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  • Review Article
  • Published:

Strategies for optimizing the response of cancer and normal tissues to radiation

Key Points

  • More than half of all patients with cancer receive radiation therapy.

  • Normal tissue tolerance for radiation limits the dose of radiation that can safely be delivered, which can limit the probability of curing a tumour.

  • As our knowledge of the mechanisms and signalling pathways that determine the response of tumour tissues and normal tissues to radiation increases, targeted drugs can be developed that selectively sensitize tumours or protect normal tissues.

  • Promising approaches to selectively enhance tumour radiosensitivity include triggering synthetic lethality, inhibiting multiple targets to simultaneously block more than one signalling pathway and targeting the tumour microenvironment.

Abstract

Approximately 50% of all patients with cancer receive radiation therapy at some point during the course of their treatment, and the majority of these patients are treated with curative intent. Despite recent advances in the planning of radiation treatment and the delivery of image-guided radiation therapy, acute toxicity and potential long-term side effects often limit the ability to deliver a sufficient dose of radiation to control tumours locally. In the past two decades, a better understanding of the hallmarks of cancer and the discovery of specific signalling pathways by which cells respond to radiation have provided new opportunities to design molecularly targeted therapies to increase the therapeutic window of radiation therapy. Here, we review efforts to develop approaches that could improve outcomes with radiation therapy by increasing the probability of tumour cure or by decreasing normal tissue toxicity.

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Figure 1: Selectively targeting tumour cells through synthetic lethality.
Figure 2: Inhibiting PI3K and the PI3K-like protein kinase family.
Figure 3: Enhancing tumour cure by modulating the tumour microenvironment.
Figure 4: The tissue-dependent role of p53 in the response of cells to radiation.
Figure 5: Strategies to protect and mitigate normal tissues from radiation damage.

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References

  1. Intensity Modulated Radiation Therapy Collaborative Working Group. Intensity-modulated radiotherapy: current status and issues of interest. Int. J. Radiat. Oncol. Biol. Phys. 51, 880–914 (2001).

  2. Lo, S. S. et al. Stereotactic body radiation therapy: a novel treatment modality. Nature Rev. Clin. Oncol. 7, 44–54 (2010). This manuscript reviews prospective clinical trials and current clinical use of stereotactic body radiation therapy.

    Article  Google Scholar 

  3. Timmerman, R. et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J. Clin. Oncol. 24, 4833–4839 (2006).

    Article  PubMed  Google Scholar 

  4. Forquer, J. A. et al. Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: dose-limiting toxicity in apical tumor sites. Radiother. Oncol. 93, 408–413 (2009).

    Article  PubMed  Google Scholar 

  5. Sahgal, A., Larson, D. A. & Chang, E. L. Stereotactic body radiosurgery for spinal metastases: a critical review. Int. J. Radiat. Oncol. Biol. Phys. 71, 652–665 (2008).

    Article  PubMed  Google Scholar 

  6. Andolino, D. L. et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 81, e447–e453 (2011).

    Article  PubMed  Google Scholar 

  7. Madsen, B. L. et al. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int. J. Radiat. Oncol. Biol. Phys. 67, 1099–1105 (2007).

    Article  PubMed  Google Scholar 

  8. Svedman, C. et al. A prospective Phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma. Acta Oncol. 45, 870–875 (2006).

    Article  PubMed  Google Scholar 

  9. Timmerman, R. et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 124, 1946–1955 (2003).

    Article  PubMed  Google Scholar 

  10. Durante, M. & Loeffler, J. S. Charged particles in radiation oncology. Nature Rev. Clin. Oncol. 7, 37–43 (2010). This article reviews potential benefits and disadvantages of particle therapy and describes contemporary clinical outcomes following charged particle therapy.

    Article  Google Scholar 

  11. Schulz-Ertner, D. & Tsujii, H. Particle radiation therapy using proton and heavier ion beams. J. Clin. Oncol. 25, 953–964 (2007).

    Article  PubMed  Google Scholar 

  12. Greco, C. & Wolden, S. Current status of radiotherapy with proton and light ion beams. Cancer 109, 1227–1238 (2007).

    Article  PubMed  Google Scholar 

  13. Sheets, N. C. et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 307, 1611–1620 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hoskin, P. J. & Bownes, P. Innovative technologies in radiation therapy: brachytherapy. Semin. Radiat. Oncol. 16, 209–217 (2006).

    Article  PubMed  Google Scholar 

  15. Bhide, S. A. & Nutting, C. M. Recent advances in radiotherapy. BMC Med. 8, 25 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dawson, L. A. & Jaffray, D. A. Advances in image-guided radiation therapy. J. Clin. Oncol. 25, 938–946 (2007).

    Article  PubMed  Google Scholar 

  17. Elshaikh, M., Ljungman, M., Ten Haken, R. & Lichter, A. S. Advances in radiation oncology. Annu. Rev. Med. 57, 19–31 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Bernier, J., Hall, E. J. & Giaccia, A. Radiation oncology: a century of achievements. Nature Rev. Cancer 4, 737–747 (2004).

    Article  CAS  Google Scholar 

  19. Seiwert, T. Y., Salama, J. K. & Vokes, E. E. The concurrent chemoradiation paradigm — general principles. Nature Clin. Practice. Oncol. 4, 86–100 (2007).

    Article  CAS  Google Scholar 

  20. Nishimura, Y. Rationale for chemoradiotherapy. Int. J. Clin. Oncol. 9, 414–420 (2004).

    Article  PubMed  Google Scholar 

  21. Dewhirst, M. W., Cao, Y. & Moeller, B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nature Rev. Cancer 8, 425–437 (2008).

    Article  CAS  Google Scholar 

  22. Harrison, L. B., Chadha, M., Hill, R. J., Hu, K. & Shasha, D. Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 7, 492–508 (2002).

    Article  PubMed  Google Scholar 

  23. Brizel, D. M., Sibley, G. S., Prosnitz, L. R., Scher, R. L. & Dewhirst, M. W. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys. 38, 285–289 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Chapman, J. D. Hypoxic sensitizers — implications for radiation therapy. N. Engl. J. Med. 301, 1429–1432 (1979).

    Article  CAS  PubMed  Google Scholar 

  25. Overgaard, J. Hypoxic radiosensitization: adored and ignored. J. Clin. Oncol. 25, 4066–4074 (2007). This article is a systematic review of randomized clinical trials providing evidence that modifying tumor hypoxia improves outcomes with radiotherapy.

    Article  PubMed  Google Scholar 

  26. Bennett, M. H., Feldmeier, J., Smee, R. & Milross, C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst. Rev. 4, CD005007 (2012).

    Google Scholar 

  27. Henke, M. et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362, 1255–1260 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Arcasoy, M. O. et al. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin. Cancer Res. 11, 20–27 (2005).

    CAS  PubMed  Google Scholar 

  29. Overgaard, J. et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5–85. Radiother. Oncol. 46, 135–146 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Lee, D. J. et al. Results of an RTOG phase III trial (RTOG 85–27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 32, 567–576 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Brown, J. M. & Koong, A. Therapeutic advantage of hypoxic cells in tumors: a theoretical study. J. Natl Cancer Inst. 83, 178–185 (1991).

    Article  CAS  PubMed  Google Scholar 

  32. Rischin, D. et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J. Clin. Oncol. 28, 2989–2995 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Le, Q.-T. et al. Prognostic and predictive significance of plasma HGF and IL-8 in a phase III trial of chemoradiation with or without tirapazamine in locoregionally advanced head and neck cancer. Clin. Cancer Res. 18, 1798–1807 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sun, X., Niu, G., Chan, N., Shen, B. & Chen, X. Tumor hypoxia imaging. Mol. Imag. Biol. 13, 399–410 (2011).

    Article  Google Scholar 

  35. Kouvaris, J. R., Kouloulias, V. E. & Vlahos, L. J. Amifostine: the first selective-target and broad-spectrum radioprotector. Oncologist 12, 738–747 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Yuhas, J. M. Active versus passive absorption kinetics as the basis for selective protection of normal tissues by S-2-(3-aminopropylamino)-ethylphosphorothioic acid. Cancer Res. 40, 1519–1524 (1980).

    CAS  PubMed  Google Scholar 

  37. Calabro-Jones, P. M., Fahey, R. C., Smoluk, G. D. & Ward, J. F. Alkaline phosphatase promotes radioprotection and accumulation of WR-1065 in V79-171 cells incubated in medium containing WR-2721. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 47, 23–27 (1985).

    Article  CAS  PubMed  Google Scholar 

  38. Yuhas, J. M. & Storer, J. B. Differential chemoprotection of normal and malignant tissues. J. Natl Cancer Inst. 42, 331–335 (1969).

    CAS  PubMed  Google Scholar 

  39. Buentzel, J. et al. Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled Phase III study. Int. J. Radiat. Oncol. Biol. Phys. 64, 684–691 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Fournel, P. et al. Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95–01 Study. J. Clin. Oncol. 23, 5910–5917 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Lorusso, D. et al. Phase III multicenter randomized trial of amifostine as cytoprotectant in first-line chemotherapy in ovarian cancer patients. Ann. Oncol. 14, 1086–1093 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Hensley, M. L. et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J. Clin. Oncol. 27, 127–145 (2009). This article provides clinical guidelines for the use of radiation protectors in combination with radiation therapy.

    Article  CAS  PubMed  Google Scholar 

  43. Glover, D., Glick, J. H., Weiler, C., Fox, K. & Guerry, D. WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma. J. Clin. Oncol. 5, 574–578 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. Rubin, J. S. et al. Audiological findings in a Phase I protocol investigating the effect of WR 2721, high-dose cisplatin and radiation therapy in patients with locally advanced cervical carcinoma. J. Laryngol. Otol. 109, 744–747 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Mollman, J. E., Glover, D. J., Hogan, W. M. & Furman, R. E. Cisplatin neuropathy. Risk factors, prognosis, and protection by WR-2721. Cancer 61, 2192–2195 (1988).

    Article  CAS  PubMed  Google Scholar 

  46. Murray-Zmijewski, F., Slee, E. A. & Lu, X. A complex barcode underlies the heterogeneous response of p53 to stress. Nature Rev. Mol. Cell Biol. 9, 702–712 (2008).

    Article  CAS  Google Scholar 

  47. Schwachofer, J. H., Hoogenhout, J., Kal, H. B., Koedam, J. & van Wezel, H. P. Radiosensitivity of different human tumor lines grown as xenografts determined from growth delay and survival data. In Vivo 4, 253–257 (1990).

    CAS  PubMed  Google Scholar 

  48. Gerweck, L. E., Zaidi, S. T. & Zietman, A. Multivariate determinants of radiocurability. I: Prediction of single fraction tumor control doses. Int. J. Radiat. Oncol. Biol. Phys. 29, 57–66 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Singh, M., Murriel, C. L. & Johnson, L. Genetically engineered mouse models: closing the gap between preclinical data and trial outcomes. Cancer Res. 72, 2695–2700 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Karar, J. & Maity, A. Modulating the tumor microenvironment to increase radiation responsiveness. Cancer Biol. Ther. 8, 1994–2001 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Roses, R. E., Xu, M., Koski, G. K. & Czerniecki, B. J. Radiation therapy and Toll-like receptor signaling: implications for the treatment of cancer. Oncogene 27, 200–207 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Med. 13, 1050–1059 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Lee, Y. et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 114, 589–595 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sharpless, N. E. & Depinho, R. A. The mighty mouse: genetically engineered mouse models in cancer drug development. Nature Rev. Drug Discov. 5, 741–754 (2006).

    Article  CAS  Google Scholar 

  56. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Graves, E. E. et al. Hypoxia in models of lung cancer: implications for targeted therapeutics. Clin. Cancer Res. 16, 4843–4852 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Maity, A. & Koumenis, C. Location, location, location-makes all the difference for hypoxia in lung tumors. Clin. Cancer Res. 16, 4685–4687 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Singh, M. et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nature Biotech. 28, 585–593 (2010).

    Article  CAS  Google Scholar 

  60. Chen, Z. et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613–617 (2012). References 59 and 60 illustrate the potential of genetically engineered mouse models to predict the outcomes of human clinical trials of cancer therapies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Suit, H., Skates, S., Taghian, A., Okunieff, P. & Efird, J. T. Clinical implications of heterogeneity of tumor response to radiation therapy. Radiother. Oncol. 25, 251–260 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Brown, J. M. & Wouters, B. G. Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res. 59, 1391–1399 (1999).

    CAS  PubMed  Google Scholar 

  63. Jiang, H. et al. The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev. 23, 1895–1909 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Choudhury, A. et al. MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res. 70, 7017–7026 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Navin, N. et al. Tumour evolution inferred by single-cell sequencing. Nature 472, 90–94 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Driessens, G., Beck, B., Caauwe, A., Simons, B. D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Schepers, A. G. et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730–735 (2012). References 66–68 illustrate that a subset of tumour cells can contribute to tumour growth and regrowth following anticancer therapy.

    Article  CAS  PubMed  Google Scholar 

  69. Calabrese, C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell 11, 69–82 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Baumann, M., Krause, M. & Hill, R. Exploring the role of cancer stem cells in radioresistance. Nature Rev. Cancer 8, 545–554 (2008).

    Article  CAS  Google Scholar 

  71. Rich, J. N. Cancer stem cells in radiation resistance. Cancer Res. 67, 8980–8984 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Pajonk, F., Vlashi, E. & McBride, W. H. Radiation resistance of cancer stem cells: the 4 R's of radiobiology revisited. Stem Cells 28, 639–648 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jang, Y.-Y. & Sharkis, S. J. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110, 3056–3063 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

    Article  CAS  PubMed  Google Scholar 

  75. Moncharmont, C. et al. Targeting a cornerstone of radiation resistance: cancer stem cell. Cancer Lett. 322, 139–147 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Kaelin, W. G. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer 5, 689–698 (2005).

    Article  CAS  Google Scholar 

  77. Núñez, M. I., McMillan, T. J., Valenzuela, M. T., Ruiz de Almodóvar, J. M. & Pedraza, V. Relationship between DNA damage, rejoining and cell killing by radiation in mammalian cells. Radiother. Oncol. 39, 155–165 (1996).

    Article  PubMed  Google Scholar 

  78. Jorgensen, T. J. Enhancing radiosensitivity: targeting the DNA repair pathways. Cancer Biol. Ther. 8, 665–670 (2009).

    Article  CAS  PubMed  Google Scholar 

  79. Helleday, T., Petermann, E., Lundin, C., Hodgson, B. & Sharma, R. A. DNA repair pathways as targets for cancer therapy. Nature Rev. Cancer 8, 193–204 (2008).

    Article  CAS  Google Scholar 

  80. Jagtap, P. & Szabó, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nature Rev. Drug Discov. 4, 421–440 (2005).

    Article  CAS  Google Scholar 

  81. Ratnam, K. & Low, J. A. Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clin. Cancer Res. 13, 1383–1388 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Tutt, A. & Ashworth, A. The relationship between the roles of BRCA genes in DNA repair and cancer predisposition. Trends Mol. Med. 8, 571–576 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. De Soto, J. A et al. The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors. Int. J. Biol. Sci. 2, 179–185 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005). References 84 and 85 demonstrate that BRCA -mutant breast cancer cells are sensitive to PARP inhibition.

    Article  CAS  PubMed  Google Scholar 

  86. McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Löser, D. A. et al. Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair. Mol. Cancer Ther. 9, 1775–1787 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Bryant, H. E. & Helleday, T. Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair. Nucleic Acids Res. 34, 1685–1691 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kennedy, R. D. et al. Fanconi anemia pathway-deficient tumor cells are hypersensitive to inhibition of ataxia telangiectasia mutated. J. Clin. Invest. 117, 1440–1449 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Liu, P., Cheng, H., Roberts, T. M. & Zhao, J. J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nature Rev. Drug Discov. 8, 627–644 (2009).

    Article  CAS  Google Scholar 

  91. Rainey, M. D., Charlton, M. E., Stanton, R. V. & Kastan, M. B. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res. 68, 7466–7474 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Westphal, C. H. et al. Loss of ATM radiosensitizes multiple p53 null tissues. Cancer Res. 58, 5637–5639 (1998).

    CAS  PubMed  Google Scholar 

  94. Raso, A. et al. Characterization of glioma stem cells through multiple stem cell markers and their specific sensitization to double-strand break-inducing agents by pharmacological inhibition of ataxia telangiectasia mutated protein. Brain Pathol. 22, 677–688 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Brown, E. J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397–402 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Brown, E. J. & Baltimore, D. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17, 615–628 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Shechter, D., Costanzo, V. & Gautier, J. ATR and ATM regulate the timing of DNA replication origin firing. Nature Cell Biol. 6, 648–655 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Toledo, L. I. et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nature Struct. Mol. Biol. 18, 721–727 (2011).

    Article  CAS  Google Scholar 

  99. Fokas, E. et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 3, e441 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Maira, S. M. et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol. Cancer Ther. 7, 1851–1863 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Konstantinidou, G. et al. Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. Cancer Res. 69, 7644–7652 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Mukherjee, B. et al. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 14, 34–43 (2012). This article demonstrates that the dual PI3K–mTOR inhibitor NVP-BEZ235 also blocks ATM and DNA-PK CS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gupta, A. K. et al. The Ras radiation resistance pathway. Cancer Res. 61, 4278–4282 (2001).

    CAS  PubMed  Google Scholar 

  104. Fokas, E. et al. Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature. Cancer Res. 72, 239–248 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Dent, P., Yacoub, A., Fisher, P. B., Hagan, M. P. & Grant, S. MAPK pathways in radiation responses. Oncogene 22, 5885–5896 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Dent, P. et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat. Res. 159, 283–300 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Golding, S. E. et al. Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response. Cancer Res. 67, 1046–1053 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Kriegs, M. et al. The epidermal growth factor receptor modulates DNA double-strand break repair by regulating non-homologous end-joining. DNA Repair 9, 889–897 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Andarawewa, K. L., Paupert, J., Pal, A. & Barcellos-Hoff, M. H. New rationales for using TGFbeta inhibitors in radiotherapy. Int. J. Radiat. Biol. 83, 803–811 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550–562 (2009).

    Article  CAS  Google Scholar 

  111. Gupta, A. K. et al. Local recurrence in head and neck cancer: relationship to radiation resistance and signal transduction. Clin. Cancer Res. 8, 885–892 (2002).

    PubMed  Google Scholar 

  112. Hambardzumyan, D. et al. PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev. 22, 436–448 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kim, I.-A. et al. Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res. 65, 7902–7910 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Bonner, J. A. et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354, 567–578 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Bonner, J. A. et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 11, 21–28 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Eberhard, D. A. et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23, 5900–5909 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Valerie, K. et al. Radiation-induced cell signaling: inside-out and outside-in. Mol. Cancer Ther. 6, 789–801 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Eriksson, D. & Stigbrand, T. Radiation-induced cell death mechanisms. Tumour Biol. 31, 363–372 (2010).

    Article  PubMed  Google Scholar 

  120. Letai, A. G. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nature Rev. Cancer 8, 121–132 (2008).

    Article  CAS  Google Scholar 

  121. Oltersdorf, T. et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435, 677–681 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).

    Article  CAS  PubMed  Google Scholar 

  123. Gandhi, L. et al. Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J. Clin. Oncol. 29, 909–916 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wilson, W. H. et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 11, 1149–1159 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Opferman, J. T. et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307, 1101–1104 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Opferman, J. T. et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426, 671–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Skvara, H. et al. Mcl-1 blocks radiation-induced apoptosis and inhibits clonogenic cell death. Anticancer Res. 25, 2697–2703 (2005).

    CAS  Google Scholar 

  128. Chen, S., Dai, Y., Harada, H., Dent, P. & Grant, S. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res. 67, 782–791 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Moretti, L., Li, B., Kim, K. W., Chen, H. & Lu, B. AT-101, a pan-Bcl-2 inhibitor, leads to radiosensitization of non-small cell lung cancer. J. Thorac. Oncol. 5, 680–687 (2010).

    Article  PubMed  Google Scholar 

  130. Zerp, S. F. et al. AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis. Radiat. Oncol. 4, 47 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Hudson, S. G. et al. Microarray determination of Bcl-2 family protein inhibition sensitivity in breast cancer cells. Exp. Biol. Med. 238, 248–256 (2013).

    Article  CAS  Google Scholar 

  132. Hollstein, M. Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  CAS  PubMed  Google Scholar 

  133. Wade, M., Wang, Y. V. & Wahl, G. M. The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol. 20, 299–309 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Shangary, S. et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc. Natl Acad. Sci. USA 105, 3933–3938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Vakifahmetoglu, H., Olsson, M. & Zhivotovsky, B. Death through a tragedy: mitotic catastrophe. Cell Death Differ. 15, 1153–1162 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Xu, B., O'Donnell, A., Kim, S.-T. & Kastan, M. B. Phosphorylation of serine 1387 in Brca1 is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation. Cancer Res. 62, 4588–4591 (2002).

    CAS  PubMed  Google Scholar 

  137. Xu, B., Kim, S.-T., Lim, D.-S. & Kastan, M. B. Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol. Cell. Biol. 22, 1049–1059 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bunz, F. et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 (1998).

    Article  CAS  PubMed  Google Scholar 

  139. Waldman, T. et al. Cell-cycle arrest versus cell death in cancer therapy. Nature Med. 3, 1034–1036 (1997).

    Article  CAS  PubMed  Google Scholar 

  140. Wouters, B. G., Giaccia, A. J., Denko, N. C. & Brown, J. M. Loss of p21Waf1/Cip1 sensitizes tumors to radiation by an apoptosis-independent mechanism. Cancer Res. 57, 4703–4706 (1997). References 139 and 140 illustrate that clonogenic survival in vitro does not always predict radiation sensitivity in vivo.

    CAS  PubMed  Google Scholar 

  141. Kirsch, D. G. et al. p53 controls radiation-induced gastrointestinal syndrome in mice independent of apoptosis. Science 327, 593–596 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. Komarova, E. A. et al. Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice. Oncogene 23, 3265–3271 (2004). This articles demonstrates the complex and tissue-dependent role of p53 in acute radiation injury.

    Article  CAS  PubMed  Google Scholar 

  143. Leibowitz, B. J. et al. Uncoupling p53 functions in radiation-induced intestinal damage via PUMA and p21. Mol. Cancer Res. 9, 616–625 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lee, C. L. et al. p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice. Sci. Signal. 5, ra52 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Rowley, R., Hudson, J. & Young, P. G. The wee1 protein kinase is required for radiation-induced mitotic delay. Nature 356, 353–355 (1992).

    Article  CAS  PubMed  Google Scholar 

  146. Sarcar, B. et al. Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Mol. Cancer Ther. 10, 2405–2414 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wang, Y. et al. Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator. Cancer Res. 61, 8211–8217 (2001).

    CAS  PubMed  Google Scholar 

  148. Caretti, V. et al. WEE1 kinase inhibition enhances the radiation response of diffuse intrinsic pontine gliomas. Mol. Cancer Ther. 12, 141–150 (2013).

    Article  CAS  PubMed  Google Scholar 

  149. De Witt Hamer, P. C., Mir, S. E., Noske, D., Van Noorden, C. J. & Würdinger, T. WEE1 kinase targeting combined with DNA-damaging cancer therapy catalyzes mitotic catastrophe. Clin. Cancer Res. 17, 4200–4207 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Bucher, N. & Britten, C. D. G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer. Br. J. Cancer 98, 523–528 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mitchell, J. B. et al. In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762. Clin. Cancer Res. 16, 2076–2084 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Morgan, M. A. et al. Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res. 70, 4972–4981 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Boutros, R., Lobjois, V. & Ducommun, B. CDC25 phosphatases in cancer cells: key players? Good targets? Nature Rev. Cancer 7, 495–507 (2007).

    Article  CAS  Google Scholar 

  154. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Kozin, S. V., Duda, D. G., Munn, L. L. & Jain, R. K. Neovascularization after irradiation: what is the source of newly formed vessels in recurring tumors? J. Natl Cancer Inst. 104, 899–905 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Garcia-Barros, M. et al. Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159 (2003).

    Article  CAS  PubMed  Google Scholar 

  157. Garcia-Barros, M. et al. Impact of stromal sensitivity on radiation response of tumors implanted in SCID hosts revisited. Cancer Res. 70, 8179–8186 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Truman, J. P. et al. Endothelial membrane remodeling is obligate for anti-angiogenic radiosensitization during tumor radiosurgery. PLoS ONE 5, e12310 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Lin, X., Fuks, Z. & Kolesnick, R. Ceramide mediates radiation-induced death of endothelium. Crit. Care Med. 28, N87–N93 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Fuks, Z. & Kolesnick, R. Engaging the vascular component of the tumor response. Cancer Cell 8, 89–91 (2005).

    Article  CAS  PubMed  Google Scholar 

  161. Budach, W., Taghian, A., Freeman, J., Gioioso, D. & Suit, H. D. Impact of stromal sensitivity on radiation response of tumors. J. Natl Cancer Inst. 85, 988–993 (1993). This article provides evidence that the sensitivity of stromal cells to radiation does not affect tumour cure following radiation therapy.

    Article  CAS  PubMed  Google Scholar 

  162. Gerweck, L. E., Vijayappa, S., Kurimasa, A., Ogawa, K. & Chen, D. J. Tumor cell radiosensitivity is a major determinant of tumor response to radiation. Cancer Res. 66, 8352–8355 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Ogawa, K. et al. Influence of tumor cell and stroma sensitivity on tumor response to radiation. Cancer Res. 67, 4016–4021 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. Ahn, G. O. & Brown, J. M. Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: experimental models and clinical perspectives. Cell Cycle 8, 970–976 (2009).

    Article  CAS  PubMed  Google Scholar 

  165. Ahn, G. O. & Brown, J. M. Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature. Angiogenesis 12, 159–164 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Spring, H., Schuler, T., Arnold, B., Hammerling, G. J. & Ganss, R. Chemokines direct endothelial progenitors into tumor neovessels. Proc. Natl Acad. Sci. USA 102, 18111–18116 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  168. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Purhonen, S. et al. Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth. Proc. Natl Acad. Sci. USA 105, 6620–6625 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Kozin, S. V., Duda, D. G., Munn, L. L. & Jain, R. K. Is vasculogenesis crucial for the regrowth of irradiated tumours? Nature Rev. Cancer 11, 532 (2011). This article is a comprehensive review on vascular damage and regrowth following radiation therapy.

    Article  CAS  Google Scholar 

  171. Kozin, S. V. et al. Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res. 70, 5679–5685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Kioi, M. et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694–705 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Ahn, G. O. & Brown, J. M. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell 13, 193–205 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ahn, G. O. et al. Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc. Natl Acad. Sci. USA 107, 8363–8368 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Tseng, D., Vasquez-Medrano, D. A. & Brown, J. M. Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. Br. J. Cancer 104, 1805–1809 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Liu, S. K. et al. Delta-like ligand 4–Notch blockade and tumor radiation response. J. Natl Cancer Inst. 103, 1778–1798 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Lee, C. G. et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 60, 5565–5570 (2000).

    CAS  PubMed  Google Scholar 

  178. Dings, R. P. et al. Scheduling of radiation with angiogenesis inhibitors anginex and avastin improves therapeutic outcome via vessel normalization. Clin. Cancer Res. 13, 3395–3402 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Teng, L.-S. et al. Advances in combination of antiangiogenic agents targeting VEGF-binding and conventional chemotherapy and radiation for cancer treatment. JCMA 73, 281–288 (2010).

    CAS  PubMed  Google Scholar 

  180. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Med. 10, 145–147 (2004).

    Article  CAS  PubMed  Google Scholar 

  181. Willett, C. G. et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J. Clin. Oncol. 27, 3020–3026 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lai, A. et al. Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J. Clin. Oncol. 29, 142–148 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Drappatz, J. et al. Phase I study of vandetanib with radiotherapy and temozolomide for newly diagnosed glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 78, 85–90 (2010).

    Article  CAS  PubMed  Google Scholar 

  184. Stiewe, T. The p53 family in differentiation and tumorigenesis. Nature Rev. Cancer 7, 165–168 (2007).

    Article  CAS  Google Scholar 

  185. Gudkov, A. V. & Komarova, E. A. The role of p53 in determining sensitivity to radiotherapy. Nature Rev. Cancer 3, 117–129 (2003).

    Article  CAS  Google Scholar 

  186. Komarova, E. A., Christov, K., Faerman, A. I. & Gudkov, A. V. Different impact of p53 and p21 on the radiation response of mouse tissues. Oncogene 19, 3791–3798 (2000).

    Article  CAS  PubMed  Google Scholar 

  187. MacCallum, D. E. et al. The p53 response to ionising radiation in adult and developing murine tissues. Oncogene 13, 2575–2587 (1996).

    CAS  PubMed  Google Scholar 

  188. Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A. & Jacks, T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362, 847–849 (1993).

    Article  CAS  PubMed  Google Scholar 

  189. Yu, H. et al. Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose gamma-irradiation. Blood 115, 3472–3480 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Brosh, R. & Rotter, V. When mutants gain new powers: news from the mutant p53 field. Nature Rev. Cancer 9, 701–713 (2009).

    Article  CAS  Google Scholar 

  191. Burdelya, L. G. et al. Inhibition of p53 response in tumor stroma improves efficacy of anticancer treatment by increasing antiangiogenic effects of chemotherapy and radiotherapy in mice. Cancer Res. 66, 9356–9361 (2006).

    Article  CAS  PubMed  Google Scholar 

  192. Gough, M. J. & Crittenden, M. R. Combination approaches to immunotherapy: the radiotherapy example. Immunotherapy 1, 1025–1037 (2009).

    Article  PubMed  Google Scholar 

  193. DuPage, M. et al. Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. Cancer Cell 19, 72–85 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. DuPage, M., Mazumdar, C., Schmidt, L. M., Cheung, A. F. & Jacks, T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482, 405–409 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–999 (2002).

    Article  CAS  Google Scholar 

  196. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  197. Ehlers, G. & Fridman, M. Abscopal effect of radiation in papillary adenocarcinoma. Br. J. Radiol. 46, 220–222 (1973).

    Article  CAS  PubMed  Google Scholar 

  198. Kingsley, D. P. An interesting case of possible abscopal effect in malignant melanoma. Br. J. Radiol. 48, 863–866 (1975).

    Article  CAS  PubMed  Google Scholar 

  199. Nobler, M. P. The abscopal effect in malignant lymphoma and its relationship to lymphocyte circulation. Radiology 93, 410–412 (1969).

    Article  CAS  PubMed  Google Scholar 

  200. Ohba, K. et al. Abscopal regression of hepatocellular carcinoma after radiotherapy for bone metastasis. Gut 43, 575–577 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. Biol. Phys. 58, 862–870 (2004). This article provides evidence that local radiation therapy can activate the immune system to fight distant metastatic disease.

    Article  PubMed  Google Scholar 

  203. Hallahan, D. E., Spriggs, D. R., Beckett, M. A., Kufe, D. W. & Weichselbaum, R. R. Increased tumor necrosis factor α mRNA after cellular exposure to ionizing radiation. Proc. Natl Acad. Sci. USA 86, 10104–10107 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Hong, J. H. et al. Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation. Int. J. Radiat. Biol. 75, 1421–1427 (1999).

    Article  CAS  PubMed  Google Scholar 

  205. Nemoto, K. et al. Expression of IL-1β mRNA in mice after whole body X-irradiation. J. Radiat. Res. 36, 125–133 (1995).

    Article  CAS  PubMed  Google Scholar 

  206. Hareyama, M. et al. Effect of radiation on the expression of carcinoembryonic antigen of human gastric adenocarcinoma cells. Cancer 67, 2269–2274 (1991).

    Article  CAS  PubMed  Google Scholar 

  207. Hauser, S. H., Calorini, L., Wazer, D. E. & Gattoni-Celli, S. Radiation-enhanced expression of major histocompatibility complex class I antigen H-2Db in B16 melanoma cells. Cancer Res. 53, 1952–1955 (1993).

    CAS  PubMed  Google Scholar 

  208. Nesslinger, N. J. et al. Standard treatments induce antigen-specific immune responses in prostate cancer. Clin. Cancer Res. 13, 1493–1502 (2007).

    Article  CAS  PubMed  Google Scholar 

  209. Schaue, D., Xie, M. W., Ratikan, J. A. & McBride, W. H. Regulatory T cells in radiotherapeutic responses. Front. Oncol. 2, 90 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).

    CAS  PubMed  Google Scholar 

  211. Kachikwu, E. L. et al. Radiation enhances regulatory T cell representation. Int. J. Radiat. Oncol. Biol. Phys. 81, 1128–1135 (2011).

    Article  PubMed  Google Scholar 

  212. Eltzschig, H. K. & Eckle, T. Ischemia and reperfusion —from mechanism to translation. Nature Med. 17, 1391–1401 (2011).

    Article  CAS  PubMed  Google Scholar 

  213. Stone, H. B. et al. Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3–4, 2003. Radiat. Res. 162, 711–728 (2004).

    Article  CAS  PubMed  Google Scholar 

  214. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    Article  CAS  PubMed  Google Scholar 

  215. Coppes, R. P., van der Goot, A. & Lombaert, I. M. Stem cell therapy to reduce radiation-induced normal tissue damage. Semin. Radiat. Oncol. 19, 112–121 (2009).

    Article  PubMed  Google Scholar 

  216. Blanpain, C., Mohrin, M., Sotiropoulou, P. A. & Passegue, E. DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell 8, 16–29 (2011).

    Article  CAS  PubMed  Google Scholar 

  217. Mitchell, J. B. et al. Inhibition of oxygen-dependent radiation-induced damage by the nitroxide superoxide dismutase mimic, tempol. Arch. Biochem. Biophys. 289, 62–70 (1991).

    Article  CAS  PubMed  Google Scholar 

  218. Metz, J. M. et al. A phase I study of topical tempol for the prevention of alopecia induced by whole brain radiotherapy. Clin. Cancer Res. 10, 6411–6417 (2004).

    Article  CAS  PubMed  Google Scholar 

  219. Citrin, D. et al. Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist 15, 360–371 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Bairati, I. et al. Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J. Clin. Oncol. 23, 5805–5813 (2005).

    Article  CAS  PubMed  Google Scholar 

  221. Meyer, F. et al. Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. Int. J. Cancer 122, 1679–1683 (2008).

    Article  CAS  PubMed  Google Scholar 

  222. Robbins, M. E. & Zhao, W. Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int. J. Radiat. Biol. 80, 251–259 (2004).

    Article  CAS  PubMed  Google Scholar 

  223. Jack, C. I. et al. Indicators of free radical activity in patients developing radiation pneumonitis. Int. J. Radiat. Oncol. Biol. Phys. 34, 149–154 (1996).

    Article  CAS  PubMed  Google Scholar 

  224. Kang, S. K. et al. Overexpression of extracellular superoxide dismutase protects mice from radiation-induced lung injury. Int. J. Radiat. Oncol. Biol. Phys. 57, 1056–1066 (2003).

    Article  CAS  PubMed  Google Scholar 

  225. Robbins, M. E., Zhao, W., Davis, C., Toyokuni, S. & Bonsib, S. M. Radiation-induced kidney injury: a role for chronic oxidative stress? Micron 33, 133–141 (2002).

    Article  CAS  PubMed  Google Scholar 

  226. Carpenter, M. et al. Inhalation delivery of manganese superoxide dismutase-plasmid/liposomes protects the murine lung from irradiation damage. Gene Ther. 12, 685–693 (2005).

    Article  CAS  PubMed  Google Scholar 

  227. Lefaix, J. L. et al. Successful treatment of radiation-induced fibrosis using Cu/Zn-SOD and Mn-SOD: an experimental study. Int. J. Radiat. Oncol. Biol. Phys. 35, 305–312 (1996).

    Article  CAS  PubMed  Google Scholar 

  228. Delanian, S. et al. Successful treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide dismutase: clinical trial. Radiother. Oncol. 32, 12–20 (1994). This study provides support for SOD to mitigate radiation-induced fibrosis in patients.

    Article  CAS  PubMed  Google Scholar 

  229. Delanian, S., Balla-Mekias, S. & Lefaix, J. L. Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol. J. Clin. Oncol. 17, 3283–3290 (1999).

    Article  CAS  PubMed  Google Scholar 

  230. Lefaix, J. L. et al. Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and α-tocopherol: an experimental study. Int. J. Radiat. Oncol. Biol. Phys. 43, 839–847 (1999).

    Article  CAS  PubMed  Google Scholar 

  231. Komarov, P. G. et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733–1737 (1999).

    Article  CAS  PubMed  Google Scholar 

  232. Takagi, M., Absalon, M. J., McLure, K. G. & Kastan, M. B. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 123, 49–63 (2005).

    Article  CAS  PubMed  Google Scholar 

  233. Chen, J. & Kastan, M. B. 5′–3′-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage. Genes Dev. 24, 2146–2156 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006). This article indicates that an acute p53 response to DNA damage is not necessary for p53-mediated tumour suppression.

    Article  CAS  PubMed  Google Scholar 

  235. Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Brady, C. A. et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 145, 571–583 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Okatani, Y., Wakatsuki, A., Shinohara, K., Kaneda, C. & Fukaya, T. Melatonin stimulates glutathione peroxidase activity in human chorion. J. Pineal Res. 30, 199–205 (2001).

    Article  CAS  PubMed  Google Scholar 

  238. Akagi, T. et al. Chronopharmacology of melatonin in mice to maximize the antitumor effect and minimize the rhythm disturbance effect. J. Pharmacol. Exp. Ther. 308, 378–384 (2004).

    Article  CAS  PubMed  Google Scholar 

  239. Berk, L. et al. Randomized phase II trial of high-dose melatonin and radiation therapy for RPA class 2 patients with brain metastases (RTOG 0119). Int. J. Radiat. Oncol. Biol. Phys. 68, 852–857 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Bertho, J.-M. et al. Comparison of autologous cell therapy and granulocyte-colony stimulating factor (G-CSF) injection versus G-CSF injection alone for the treatment of acute radiation syndrome in a non-human primate model. Int. J. Radiat. Oncol. Biol. Phys. 63, 911–920 (2005).

    Article  CAS  PubMed  Google Scholar 

  241. Uckun, F. M., Souza, L., Waddick, K. G., Wick, M. & Song, C. W. In vivo radioprotective effects of recombinant human granulocyte colony-stimulating factor in lethally irradiated mice. Blood 75, 638–645 (1990).

    Article  CAS  PubMed  Google Scholar 

  242. Finch, P. W. & Rubin, J. S. Keratinocyte growth factor/fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair. Adv. Cancer Res. 91, 69–136 (2004).

    Article  CAS  PubMed  Google Scholar 

  243. Lombaert, I. M. et al. Keratinocyte growth factor prevents radiation damage to salivary glands by expansion of the stem/progenitor pool. Stem Cells 26, 2595–2601 (2008).

    Article  CAS  PubMed  Google Scholar 

  244. Farrell, C. L. et al. Effects of keratinocyte growth factor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice. Int. J. Radiat. Biol. 75, 609–620 (1999).

    Article  CAS  PubMed  Google Scholar 

  245. Brizel, D. M. et al. Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma. J. Clin. Oncol. 26, 2489–2496 (2008).

    Article  CAS  PubMed  Google Scholar 

  246. Paris, F. et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293, 293–297 (2001).

    Article  CAS  PubMed  Google Scholar 

  247. Schuller, B. W. et al. No significant endothelial apoptosis in the radiation-induced gastrointestinal syndrome. Int. J. Radiat. Oncol. Biol. Phys. 68, 205–210 (2007).

    Article  CAS  PubMed  Google Scholar 

  248. Fuks, Z. et al. Basic fibroblast growth factor protects endothelial cells against radiation-induced programmed cell death in vitro and in vivo. Cancer Res. 54, 2582–2590 (1994).

    CAS  PubMed  Google Scholar 

  249. Rotolo, J. et al. Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice. J. Clin. Invest. 122, 1786–1790 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Zhang, L. et al. Mitigation effect of an FGF-2 peptide on acute gastrointestinal syndrome after high-dose ionizing radiation. Int. J. Radiat. Oncol. Biol. Phys. 77, 261–268 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Wang, Y. et al. Activation of nuclear factor κB in vivo selectively protects the murine small intestine against ionizing radiation-induced damage. Cancer Res. 64, 6240–6246 (2004).

    Article  CAS  PubMed  Google Scholar 

  252. Burdelya, L. G. et al. An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320, 226–230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Martin, M., Lefaix, J. & Delanian, S. TGF-β1 and radiation fibrosis: a master switch and a specific therapeutic target? Int. J. Radiat. Oncol. Biol. Phys. 47, 277–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  254. Anscher, M. S., Thrasher, B., Rabbani, Z., Teicher, B. & Vujaskovic, Z. Antitransforming growth factor-β antibody 1D11 ameliorates normal tissue damage caused by high-dose radiation. Int. J. Radiat. Oncol. Biol. Phys. 65, 876–881 (2006).

    Article  CAS  PubMed  Google Scholar 

  255. Anscher, M. S. et al. Small molecular inhibitor of transforming growth factor-β protects against development of radiation-induced lung injury. Int. J. Radiat. Oncol. Biol. Phys. 71, 829–837 (2008).

    Article  CAS  PubMed  Google Scholar 

  256. Zheng, H., Wang, J., Koteliansky, V. E., Gotwals, P. J. & Hauer-Jensen, M. Recombinant soluble transforming growth factor β type II receptor ameliorates radiation enteropathy in mice. Gastroenterology 119, 1286–1296 (2000).

    Article  CAS  PubMed  Google Scholar 

  257. Verheij, M., Stewart, F., Oussoren, Y., Weening, J. & Dewit, L. Amelioration of radiation nephropathy by acetylsalicylic acid. Int. J. Radiat. Biol. 67, 587–596 (1995).

    Article  CAS  PubMed  Google Scholar 

  258. Wang, J. et al. Hirudin ameliorates intestinal radiation toxicity in the rat: support for thrombin inhibition as strategy to minimize side-effects after radiation therapy and as countermeasure against radiation exposure. J. Thromb. Haemost. 2, 2027–2035 (2004).

    Article  CAS  PubMed  Google Scholar 

  259. Wang, J. et al. Short-term inhibition of ADP-induced platelet aggregation by clopidogrel ameliorates radiation-induced toxicity in rat small intestine. Thromb. Haemostasis 87, 122–128 (2002).

    Article  CAS  Google Scholar 

  260. Glantz, M. J. et al. Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 44, 2020–2027 (1994).

    Article  CAS  PubMed  Google Scholar 

  261. Mosnier, L. O., Zlokovic, B. V. & Griffin, J. H. The cytoprotective protein C pathway. Blood 109, 3161–3172 (2007).

    Article  CAS  PubMed  Google Scholar 

  262. Geiger, H. et al. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nature Med. 18, 1123–1129 (2012). This article demonstrates mitigation of acute radiation injury when the thrombomodulin-activated protein C pathway is targeted 24 hours after exposure to radiation.

    Article  CAS  PubMed  Google Scholar 

  263. Jain, M. K. & Ridker, P. M. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nature Rev. Drug Discov. 4, 977–987 (2005).

    Article  CAS  Google Scholar 

  264. Williams, J. P. et al. Effect of administration of lovastatin on the development of late pulmonary effects after whole-lung irradiation in a murine model. Radiat. Res. 161, 560–567 (2004).

    Article  CAS  PubMed  Google Scholar 

  265. Wang, J. et al. Simvastatin ameliorates radiation enteropathy development after localized, fractionated irradiation by a protein C-independent mechanism. Int. J. Radiat. Oncol. Biol. Phys. 68, 1483–1490 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Haydont, V. et al. Successful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection. Int. J. Radiat. Oncol. Biol. Phys. 68, 1471–1482 (2007).

    Article  CAS  PubMed  Google Scholar 

  267. Daynes, R. A. & Jones, D. C. Emerging roles of PPARs in inflammation and immunity. Nature Rev. Immunol. 2, 748–759 (2002).

    Article  CAS  Google Scholar 

  268. Ramanan, S. et al. The PPARα agonist fenofibrate preserves hippocampal neurogenesis and inhibits microglial activation after whole-brain irradiation. Int. J. Radiat. Oncol. Biol. Phys. 75, 870–877 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Molteni, A. et al. Effect of an angiotensin II receptor blocker and two angiotensin converting enzyme inhibitors on transforming growth factor-β (TGF-β) and α-actomyosin (α SMA), important mediators of radiation-induced pneumopathy and lung fibrosis. Curr. Pharm. Design 13, 1307–1316 (2007).

    Article  CAS  Google Scholar 

  270. Moulder, J. E., Fish, B. L. & Cohen, E. P. ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy. Curr. Pharm. Design 9, 737–749 (2003).

    Article  CAS  Google Scholar 

  271. Ryu, S., Kolozsvary, A., Jenrow, K. A., Brown, S. L. & Kim, J. H. Mitigation of radiation-induced optic neuropathy in rats by ACE inhibitor ramipril: importance of ramipril dose and treatment time. J. Neuro-Oncol. 82, 119–124 (2007).

    Article  CAS  Google Scholar 

  272. Moulder, J. E. & Cohen, E. P. Future strategies for mitigation and treatment of chronic radiation-induced normal tissue injury. Semin. Radiat. Oncol. 17, 141–148 (2007).

    Article  PubMed  Google Scholar 

  273. Waselenko, J. K. et al. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann. Internal Med. 140, 1037–1051 (2004).

    Article  Google Scholar 

  274. Lombaert, I. M. et al. Rescue of salivary gland function after stem cell transplantation in irradiated glands. PLoS ONE 3, e2063 (2008). This article illustrates that stem cell transplantation can contribute to the function of solid organs after radiation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  275. Vieyra, D. S., Jackson, K. A. & Goodell, M. A. Plasticity and tissue regenerative potential of bone marrow-derived cells. Stem Cell Rev. 1, 65–69 (2005).

    Article  PubMed  Google Scholar 

  276. Lombaert, I. M. et al. Mobilization of bone marrow stem cells by granulocyte colony-stimulating factor ameliorates radiation-induced damage to salivary glands. Clin. Cancer Res. 12, 1804–1812 (2006).

    Article  CAS  PubMed  Google Scholar 

  277. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

    Article  CAS  PubMed  Google Scholar 

  278. Epperly, M. W. et al. Bone marrow origin of cells with capacity for homing and differentiation to esophageal squamous epithelium. Radiat. Res. 162, 233–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  279. Murry, C. E. & Keller, G. Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development. Cell 132, 661–680 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the US National Institutes of Health and the Duke Cancer Institute for long-term financial support.

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Haematopoietic syndrome

Acute radiation toxicity caused by bone marrow failure that occurs within a month after whole-body exposure to radiation.

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Moding, E., Kastan, M. & Kirsch, D. Strategies for optimizing the response of cancer and normal tissues to radiation. Nat Rev Drug Discov 12, 526–542 (2013). https://doi.org/10.1038/nrd4003

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