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.

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.

References

  1. 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. 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.

    Google Scholar 

  3. 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).

    PubMed  Google Scholar 

  4. 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).

    PubMed  Google Scholar 

  5. 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).

    PubMed  Google Scholar 

  6. 6

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

    PubMed  Google Scholar 

  7. 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).

    PubMed  Google Scholar 

  8. 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).

    PubMed  Google Scholar 

  9. 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).

    PubMed  Google Scholar 

  10. 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.

    Google Scholar 

  11. 11

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

    PubMed  Google Scholar 

  12. 12

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

    PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

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

    PubMed  Google Scholar 

  15. 15

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

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

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

    PubMed  Google Scholar 

  17. 17

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

    CAS  PubMed  Google Scholar 

  18. 18

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

    CAS  Google Scholar 

  19. 19

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

    CAS  Google Scholar 

  20. 20

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

    PubMed  Google Scholar 

  21. 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).

    CAS  Google Scholar 

  22. 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).

    PubMed  Google Scholar 

  23. 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).

    CAS  PubMed  Google Scholar 

  24. 24

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

    CAS  PubMed  Google Scholar 

  25. 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.

    PubMed  Google Scholar 

  26. 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. 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).

    CAS  PubMed  Google Scholar 

  28. 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. 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).

    CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. 31

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

    CAS  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

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

    Google Scholar 

  35. 35

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

    CAS  PubMed  Google Scholar 

  36. 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. 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).

    CAS  PubMed  Google Scholar 

  38. 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. 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).

    CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  Google Scholar 

  42. 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.

    CAS  PubMed  Google Scholar 

  43. 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).

    CAS  PubMed  Google Scholar 

  44. 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).

    CAS  PubMed  Google Scholar 

  45. 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).

    CAS  PubMed  Google Scholar 

  46. 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).

    CAS  Google Scholar 

  47. 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. 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).

    CAS  PubMed  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. 50

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

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  PubMed  Google Scholar 

  53. 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).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    CAS  Google Scholar 

  56. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

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

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

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

    PubMed  PubMed Central  Google Scholar 

  59. 59

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

    CAS  Google Scholar 

  60. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

  62. 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. 63

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

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

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

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

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

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

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

    CAS  Google Scholar 

  70. 70

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

    CAS  Google Scholar 

  71. 71

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

    CAS  PubMed  Google Scholar 

  72. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

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

    CAS  PubMed  Google Scholar 

  75. 75

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

    CAS  PubMed  Google Scholar 

  76. 76

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

    CAS  Google Scholar 

  77. 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).

    PubMed  Google Scholar 

  78. 78

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

    CAS  PubMed  Google Scholar 

  79. 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).

    CAS  Google Scholar 

  80. 80

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

    CAS  Google Scholar 

  81. 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).

    CAS  PubMed  Google Scholar 

  82. 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).

    CAS  PubMed  Google Scholar 

  83. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

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

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 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.

    CAS  Google Scholar 

  86. 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).

    CAS  PubMed  Google Scholar 

  87. 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).

    PubMed  PubMed Central  Google Scholar 

  88. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 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).

    CAS  Google Scholar 

  91. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. 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. 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).

    CAS  PubMed  Google Scholar 

  95. 95

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

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 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).

    CAS  PubMed  Google Scholar 

  98. 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).

    CAS  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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).

    CAS  PubMed  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

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

    CAS  PubMed  Google Scholar 

  104. 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).

    CAS  PubMed  Google Scholar 

  105. 105

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

    CAS  PubMed  Google Scholar 

  106. 106

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

    CAS  PubMed  Google Scholar 

  107. 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).

    CAS  PubMed  Google Scholar 

  108. 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).

    CAS  PubMed  Google Scholar 

  109. 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).

    CAS  PubMed  Google Scholar 

  110. 110

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

    CAS  Google Scholar 

  111. 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. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 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).

    CAS  PubMed  Google Scholar 

  114. 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).

    CAS  PubMed  Google Scholar 

  115. 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).

    CAS  PubMed  Google Scholar 

  116. 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).

    CAS  PubMed  Google Scholar 

  117. 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).

    CAS  PubMed  Google Scholar 

  118. 118

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

    CAS  PubMed  Google Scholar 

  119. 119

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

    PubMed  Google Scholar 

  120. 120

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

    CAS  Google Scholar 

  121. 121

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

    CAS  PubMed  Google Scholar 

  122. 122

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

    CAS  PubMed  Google Scholar 

  123. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 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).

    CAS  PubMed  Google Scholar 

  126. 126

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

    CAS  PubMed  Google Scholar 

  127. 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. 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).

    CAS  PubMed  Google Scholar 

  129. 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).

    PubMed  Google Scholar 

  130. 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).

    PubMed  PubMed Central  Google Scholar 

  131. 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).

    CAS  Google Scholar 

  132. 132

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

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 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).

    CAS  PubMed  Google Scholar 

  135. 135

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

    CAS  PubMed  Google Scholar 

  136. 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. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

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

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

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

    CAS  PubMed  Google Scholar 

  140. 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. 141

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

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 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.

    CAS  PubMed  Google Scholar 

  143. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

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

    PubMed  PubMed Central  Google Scholar 

  145. 145

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

    CAS  PubMed  Google Scholar 

  146. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 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. 148

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

    CAS  PubMed  Google Scholar 

  149. 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).

    CAS  PubMed  Google Scholar 

  150. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

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

    CAS  Google Scholar 

  154. 154

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

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 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).

    PubMed  PubMed Central  Google Scholar 

  156. 156

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

    CAS  PubMed  Google Scholar 

  157. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

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

    PubMed  PubMed Central  Google Scholar 

  159. 159

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

    CAS  PubMed  Google Scholar 

  160. 160

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

    CAS  PubMed  Google Scholar 

  161. 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.

    CAS  PubMed  Google Scholar 

  162. 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).

    CAS  PubMed  Google Scholar 

  163. 163

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

    CAS  PubMed  Google Scholar 

  164. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 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).

    CAS  PubMed  Google Scholar 

  167. 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).

    CAS  Google Scholar 

  168. 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).

    CAS  PubMed  Google Scholar 

  169. 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).

    CAS  PubMed  Google Scholar 

  170. 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.

    CAS  Google Scholar 

  171. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 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).

    CAS  PubMed  Google Scholar 

  175. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

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

    CAS  PubMed  Google Scholar 

  177. 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. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 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. 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).

    CAS  PubMed  Google Scholar 

  181. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 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).

    CAS  PubMed  Google Scholar 

  183. 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).

    CAS  PubMed  Google Scholar 

  184. 184

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

    CAS  Google Scholar 

  185. 185

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

    CAS  Google Scholar 

  186. 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).

    CAS  PubMed  Google Scholar 

  187. 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. 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).

    CAS  PubMed  Google Scholar 

  189. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

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

    CAS  Google Scholar 

  191. 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).

    CAS  PubMed  Google Scholar 

  192. 192

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

    PubMed  Google Scholar 

  193. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 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).

    CAS  Google Scholar 

  196. 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).

    CAS  Google Scholar 

  197. 197

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

    CAS  PubMed  Google Scholar 

  198. 198

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

    CAS  PubMed  Google Scholar 

  199. 199

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

    CAS  PubMed  Google Scholar 

  200. 200

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

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 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.

    PubMed  Google Scholar 

  203. 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).

    CAS  PubMed  Google Scholar 

  204. 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).

    CAS  PubMed  Google Scholar 

  205. 205

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

    CAS  PubMed  Google Scholar 

  206. 206

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

    CAS  PubMed  Google Scholar 

  207. 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. 208

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

    CAS  PubMed  Google Scholar 

  209. 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. 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. 211

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

    PubMed  Google Scholar 

  212. 212

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

    CAS  PubMed  Google Scholar 

  213. 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).

    CAS  PubMed  Google Scholar 

  214. 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).

    CAS  PubMed  Google Scholar 

  215. 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).

    PubMed  Google Scholar 

  216. 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).

    CAS  PubMed  Google Scholar 

  217. 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).

    CAS  PubMed  Google Scholar 

  218. 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).

    CAS  PubMed  Google Scholar 

  219. 219

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

    PubMed  PubMed Central  Google Scholar 

  220. 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).

    CAS  PubMed  Google Scholar 

  221. 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).

    CAS  PubMed  Google Scholar 

  222. 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).

    CAS  PubMed  Google Scholar 

  223. 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).

    CAS  PubMed  Google Scholar 

  224. 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).

    CAS  PubMed  Google Scholar 

  225. 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).

    CAS  PubMed  Google Scholar 

  226. 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).

    CAS  PubMed  Google Scholar 

  227. 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).

    CAS  PubMed  Google Scholar 

  228. 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.

    CAS  PubMed  Google Scholar 

  229. 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).

    CAS  PubMed  Google Scholar 

  230. 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).

    CAS  PubMed  Google Scholar 

  231. 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).

    CAS  PubMed  Google Scholar 

  232. 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).

    CAS  PubMed  Google Scholar 

  233. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 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.

    CAS  Google Scholar 

  235. 235

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

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 236

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

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 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).

    CAS  PubMed  Google Scholar 

  238. 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).

    CAS  PubMed  Google Scholar 

  239. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 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).

    CAS  PubMed  Google Scholar 

  241. 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).

    CAS  PubMed  Google Scholar 

  242. 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).

    CAS  PubMed  Google Scholar 

  243. 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).

    CAS  PubMed  Google Scholar 

  244. 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).

    CAS  PubMed  Google Scholar 

  245. 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).

    CAS  PubMed  Google Scholar 

  246. 246

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

    CAS  PubMed  Google Scholar 

  247. 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).

    CAS  PubMed  Google Scholar 

  248. 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. 249

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

    CAS  PubMed  PubMed Central  Google Scholar 

  250. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  251. 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).

    CAS  PubMed  Google Scholar 

  252. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. 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).

    CAS  PubMed  Google Scholar 

  254. 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).

    CAS  PubMed  Google Scholar 

  255. 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).

    CAS  PubMed  Google Scholar 

  256. 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).

    CAS  PubMed  Google Scholar 

  257. 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).

    CAS  PubMed  Google Scholar 

  258. 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).

    CAS  PubMed  Google Scholar 

  259. 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).

    CAS  Google Scholar 

  260. 260

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

    CAS  PubMed  Google Scholar 

  261. 261

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

    CAS  PubMed  Google Scholar 

  262. 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.

    CAS  PubMed  Google Scholar 

  263. 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).

    CAS  Google Scholar 

  264. 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).

    CAS  PubMed  Google Scholar 

  265. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  266. 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).

    CAS  PubMed  Google Scholar 

  267. 267

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

    CAS  Google Scholar 

  268. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. 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).

    CAS  Google Scholar 

  270. 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).

    CAS  Google Scholar 

  271. 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).

    CAS  Google Scholar 

  272. 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).

    PubMed  Google Scholar 

  273. 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).

    Google Scholar 

  274. 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.

    PubMed  PubMed Central  Google Scholar 

  275. 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).

    PubMed  Google Scholar 

  276. 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).

    CAS  PubMed  Google Scholar 

  277. 277

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

    CAS  PubMed  Google Scholar 

  278. 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).

    CAS  PubMed  Google Scholar 

  279. 279

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

    CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Affiliations

Authors

Corresponding author

Correspondence to David G. Kirsch.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

Kirsch research laboratory

PowerPoint slides

Glossary

Haematopoietic syndrome

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing