A large body of clinical evidence exists to suggest that tumor hypoxia negatively impacts radiotherapy. As a result, there has been longstanding active research into novel methods of improving tumor oxygenation, targeting hypoxic tumor cells, and otherwise modulating the effect hypoxia has on how tumors respond to radiation. Over time, as more has been learned about the many ways hypoxia affects tumors, our understanding of the mechanisms connecting hypoxia to radiosensitivity has become increasingly broad and complicated. This has opened up new potential avenues for interrupting hypoxia’s negative effects on tumor radiosensitivity. Here, we will review what is currently known about the spectrum of influence hypoxia has over the way tumors respond to radiation. Particular focus will be placed on recent discoveries suggesting that hypoxia-inducible factor-1 (HIF-1), a transcription factor that upregulates its target genes under hypoxic conditions, plays a major role in determining tumor radiosensitivity. HIF-1 and/or its target genes may represent therapeutic targets which could be manipulated to influence hypoxia’s impact on tumor radiosensitivity.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Deschner, E. E., & Gray, L. H. (1959) Influence of oxygen tension on x-ray-induced chromosomal damage in Ehrlich ascites tumor cells irradiated in vitro and in vivo. Radiation Research, 11, 115–146.
Gray, L. H., Conger, A. D., Ebert, M., Hornsey, S., & Scott, O. C. (1953). The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. British Journal of Radiology, 26, 638–648.
Henk, J. M., Kunkler, P. B., & Smith, C. W. (1977). Radiotherapy and hyperbaric oxygen in head and neck cancer. Final report of first controlled clinical trial. Lancet, 2, 101–103.
Dische, S., Anderson, P. J., Sealy, R., & Watson, E. R. (1983). Carcinoma of the cervix-anaemia, radiotherapy and hyperbaric oxygen. British Journal of Radiology, 56, 251–255.
Bennett, M., Feldmeier, J., Smee, R., & Milross, C. (2005) Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst Rev, CD005007.
Evans, J. C., & Bergsjo, P. (1965). The influence of anemia on the results of radiotherapy in carcinoma of the cervix. Radiology, 84, 709–717.
Henke, M., Laszig, R., Rube, C., Schafer, U., Haase, K. D., Schilcher, B., et al. (2003). Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet, 362, 1255–1260.
Hill, S. A., Collingridge, D. R., Vojnovic, B., & Chaplin, D. J. (1998). Tumour radiosensitization by high-oxygen-content gases: Influence of the carbon dioxide content of the inspired gas on PO2, microcirculatory function and radiosensitivity. International Journal of Radiation Oncology Biology Physics, 40, 943–951.
Powell, M. E., Collingridge, D. R., Saunders, M. I., Hoskin, P. J., Hill, S. A., & Chaplin, D. J. (1999). Improvement in human tumour oxygenation with carbogen of varying carbon dioxide concentrations. Radiotherapy and Oncology, 50, 167–171.
Dewhirst, M. W., Ong, E. T., Rosner, G. L., Rehmus, S. W., Shan, S., Braun, R., et al. (1996). Arteriolar oxygenation in tumour and subcutaneous arterioles: Effects of inspired air oxygen content. British Journal of Cancer Supplement, 27, S241–S246.
Horsman, M. R., Chaplin, D. J., & Brown, J. M. (1989). Tumor radiosensitization by nicotinamide: A result of improved perfusion and oxygenation. Radiation Research, 118, 139–150.
Kaanders, J. H., Bussink, J., & van der Kogel, A. J. (2002). ARCON: A novel biology-based approach in radiotherapy. Lancet Oncology, 3, 728–737.
Kavanagh, B. D., Khandelwal, S. R., Schmidt-Ullrich, R. K., Roberts, J. D., Shaw, E. G., Pearlman, A. D., et al. (2001). A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: Tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics. International Journal of Radiation Oncology Biology Physics, 49, 1133–1139.
Teicher, B. A., Herman, T. S., & Menon, K. (1992). Enhancement of fractionated radiation therapy by an experimental concentrated perflubron emulsion (Oxygent) in the Lewis lung carcinoma. Biomaterials Artificial Cells and Immobilization Biotechnology, 20, 899–902.
Teicher, B. A., Holden, S. A., Ara, G., Herman, T. S., Hopkins, R. E., & Menon, K. (1992). Effect of a bovine hemoglobin preparation (SBHS) on the response of two murine solid tumors to radiation therapy or chemotherapeutic alkylating agents. Biomaterials Artificial Cells and Immobilization Biotechnology, 20, 657–660.
Kavanagh, B. D., Coffey, B. E., Needham, D., Hochmuth, R. M., & Dewhirst, M. W. (1993). The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. British Journal of Cancer, 67, 734–741.
Chapman, J. D. (1979). Hypoxic sensitizers—Implications for radiation therapy. New England Journal of Medicine, 301, 1429–1432.
Overgaard, J. (1994). Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncology Research, 6, 509–518.
Rischin, D., Peters, L., Fisher, R., Macann, A., Denham, J., Poulsen, M., et al. (2005). Tirapazamine, cisplatin, and radiation versus fluorouracil, cisplatin, and radiation in patients with locally advanced head and neck cancer: A randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). Journal of Clinical Oncology, 23, 79–87.
Song, C. W., Park, H. J., Lee, C. K., & Griffin, R. (2005). Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. International Journal of Hyperthermia, 21, 761–767.
Brizel, D. M., Scully, S. P., Harrelson, J. M., Layfield, L. J., Dodge, R. K., Charles, H. C., et al. (1996). Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Research, 56, 5347–5350.
Jones, E. L., Oleson, J. R., Prosnitzm, L. R., Samulski, T. V., Vujaskovic, Z., Yu, D., et al. (2005). Randomized trial of hyperthermia and radiation for superficial tumors. Journal of Clinical Oncology, 23, 3079–3085.
Secomb, T. W., Hsu, R., & Dewhirst, M. W. (2004). Synergistic effects of hyperoxic gas breathing and reduced oxygen consumption on tumor oxygenation: A theoretical model. International Journal of Radiation Oncology Biology Physics, 59, 572–578.
Kirkpatrick, J. P., Brizel, D. M., & Dewhirst, M. W. (2003). A mathematical model of tumor oxygen and glucose mass transport and metabolism with complex reaction kinetics. Radiation Research, 159, 336–344.
Snyder, S. A., Lanzen, J. L., Braun, R. D., Rosner, G., Secomb, T. W., Biaglow, J., et al. (2001). Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone. International Journal of Radiation Oncology Biology Physics, 51, 494–506.
Shrieve, D. C., & Harris, J. W. (1985). The in vitro sensitivity of chronically hypoxic EMT6/SF cells to X-radiation and hypoxic cell radiosensitizers. International Journal of Radiation Biology and Related Studies in Physics Chemistry and Medicine, 48, 127–138.
Pettersen, E. O., & Wang, H. (1996). Radiation-modifying effect of oxygen in synchronized cells pre-treated with acute or prolonged hypoxia. International Journal of Radiation Biology, 70, 319–326.
Moeller, B. J., Dreher, M. R., Rabbani Z. N., Schroeder, T., Cao, Y., Li, C. Y., et al. (2005). Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell, 8, 99–110.
Moeller, B. J., & Dewhirst, M. W. (2006). HIF-1 and tumour radiosensitivity. British Journal of Cancer, 95, 1–5.
Moeller, B. J., Cao, Y., Li, C. Y., & Dewhirst, M. W. (2004). Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules. Cancer Cell, 5, 429–441.
Williams, K. J., Telfer, B. A., Xenaki, D., Sheridan, M. R., Desbaillets, I., Peters, H. J.,et al. (2005). Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiotherapy and Oncology, 75, 89–98.
Folkman, J. (2002). Role of angiogenesis in tumor growth and metastasis. Seminars in Oncology, 29, 15–18.
Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., et al. (2003). Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science, 300, 1155–1159.
Geng, L., Donnelly, E., McMahon, G., Lin, P. C., Sierra-Rivera, E., Oshinka, H., et al. (2001). Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Research, 61, 2413–2419.
Hess, C., Vuong, V., Hegyi, I., Riesterer, O., Wood, J., Fabbro, D., et al. (2001). Effect of VEGF receptor inhibitor PTK787/ZK222584 [correction of ZK222548] combined with ionizing radiation on endothelial cells and tumour growth. British Journal of Cancer, 85, 2010–2016.
Kozin, S. V., Boucher, Y., Hicklin, D. J., Bohlen, P., Jain, R. K., & Suit, H. D. (2001). Vascular endothelial growth factor receptor-2-blocking antibody potentiates radiation-induced long-term control of human tumor xenografts. Cancer Research, 61, 39–44.
Lund, E. L., Bastholm, L., & Kristjansen, P. E. (2000). Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. Clincal Cancer Research, 6, 971–978.
Ning, S., Laird, D., Cherrington, J. M., & Knox, S. J. (2002). The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation. Radiation Research, 157, 45–51.
Dunst, J., Stadler, P., Becker, A., Lautenschlager, C., Pelz, T., Hansgen, G., et al. (2003). Tumor volume and tumor hypoxia in head and neck cancers. The amount of the hypoxic volume is important. Strahlentherapie und Onkologie, 179, 521–526.
Nordsmark, M., & Overgaard, J. (2000). A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiotherapy and Oncology, 57, 39–43.
Stadler, P., Becker, A., Feldmann, H. J., Hansgen, G., Dunst, J., Wurschmidt, F., et al. (1999). Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. International Journal of Radiation Oncology Biology Physics, 44, 749–754.
Nordsmark, M., Overgaard, M., & Overgaard, J. (1996). Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiotherapy and Oncology, 41, 31–39.
Nordsmark, M., Bentzen, S. M., Rudat, V., Brizel, D., Lartigau, E., Stadler, P., et al. (2005). Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiotherapy and Oncology, 77, 18–24.
Brizel, D. M., Dodge, R. K., Clough, R. W., & Dewhirst, M. W. (1999). Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiotherapy and Oncology, 53, 113–117.
Rudat, V., Stadler, P., Becker, A., Vanselow, B., Dietz, A., Wannenmacher, M., et al. (2001). Predictive value of the tumor oxygenation by means of pO2 histography in patients with advanced head and neck cancer. Strahlentherapie und Onkologie, 177, 462–468.
Rudat, V., Vanselow, B., Wollensack, P., Bettscheider, C., Osman-Ahmet, S., Eble, M. J., et al. (2000). Repeatability and prognostic impact of the pretreatment pO(2) histography in patients with advanced head and neck cancer. Radiotherapy and Oncology, 57, 31–37.
Adam, M. F., Gabalski, E. C., Bloch, D. A., Oehlert, J. W., Brown, J. M., Elsaid, A. A., et al. (1999). Tissue oxygen distribution in head and neck cancer patients. Head Neck, 21, 146–153.
Gatenby, R. A., Kessler, H. B., Rosenblum, J. S., Coia, L. R., Moldofsky, P. J., Hartz, W. H., et al. (1988). Oxygen distribution in squamous cell carcinoma metastases and its relationship to outcome of radiation therapy. International Journal of Radiation Oncology Biology Physics, 14, 831–838.
Fyles, A., Milosevic, M., Hedley, D., Pintilie, M., Levin, W., Manchul, L., et al. (2002). Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. Journal of Clinical Oncology, 20, 680–687.
Rofstad, E. K., Sundfor, K., Lyng, H., & Trope, C. G. (2000). Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis. British Journal of Cancer, 83, 354–359.
Sundfor, K., Lyng, H., Trope, C. G., & Rofstad, E. K. (2000). Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: Relationships to pretreatment tumor oxygenation and vascularization. Radiotherapy and Oncology, 54, 101–107.
Fyles, A. W., Milosevic, M., Wong, R., Kavanagh, M. C., Pintilie, M., Sun, A., et al. (1998). Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiotherapy and Oncology, 48, 149–156.
Knocke, T. H., Weitmann, H. D., Feldmann, H. J., Selzer, E., & Potter, R. (1999). Intratumoral pO2-measurements as predictive assay in the treatment of carcinoma of the uterine cervix. Radiotherapy Oncology, 53, 99–104.
Hockel, M., Schlenger, K., Aral, B., Mitze, M., Schaffer, U., & Vaupel, P. (1996). Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Research, 56, 4509–4515.
Nordsmark, M., Alsner, J., Keller, J., Nielsen, O. S., Jensen, O. M., Horsman, M. R., et al. (2001). Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations. British Journal Cancer, 84, 1070–1075.
Brizel, D. M., Scully, S. P., Harrelson, J. M., Layfield, L. J., Bean, J. M., Prosnitz L. R., et al. (1996). Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Research, 56, 941–943.
About this article
Cite this article
Moeller, B.J., Richardson, R.A. & Dewhirst, M.W. Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev 26, 241–248 (2007). https://doi.org/10.1007/s10555-007-9056-0