply, and metabolic environment of human tumors: a review. Cancer Res. 49, 6449–6465.PubMedGoogle Scholar
  16. 16.
    Jain, R. K. (1988) Determinants of tumor blood flow: a review. Cancer Res. 48, 2641–2658.PubMedGoogle Scholar
  17. 17.
    Chaplin, D. J., Durand, R. E., and Olive, P. L. (1986) Acute hypoxia in tumors: implications for modifiers of radiation effects. Int. J. Radiat. Oncol. Biol. Phys. 12, 1091–1095.PubMedCrossRefGoogle Scholar
  18. 18.
    Hirst, G. H. (1986) Anemia: a problem or an opportunity in radiotherapy? Int. J. Radiat. Oncol. Biol. Phys. 12, 2009–2017.PubMedCrossRefGoogle Scholar
  19. 19.
    Vaupel, P. W., ed. (1994) Blood Flow, Oxygenation, Tissue pH Distribution, and Bioenergetic Status of Tumours. Ernst Schering Research Foundation, Berlin.Google Scholar
  20. 20.
    Milross, C. G., Peters, L. J., Hunter, N. R., Mason, K. A., Tucker, S. L., and Milas, L. (1996) Polarographic pO2 in mice: effect of tumor type, site of implantation and anesthesia. Radiat. Oncol. Invest. 4, 108–114.CrossRefGoogle Scholar
  21. 21.
    Milross, C. G., Tucker, S. L., Mason, K. A., Hunter, N. R., Peters, L. J., and Milas, L. (1997) Effect of tumour size on necrosis and polarographically measured pO2. Acta Oncol. 36, 183–189.PubMedCrossRefGoogle Scholar
  22. 22.
    Davies, P. W. and Brink, F. (1946) Microelectrodes formeasuring local oxygen tension in animal tissues. Rev. Sci. Instrum. 13, 524–533.CrossRefGoogle Scholar
  23. 23.
    Vanderkooi, J. M., Erecinska, M., and Silver, I. A. (1991) Oxygen in mammalian tissue: methods of measurement and affinities of various reactions. Am. J. Physiol. 260(Cell Physiol. 29), C 1131–C 1150.Google Scholar
  24. 24.
    Chou, S-C., Flood, P. M., and Raleigh, J. A. (1996) Marking hypoxic cells for complement and cytotoxic T lymphocyte-mediated lysis: using pimonidazole. Br. J. Cancer 74(Suppl. XXVII), S213–S216.Google Scholar
  25. 25.
    Matthews, J., Adomat, H., Farrell, N., et al. (1996) Immunocytochemical labelling of aerobic and hypoxic mammalian cells using a platinated derivative of EF5. Br. J. Cancer 74(Suppl. XXVII), S200–S203.Google Scholar
  26. 26.
    Chapman, J. D. Coia, L. R., Stobbe, C. C., Engelhardt, E. L., Fenning, M. C., and Schneider, R. F. (1996) Prediction of tumour hypoxia and radioresistance with nuclear medecine markers.Br. J. Cancer 74, (Suppl. XXVII) S204–S208.Google Scholar
  27. 27.
    Guichard, M., Lartigau, E., Tinet, E., Thomas, C., and Avrillier, S. (1997) Suivi non invasifde l’evolution de 1’oxygenation des tumeurs par réflectivité différentielle. J. Optics 28, 265–269.CrossRefGoogle Scholar
  28. 28.
    Young, W. K., Vojnovic, B., and Wardman, P. (1996) Measurement of oxygen tension in tumours byGoogle Scholar
  29. time-resolved fluorescence. Br. J. Cancer 74(Suppl. XXVII), S256–S259. 29. Olive, P. L., Viske, C. M., and Durand, R. E. (1994) Hypoxic fractions measured in murine tumors and normal tissues using the comet assay. Int. J. Radiat. Oncol. Biol. Phys. 29, 487–491.Google Scholar
  30. 30.
    Urtasun, R. C., Parliament, M. B., McEwan, A. J., Mercer, J. R., Mannan, R. H., Wiebe, L. I., Morin, C., and Chapman, J. D. (1996) Measurement of hypoxia in human tumours by non-invasive spect imaging of iodoazomycin arabinoside. Br. J. Cancer 74(Suppl. XXVII), S209–S212.Google Scholar
  31. 31.
    McCoy, C. L., McIntyre, D. J. O., Robinson, S. P., Aboagye, E. O., and Griffiths, J. R. (1996) Magnetic resonance spectroscopy and imaging methods for measuring tumour and tissue oxygenation. Br. J. Cancer 74(Suppl. XXVII), S226–S231.Google Scholar
  32. 32.
    Stone, H. B., Brown, J. M., Philips, T. L., and Sutherland, R. M. (1993) Oxygen in human tumors: correlation between methods of measurements and response to therapy. Radiat. Res. 136, 422–434.PubMedCrossRefGoogle Scholar
  33. 33.
    Cater, D. B. and Silver, I. A. (1960) Quantitative measurements of oxygen tension in normal tissues and in the tumors of patients before and after radiotherapy. Acta Radiol. 53, 233–256.PubMedCrossRefGoogle Scholar
  34. 34.
    Kolstad, P. (1968) Intercapillary distance, oxygen tension and local recurrence in cervix cancer. Scand. J. Clin. Lab. Invt. 106(Suppl.), 145–157.Google Scholar
  35. 35.
    Bergsjo, P. and Evans, J. C. (1968) Oxygen tension of cervical carcinoma during the early phase of external irradiation. Clinical trial with atmospheric oxygen breathing during radiotherapy of cancer of the cervix. Scand. J. Clin. Lab. Inv. 106(Suppl.), 167–171.Google Scholar
  36. 36.
    Badib, A. O. and Webster, J. H. (1969) Changes in tumor oxygen tension during radiation therapy. Acta Radiol. Ther. Phys. Biol. 8, 247–257.Google Scholar
  37. 37.
    Gatenby, R. A., Coia, L. R., Richter, M. P., Katz, H., Moldofsky, P. J., and Engstrom, P. (1985) Oxygen tension in human tumors: in vivo mapping using CT-guided probes. Radiology 156, 211–214.PubMedGoogle Scholar
  38. 38.
    Gatenby, R. A., Kessler, H. B., Rosenblum, J. S., Coia, L. R., Modofsky, P. J., Hart, W. H., and Broder, G. J. (1988) Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 10, 831–838.CrossRefGoogle Scholar
  39. 39.
    Pappova, N., Siracka, E., Vacek, A., and Durkovsky, J. (1982) Oxygen tension and prediction of the radiation response. Polarographic study in human breast cancer. Neoplasma 29, 669–674.PubMedGoogle Scholar
  40. 40.
    Schramm, U., Fleckenstein, W., and Weber, C. (1990) Morphological assessment of skeletal muscular injury caused by p02 measurements with hypodermic needle probes, in Clinical Oxygen Pressure Measurement II (Ehrly, A. M., Fleckenstein, W., Hauss, J., and Huch, R., eds.), Blackwell Ueberreuter Wissenschaft, Berlin, pp. 38–50.Google Scholar
  41. 41.
    Lartigau, E., Lespinasse, F., Vitu, L., and Guichard, M. (1992) Does the direct measurement of oxygen tension in tumours have any adverse effect? Int. J. Radiat. Oncol. Biol. Phys. 22, 949–951.PubMedCrossRefGoogle Scholar
  42. 42.
    Khalili, A. A., Horsman, M. R., Nordsmark, M., Grau, C., and Overgaard, J. (1995) Oxygenation status in an experimental murine tumour system, in Tumor Oxygenation (Vaupel, P. W., ed.), Gustav Fischer Verlag, Stutgart, pp. 107–117.Google Scholar
  43. 43.
    Vaupel, P. W., Frinak, S., and Bicher, H. I. (1981) Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res. 41, 2008–2013.PubMedGoogle Scholar
  44. 44.
    Kallinowski, F., Zander, R., Höckel, M., and Vaupel, P. (1990) Tumor tissue oxygenation as evaluated by computerized-pO2-histography. Int. J. Radiat. Oncol. Biol. Phys. 19, 953–961.PubMedCrossRefGoogle Scholar
  45. 45.
    Horsman, M. R., Hansen, P. V., and Overgaard, J. (1989) Radiosensitization by nicotinamide in tumors and normal tissues: the importance of tissue oxygenation status. Int. J. Radiat. Oncol. Biol. Phys. 16, 1273–1276.Google Scholar
  46. 46.
    Simon, J. M., Lartigau, E., and Guichard, M. (1993) Nicotinamide and carbogen: major effect on the radiosensitivity of EMT6 and HRT18 tumors. Radiother. Oncol. 28, 203–207.PubMedCrossRefGoogle Scholar
  47. 47.
    Thomas, C. D., Prade, M., and Guichard, M. (1995) Tumour oxygenation, radiosensitivity and necrosis before and/or after nicotinamide, carbogen and perflubron emulsion administration. Int. J. Radiat. Biol. 67, 597–605.PubMedCrossRefGoogle Scholar
  48. 48.
    Nozue, M., Lee, I., Yuan, F., Teicher, B. A., Brizel, D. M., Dewhirst, M. W., et al. (1997) Inter-laboratory variation in oxygen tension measurement by Eppendorf “Histograph” and comparison with hypoxic marker. Surg. Oncol. 66, 30–38.CrossRefGoogle Scholar
  49. 49.
    Vaupel, P. W. (1990) Oxygenation of human tumors. Stralenther. Onkol. 166, 377–386.Google Scholar
  50. 50.
    Lartigau, E., Vitu, L., Haie-Meder, C., Cosser, M. F., Delapierre, M., Gerbaulet, A., Eschwege, F., and Guichard, M. (1992) Feasibility of measuring oxygen tension in uterine cervix carcinoma. Eur. J. Cancer 28, 1354–1357.CrossRefGoogle Scholar
  51. 51.
    Lartigau, E., Le Ridant, A. M., Lambin, P., Weeger, P., Martin, L., Sigal, R., et al. (1993) Oxygenation of head and neck tumors. Cancer 71, 2319–2325.PubMedCrossRefGoogle Scholar
  52. 52.
    Lartigau, E., Randrianarivelo, H., Martin, L., Stern, S., Thomas, C. D., Guichard, M., et al. (1994) Oxygen tension measurements in human tumors: the Institut Gustave-Roussy Experience. Radiat. Oncol. Invest. 1, 285–291.CrossRefGoogle Scholar
  53. 53.
    Fleckenstein, W., Jungblut, J. R., and Suckfull, M. (1990) Distribution ofoxygen pressure in the periphery and centre ofmalignant head and neck tumors, in Clinical Oxygen Pressure Measurement II (Ehrly, A. M., Fleckenstein, W., Hauss, J., and Huch, R., eds.), Blackwell Ueberreuter Wissenschaft, Berlin, pp. 81–90.Google Scholar
  54. 54.
    Nordsmark, M., Overgaard, M., and Overgaard, J. (1996) Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother. Oncol. 41, 31–39.PubMedGoogle Scholar
  55. 55.
    Terris, D. J. and Dunphy, E. P. (1994) Oxygen tension of head and neck cancers. Arch. Otolaryngol. Head Neck Surg. 120, 283–287.PubMedCrossRefGoogle Scholar
  56. 56.
    Vaupel, P. W. and Höckel, M. (1995) Oxygenation status of human tumours: a reappraisal using computerized pO2 histography, in Tumor Oxygenation (Vaupel, P. W., Kelleher, D. K., and Gunderoth, M., eds.), Gustav Fischer Verlag, Stuttgart, pp. 219–232.Google Scholar
  57. 57.
    Höckel, M., Knoop, C., Schlenger, K., Vorndran, B., Baussmann, E., Mitze, M., Knapstein, P. G., and Vaupel, P. (1993) Intratumoral pO2 predicts survival in advanced cancer ofthe uterine cervix. Radiother. Oncol. 26, 45–50.PubMedCrossRefGoogle Scholar
  58. 58.
    Höckel, M., Vorndran, B., Schlenger, K., Baussmann, E., and Knapstein, P. G. (1993) Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix. Gyn. Oncol. 51, 141–149.CrossRefGoogle Scholar
  59. 59.
    Wong, R. K. W., Fyles, A., Milosevic, M., Pintilie, M., and Hill, R. P. (1997) Heterogeneity of polarographic oxygen tension measurements in cervix cancer: an evaluation of within and between tumor variability, probe position and track depth. Int. J. Radiat. Oncol. Biol. Phys. 39, 405–412.PubMedCrossRefGoogle Scholar
  60. 60.
    Rampling, R., Cruickshank, G., Lewis, A. D., Fitzsimmons, S. A., and Workman, P. (1994) Pretreatment oxygenation profiles of human soft tissue sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 29, 427–431.PubMedCrossRefGoogle Scholar
  61. 61.
    Brizel, D. M., Rosner, G. L., Harrelson, J., Prosnitz, L. R., and Dewhirst, M. W. (1994) Direct measurement of pO2 distribution and bioreductive enzymes in human malignant brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 30, 635–642.PubMedCrossRefGoogle Scholar
  62. 62.
    Lusinchi, A., Lartigau, E., Luboinski, B., and Eschwege, F. (1994) Accelerated radiation therapy in the treatment of very advanced and inoperable head and neck cancers. In. J. Radiat. Oncol. Biol. Phys. 29, 149–152.CrossRefGoogle Scholar
  63. 63.
    Keresteci, Q. G. and Rider, M. B. (1973) Use oforthobaric oxygen in the radiotherapy ofbladder tumors. Can. J. Surg. 16, 127–129.PubMedGoogle Scholar
  64. 64.
    Rubin, P., Hanley, J., Keys, H. M., Marcial, V., and Brady, L. (1979) Carbogen breathing during radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 5, 1963–1970.PubMedCrossRefGoogle Scholar
  65. 65.
    Henk, J. M. (1981) Does hyperbaric oxygen have a future in radiation therapy? Int. J. Radiat. Oncol. Biol. Phys. 7, 1125–1128.PubMedCrossRefGoogle Scholar
  66. 66.
    Martin, L., Lartigau, E., Weeger, P., Lambin, P., Le Ridant, A. M., Lusinchi, A., et al. (1993) Changes in the oxygenation of head and neck tumors during carbogen breathing. Radiother. Oncol. 27,123–130.PubMedCrossRefGoogle Scholar
  67. 67.
    Falk, S. J., Ward, R., and Bleehen, N. M. (1992) The influence of carbogen breathing on tumour tissue oxygenation in man evaluated by computerised pO2 histography. Br. J. Cancer 66, 919–924.PubMedCrossRefGoogle Scholar
  68. 68.
    Brown, J. M. (1989) Hypoxic cells radiosensitizers: where next? Int. J. Radiat. Oncol. Biol. Phys. 16, 987–993.PubMedCrossRefGoogle Scholar
  69. 69.
    Guichard, M. (1991) The use of fluorocarbon emulsions in cancer radiotherapy. Radiother. Oncol. 20(Suppl.), 59–64.PubMedCrossRefGoogle Scholar
  70. 70.
    Dische, S. (1991) Radiotherapy and anaemia. The clinical experience. Radiother. Oncol. 20(Suppl.), 35–40.PubMedCrossRefGoogle Scholar
  71. 71.
    Workman, P. and Stratford, I. J. (1993) The experimental development of bioreductive drugs and their role in cancer therapy. Cancer Metatesis Rev. 12, 73–82.CrossRefGoogle Scholar
  72. 72.
    Brown, J. M. (1993) SR-4233 (Tirapazamine): a new anticancer drug exploiting hypoxia in solid tumors. Br. J. Cancer 67, 1163–1170.PubMedCrossRefGoogle Scholar
  73. 73.
    Lartigau, E. and Guichard, M. (1995) Does tirapazamine (SR-4233) have any cytotoxic or sensitising effect on 3 human cell lines at clinically relevant partial oxygen pressure? Int. J. Radiat. Biol. 2, 211–216.CrossRefGoogle Scholar
  74. 74.
    Horsman, M. R. and Overgaard, J. (1997) Can mild hyperthermia improve tumour oxygenation? Int. J. Hyperthermia 13, 141–147.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Eric Lartigau
  • Marcelle Guichard

There are no affiliations available

Personalised recommendations