Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology


Radiation therapy has curative or palliative potential in roughly half of all incident solid tumours, and offers organ and function preservation in most cases. Unfortunately, early and late toxicity limits the deliverable intensity of radiotherapy, and might affect the long-term health-related quality of life of the patient. Recent progress in molecular pathology and normal-tissue radiobiology has improved the mechanistic understanding of late normal-tissue effects and shifted the focus from initial-damage induction to damage recognition and tissue remodelling. This stimulates research into new pharmacological strategies for preventing or reducing the side effects of radiation therapy.

Key Points

  • Around 50% of patients with solid malignant tumours receive radiation therapy with curative or palliative intent at some point in the course of their disease. Early and late side effects limit radiation dose and might affect the long-term health-related quality of life of the patient.

  • The classical framework for discussing early and late side effects was the target-cell hypothesis: that the severity of side effects mainly reflected cell depletion as a result of the direct cell killing of a putative target cell leading to subsequent functional deficiency. This was the prevailing biological model until the mid 1990s.

  • Recent research in radiobiology and molecular pathology has caused a change of paradigm, particularly in the understanding of late effects: radiation induces a concerted biological response at the cell and tissue level effected by the early activation of cytokine cascades.

  • Fibrogenesis and excessive extracellular matrix and collagen deposition has a key role in the development and expression of many types of late effects. This can be seen as a wound-healing response gone wrong.

  • Transforming growth factor-β is a key fibrogenic cytokine. Its activation, signalling pathway and downstream effects are understood in some detail and offer a number of potential targets for therapeutic intervention in the pathogenic process. This 'bottom-up' approach has benefited from the translation of findings from molecular pathology studies of other diseases characterized by the excessive development of fibrosis.

  • Patient-to-patient variability in the response to radiotherapy represents a 'top-down' discovery strategy whereby clinical outcome data are linked with data from high-throughput assays.

  • Radiogenomics is the study of genetic variation as an explanation for inter-individual differences in radiotherapy response. Most of the research so far has concentrated on single-nucleotide polymorphisms (SNPs) in selected candidate genes, but genome-wide approaches seem to be within reach in the near future.

  • Advances in molecular radiation pathology combined with advances in clinical radiobiology, radiation therapy planning and delivery technology are likely to improve radiation therapy outcome within the next 5–10 years.

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Figure 1: Phases of normal wound healing and radiation-induced fibrosis over time.
Figure 2: Key processes in radiation fibrogenesis.


  1. 1

    Ringborg, U. et al. The Swedish Council on Technology Assessment in Health Care (SBU) systematic overview of radiotherapy for cancer including a prospective survey of radiotherapy practice in Sweden 2001 — summary and conclusions. Acta Oncol. 42, 357–365 (2003).

  2. 2

    Center for Disease Control (USA). Cancer Survivorship — United States, 1971–2001. Center for Disease Control [online]

  3. 3

    Bentzen, S. M. & Overgaard, M. in Advances in Radiation Biology, Vol. 18 (eds Altman, K. I. & Lett, J. T.) 25–51 (Academic Press, San Diego, 1994).

  4. 4

    Hawkins, M. M. Long-term survivors of childhood cancers: what knowledge have we gained? Nature Clin. Pract. Oncol. 1, 26–31 (2004).

  5. 5

    Yabroff, K. R., Lawrence, W. F., Clauser, S., Davis, W. W. & Brown, M. L. Burden of illness in cancer survivors: findings from a population-based national sample. J. Natl Cancer Inst. 96, 1322–1330 (2004). Important population-based study of the long-term consequences of cancer survivorship in 1,823 cancer survivors and 5,469 age-, sex- and educational-attainment-matched control subjects.

  6. 6

    Bentzen, S. M. et al. Normal tissue effects: reporting and analysis. Semin. Radiat. Oncol. 13, 189–202 (2003).

  7. 7

    Soares, H. P. et al. Evaluation of new treatments in radiation oncology: are they better than standard treatments? JAMA 293, 970–978 (2005).

  8. 8

    Allan, J. M. & Travis, L. B. Mechanisms of therapy-related carcinogenesis. Nature Rev. Cancer. 5, 943–955 (2005).

  9. 9

    Bentzen, S. M., Saunders, M. I., Dische, S. & Bond, S. J. Radiotherapy-related early morbidity in head and neck cancer: quantitative clinical radiobiology as deduced from the CHART trial. Radiother. Oncol. 60, 123–135 (2001).

  10. 10

    Bentzen, S. M., Thames, H. D. & Overgaard, M. Latent-time estimation for late cutaneous and subcutaneous radiation reactions in a single-follow-up clinical study. Radiother. Oncol. 15, 267–274 (1989).

  11. 11

    Prise, K. M., Schettino, G., Folkard, M. & Held, K. D. New insights on cell death from radiation exposure. Lancet Oncol. 6, 520–528 (2005).

  12. 12

    Loeffler, J. S., Harris, J. R., Dahlberg, W. K. & Little, J. B. In vitro radiosensitivity of human diploid fibroblasts derived from women with unusually sensitive clinical responses to definitive radiation therapy for breast cancer. Rad. Res. 121, 227–231 (1990). Pioneering study that initiated a whole field of research on the potential association between in vitro cellular radiosensitivity and clinical normal-tissue effects of radiotherapy.

  13. 13

    Brock, W. A. et al. Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer. Int. J. Radiat. Oncol. Biol. Phys. 32, 1371–1379 (1995).

  14. 14

    Burnet, N. G. et al. Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity. Lancet 339, 1570–1571 (1992).

  15. 15

    Geara, F. B., Peters, L. J., Ang, K. K., Wike, J. L. & Brock, W. A. Prospective comparison of in vitro normal cell radiosensitivity and normal tissue reactions in radiotherapy patients. Int. J. Radiat. Oncol. Biol. Phys. 27, 1173–1179 (1993).

  16. 16

    Johansen, J., Bentzen, S. M., Overgaard, J. & Overgaard, M. Evidence for a positive correlation between in vitro radiosensitivity of normal human skin fibroblasts and the occurrence of subcutaneous fibrosis after radiotherapy. Int. J. Radiat. Biol. 66, 407–412 (1994).

  17. 17

    Peacock, J. et al. Cellular radiosensitivity and complication risk after curative radiotherapy. Radiother. Oncol. 55, 173–178 (2000).

  18. 18

    Russell, N. S. et al. Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer. Int. J. Radiat. Biol. 73, 661–670 (1998).

  19. 19

    Dorr, W. Three A's of repopulation during fractionated irradiation of squamous epithelia: Asymmetry loss, Acceleration of stem-cell divisions and Abortive divisions. Int. J. Radiat. Biol. 72, 635–643 (1997). A comprehensive overview of the experimental data underpinning our current model of the early effects of radiation therapy.

  20. 20

    Bentzen, S. M., Overgaard, M. & Thames, H. D. Fractionation sensitivity of a functional endpoint: impaired shoulder movement after postmastectomy radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 17, 531–537 (1989).

  21. 21

    Bentzen, S. M., Skoczylas, J. Z., Overgaard, M. & Overgaard, J. Radiotherapy-related lung fibrosis enhanced by tamoxifen. J. Natl Cancer Inst. 88, 918–922 (1996). Example of the quantitative analysis of clinical radiobiological data. This study showed that tamoxifen increases lung fibrosis after radiotherapy — a finding that was difficult to explain under the target-cell hypothesis.

  22. 22

    Koc, M., Polat, P. & Suma, S. Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Radiother. Oncol. 64, 171–175 (2002).

  23. 23

    Huang, E. Y. et al. Multivariate analysis of pulmonary fibrosis after electron beam irradiation for postmastectomy chest wall and regional lymphatics: evidence for non-dosimetric factors. Radiother. Oncol. 57, 91–96 (2000).

  24. 24

    Dorr, W., Bertmann, S. & Herrmann, T. Radiation induced lung reactions in breast cancer therapy. Modulating factors and consequential effects. Strahlenther. Onkol. 181, 567–573 (2005).

  25. 25

    Rubin, P., Johnston, C. J., Williams, J. P., McDonald, S. & Finkelstein, J. N. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int. J. Radiat. Oncol. Biol. Phys. 33, 99–109 (1995). Ground breaking study of the active biological response to irradiation — a paper that was much more controversial at the time of publication than it seems today.

  26. 26

    Williams, J., Chen, Y., Rubin, P., Finkelstein, J. & Okunieff, P. The biological basis of a comprehensive grading system for the adverse effects of cancer treatment. Semin. Radiat. Oncol. 13, 182–188 (2003).

  27. 27

    Kelly, M., Kolb, M., Bonniaud, P. & Gauldie, J. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr. Pharm. Des. 9, 39–49 (2003).

  28. 28

    Grose, R. & Werner, S. Wound-healing studies in transgenic and knockout mice. Mol. Biotechnol. 28, 147–166 (2004).

  29. 29

    Border, W. A. & Noble, N. A. Transforming growth factor β in tissue fibrosis. N. Engl. J. Med. 331, 1286–1292 (1994).

  30. 30

    Moussad, E. E. & Brigstock, D. R. Connective tissue growth factor: what's in a name? Mol. Genet. Metab. 71, 276–292 (2000).

  31. 31

    Leask, A. & Abraham, D. J. TGFβ signaling and the fibrotic response. FASEB J. 18, 816–827 (2004).

  32. 32

    Hatamochi, A., Mori, K. & Ueki, H. Role of cytokines in controlling connective tissue gene expression. Arch. Dermatol. Res. 287, 115–121 (1994).

  33. 33

    Kim, J. H. et al. Natural killer T (NKT) cells attenuate bleomycin-induced pulmonary fibrosis by producing interferon-γ. Am. J. Pathol. 167, 1231–1241 (2005).

  34. 34

    Chen, E. S., Greenlee, B. M., Wills-Karp, M. & Moller, D. R. Attenuation of lung inflammation and fibrosis in interferon-γ-deficient mice after intratracheal bleomycin. Am. J. Respir. Cell Mol. Biol. 24, 545–555 (2001).

  35. 35

    Gurujeyalakshmi, G. & Giri, S. N. Molecular mechanisms of antifibrotic effect of interferon γ in bleomycin-mouse model of lung fibrosis: downregulation of TGF-β and procollagen I and III gene expression. Exp. Lung Res. 21, 791–808 (1995).

  36. 36

    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). Another important paper in promoting the paradigm shift from target cells to concerted biological response in normal-tissue radiobiology.

  37. 37

    Eckes, B. et al. Fibroblast-matrix interactions in wound healing and fibrosis. Matrix Biol. 19, 325–332 (2000).

  38. 38

    Feng, X. H. & Derynck, R. Specificity and versatility in tgf-β signaling through Smads. Annu. Rev. Cell Dev. Biol. 21: 659–93., 659–693 (2005).

  39. 39

    Dumont, N. & Arteaga, C. L. Targeting the TGF β signaling network in human neoplasia. Cancer Cell. 3, 531–536 (2003).

  40. 40

    Siegel, P. M. & Massague, J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nature Rev. Cancer. 3, 807–821 (2003).

  41. 41

    Reiss, M. & Barcellos-Hoff, M. H. Transforming growth factor-β in breast cancer: a working hypothesis. Breast Cancer Res. Treat. 45, 81–95 (1997).

  42. 42

    Siegel, P. M., Shu, W., Cardiff, R. D., Muller, W. J. & Massague, J. Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl Acad. Sci. USA 100, 8430–8435 (2003).

  43. 43

    Wakefield, L. M. & Roberts, A. B. TGF-β signaling: positive and negative effects on tumorigenesis. Curr. Opin. Genet. Dev. 12, 22–29 (2002).

  44. 44

    Lawrence, D. A. Latent-TGF-β: an overview. Mol. Cell Biochem. 219, 163–170 (2001).

  45. 45

    Ewan, K. B. et al. Transforming growth factor-β1 mediates cellular response to DNA damage in situ. Cancer Res. 62, 5627–5631 (2002).

  46. 46

    Ehrhart, E. J., Segarini, P., Tsang, M. L., Carroll, A. G. & Barcellos-Hoff, M. H. Latent transforming growth factor β1 activation in situ: quantitative and functional evidence after low-dose gamma-irradiation. FASEB J. 11, 991–1002 (1997).

  47. 47

    Wrana, J. L., Attisano, L., Wieser, R., Ventura, F. & Massague, J. Mechanism of activation of the TGF-β receptor. Nature. 370, 341–347 (1994).

  48. 48

    Attisano, L. & Wrana, J. L. Signal transduction by the TGF-β superfamily. Science. 296, 1646–1647 (2002).

  49. 49

    Bayreuther, K. et al. Human skin fibroblasts in vitro differentiate along a terminal cell lineage. Proc. Natl Acad. Sci. USA 85, 5112–5116 (1988).

  50. 50

    Herskind, C. & Rodemann, H. P. Spontaneous and radiation-induced differentiationof fibroblasts. Exp. Gerontol. 35, 747–755 (2000).

  51. 51

    Martin, G. M., Sprague, C. A., Norwood, T. H. & Pendergrass, W. R. Clonal selection, attenuation and differentiation in an in vitro model of hyperplasia. Am. J. Pathol. 74, 137–154 (1974).

  52. 52

    Rodemann, H. P., Peterson, H. P., Schwenke, K. & von Wangenheim, K. H. Terminal differentiation of human fibroblasts is induced by radiation. Scanning Microsc. 5, 1135–1142 (1991).

  53. 53

    Herskind, C. et al. Differentiation state of skin fibroblast cultures versus risk of subcutaneous fibrosis after radiotherapy. Radiother. Oncol. 47, 263–269 (1998).

  54. 54

    Russell, N. S. et al. In vitro differentiation characteristics of human skin fibroblasts: correlations with radiotherapy-induced breast fibrosis in patients. Int. J. Radiat. Biol. 76, 231–240 (2000).

  55. 55

    Kalluri, R. & Neilson, E. G. Epithelial–mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776–1784 (2003).

  56. 56

    Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

  57. 57

    Roberts, A. B. et al. Smad3 is key to TGF-β-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis. Cytokine Growth Factor Rev. 17, 19–27 (2006).

  58. 58

    Abe, S. et al. Cells derived from the circulation contribute to the repair of lung injury. Am. J. Respir. Crit. Care Med. 170, 1158–1163 (2004).

  59. 59

    Epperly, M. W., Guo, H., Gretton, J. E. & Greenberger, J. S. Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 29, 213–224 (2003).

  60. 60

    Francois, S. et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells. 24, 1020–1029 (2006).

  61. 61

    Delanian, S. & Lefaix, J. L. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother. Oncol. 73, 119–131 (2004).

  62. 62

    Vujaskovic, Z. et al. Radiation-induced hypoxia may perpetuate late normal tissue injury. Int. J. Radiat. Oncol. Biol. Phys. 50, 851–855 (2001).

  63. 63

    Nangaku, M. Hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. Nephron Exp. Nephrol. 98, e8–e12 (2004).

  64. 64

    Urquhart, D. S., Montgomery, H. & Jaffe, A. Assessment of hypoxia in children with cystic fibrosis. Arch. Dis. Child. 90, 1138–1143 (2005).

  65. 65

    Siegmund, S. V. & Brenner, D. A. Molecular pathogenesis of alcohol-induced hepatic fibrosis. Alcohol Clin. Exp. Res. 29, 102S–109S (2005).

  66. 66

    Mikkelsen, R. B. & Wardman, P. Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene. 22, 5734–5754 (2003). A comprehensive review of the role of ROS and RNS in cell–cell signalling after irradiation.

  67. 67

    Cadenas, E. & Davies, K. J. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med. 29, 222–230 (2000).

  68. 68

    Kinnula, V. L. & Crapo, J. D. Superoxide dismutases in the lung and human lung diseases. Am. J. Respir. Crit. Care Med. 167, 1600–1619 (2003).

  69. 69

    Vaziri, N. D. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin. Nephrol. 24, 469–473 (2004).

  70. 70

    Fubini, B. & Hubbard, A. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic. Biol. Med. 34, 1507–1516 (2003).

  71. 71

    Duprez, D. A. Role of the renin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J. Hypertens. 24, 983–991 (2006).

  72. 72

    Weir, M. R. & Dzau, V. J. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am. J. Hypertens. 12, 205S–213S (1999).

  73. 73

    Robbins, M. E. & Diz, D. I. Pathogenic role of the renin-angiotensin system in modulating radiation-induced late effects. Int. J. Radiat. Oncol. Biol. Phys. 64, 6–12 (2006).

  74. 74

    Turesson, I. The progression rate of late radiation effects in normal tissues and its impact on dose-response relationships. Radiother. Oncol. 15, 217–226 (1989).

  75. 75

    Bentzen, S. M. & Overgaard, J. Patient-to-patient variability in the expression of radiation-induced normal-tissue injury. Sem. Rad. Oncol. 4, 68–80 (1994).

  76. 76

    Safwat, A., Bentzen, S. M., Turesson, I. & Hendry, J. H. Deterministic rather than stochastic factors explain most of the variation in the expression of skin telangiectasia after radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 52, 198–204 (2002).

  77. 77

    Aziz, N. M. & Rowland, J. H. Trends and advances in cancer survivorship research: challenge and opportunity. Semin. Radiat. Oncol. 13, 248–266 (2003).

  78. 78

    Bentzen, S. M. High-tech in radiation oncology: should there be a ceiling? Int. J. Radiat. Oncol. Biol. Phys. 58, 320–330 (2004).

  79. 79

    Bentzen, S. M. Potential clinical impact of normal-tissue intrinsic radiosensitivity testing. Radiother. Oncol. 43, 121–131 (1997).

  80. 80

    Gatti, R. A. The inherited basis of human radiosensitivity. Acta Oncol. 40, 702–711 (2001).

  81. 81

    Hall, J. The Ataxia-telangiectasia mutated gene and breast cancer: gene expression profiles and sequence variants. Cancer Lett. 227, 105–114 (2005).

  82. 82

    Swift, M., Reitnauer, P. J., Morrell, D. & Chase, C. L. Breast and other cancers in families with ataxia-telangiectasia. N. Engl. J. Med. 316, 1289–1294 (1987).

  83. 83

    Lange, E. et al. Localization of an ataxia-telangiectasia gene to an approximately 500-kb interval on chromosome 11q23. 1: linkage analysis of 176 families by an international consortium. Am. J. Hum. Genet. 57, 112–119 (1995).

  84. 84

    Gatti, R. A. et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22–23. Nature. 336, 577–580 (1988).

  85. 85

    Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749–1753 (1995).

  86. 86

    Zgheib, O. et al. ATM signaling and 53BP1. Radiother. Oncol. 76, 119–122 (2005).

  87. 87

    Taylor, A. M. et al. Ataxia telangiectasia: a human mutation with abnormal radiation sensitivity. Nature 258, 427–429 (1975). An important paper providing what remains the most convincing demonstration of a genotype associated with a hyper-radiosensitive phenotype both in vitro and in the clinic.

  88. 88

    Abadir, R. & Hakami, N. Ataxia telangiectasia with cancer. An indication for reduced radiotherapy and chemotherapy doses. Br. J. Radiol. 56, 343–345 (1983).

  89. 89

    Hart, R. M., Kimler, B. F., Evans, R. G. & Park, C. H. Radiotherapeutic management of medulloblastoma in a pediatric patient with ataxia telangiectasis. Int. J. Radiat. Oncol. Biol. Phys. 13, 1237–1240 (1987).

  90. 90

    Tamminga, R. Y., Dolsma, W. V., Leeuw, J. A. & Kampinga, H. H. Chemo- and radiosensitivity testing in a patient with ataxia telangiectasia and Hodgkin disease. Pediatr. Hematol. Oncol. 19, 163–171 (2002).

  91. 91

    Worgul, B. V. et al. Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts. Proc. Natl Acad. Sci. USA 99, 9836–9839 (2002).

  92. 92

    Broeks, A. et al. ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am. J. Hum. Genet. 66, 494–500 (2000).

  93. 93

    Appleby, J. M. et al. Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy. Br. J. Cancer 76, 1546–1549 (1997).

  94. 94

    Ramsay, J., Birrell, G. & Lavin, M. Testing for mutations of the ataxia telangiectasia gene in radiosensitive breast cancer patients. Radiother. Oncol. 47, 125–128 (1998).

  95. 95

    Shayeghi, M. et al. Heterozygosity for mutations in the ataxia telangiectasia gene is not a major cause of radiotherapy complications in breast cancer patients. Br. J. Cancer 78, 922–927 (1998).

  96. 96

    Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science. 286, 1162–1166 (1999).

  97. 97

    Wang, H. C., Chou, W. C., Shieh, S. Y. & Shen, C. Y. Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1 to promote the fidelity of DNA end-joining. Cancer Res. 66, 1391–1400 (2006).

  98. 98

    Newman, B. et al. Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA. 279, 915–921 (1998).

  99. 99

    Dumitrescu, R. G. & Cotarla, I. Understanding breast cancer risk-- where do we stand in 2005? J. Cell Mol. Med. 9, 208–221 (2005).

  100. 100

    Chen, S. et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J. Clin. Oncol. 24, 863–871 (2006).

  101. 101

    Leong, T. et al. Mutation analysis of BRCA1 and BRCA2 cancer predisposition genes in radiation hypersensitive cancer patients. Int. J. Radiat. Oncol. Biol. Phys. 48, 959–965 (2000).

  102. 102

    Gaffney, D. K. et al. Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations. Radiother. Oncol. 47, 129–136 (1998).

  103. 103

    Pierce, L. J. et al. Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J. Clin. Oncol. 18, 3360–3369 (2000).

  104. 104

    Andreassen, C. N., Alsner, J. & Overgaard, J. Does variability in normal tissue reactions after radiotherapy have a genetic basis--where and how to look for it? Radiother. Oncol 64, 131–140 (2002).

  105. 105

    Houlston, R. S. & Peto, J. The search for low-penetrance cancer susceptibility alleles. Oncogene. 23, 6471–6476 (2004).

  106. 106

    Imyanitov, E. N., Togo, A. V. & Hanson, K. P. Searching for cancer-associated gene polymorphisms: promises and obstacles. Cancer Lett. 204, 3–14 (2004).

  107. 107

    Ross, J. S. et al. Pharmacogenomics. Adv. Anat. Pathol. 11, 211–220 (2004).

  108. 108

    Andreassen, C. N. Can risk of radiotherapy-induced normal tissue complications be predicted from genetic profiles? Acta Oncol. 44, 801–815 (2005). Up-to-date and comprehensive summary of the current studies into a genetic basis for clinical normal-tissue responsiveness.

  109. 109

    Bahlo, M. et al. Detecting genome wide haplotype sharing using SNP or microsatellite haplotype data. Hum. Genet. 119, 38–50 (2006).

  110. 110

    Hirschhorn, J. N. & Daly, M. J. Genome-wide association studies for common diseases and complex traits. Nature Rev. Genet. 6, 95–108 (2005).

  111. 111

    Wang, W. Y., Barratt, B. J., Clayton, D. G. & Todd, J. A. Genome-wide association studies: theoretical and practical concerns. Nature Rev. Genet. 6, 109–118 (2005).

  112. 112

    Bentzen, S. M. Radiobiological considerations in the design of clinical trials. Radiother. Oncol. 32, 1–11 (1994).

  113. 113

    Andreassen, C. N., Alsner, J., Overgaard, M. & Overgaard, J. Prediction of normal tissue radiosensitivity from polymorphisms in candidate genes. Radiother. Oncol. 69, 127–135 (2003).

  114. 114

    Chang-Claude, J. et al. Association between polymorphisms in the DNA repair genes, XRCC1, APE1, and XPD and acute side effects of radiotherapy in breast cancer patients. Clin. Cancer Res. 11, 4802–4809 (2005).

  115. 115

    Quarmby, S. et al. Differential expression of cytokine genes in fibroblasts derived from skin biopsies of patients who developed minimal or severe normal tissue damage after radiotherapy. Radiat. Res. 157, 243–248 (2002).

  116. 116

    Rodningen, O. K., Overgaard, J., Alsner, J., Hastie, T. & Borresen-Dale, A. L. Microarray analysis of the transcriptional response to single or multiple doses of ionizing radiation in human subcutaneous fibroblasts. Radiother. Oncol. 77, 231–240 (2005).

  117. 117

    Kruse, J. J., te Poele, J. A., Russell, N. S., Boersma, L. J. & Stewart, F. A. Microarray analysis to identify molecular mechanisms of radiation-induced microvascular damage in normal tissues. Int. J. Radiat. Oncol. Biol. Phys. 58, 420–426 (2004).

  118. 118

    Snyder, A. R. & Morgan, W. F. Lack of consensus gene expression changes associated with radiation-induced chromosomal instability. DNA Repair (Amst.). 4, 958–970 (2005).

  119. 119

    Bentzen, S. M. et al. Clinical impact of dosimetry quality assurance programmes assessed by radiobiological modelling of data from the thermoluminescent dosimetry study of the European Organization for Research and Treatment of Cancer. Eur. J. Cancer 36, 615–620 (2000).

  120. 120

    West, C. M. et al. Molecular markers predicting radiotherapy response: report and recommendations from an International Atomic Energy Agency technical meeting. Int. J. Radiat. Oncol. Biol. Phys. 62, 1264–1273 (2005).

  121. 121

    Brizel, D. M. et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J. Clin. Oncol. 18, 3339–3345 (2000).

  122. 122

    Rades, D. et al. Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients. Radiother. Oncol. 70, 261–264 (2004).

  123. 123

    Lindegaard, J. C. & Grau, C. Has the outlook improved for amifostine as a clinical radioprotector? Radiother. Oncol. 57, 113–118 (2000).

  124. 124

    Stone, H. B., McBride, W. H. & Coleman, C. N. Modifying normal tissue damage postirradiation. Report of a workshop sponsored by the Radiation Research Program, National Cancer Institute, Bethesda, Maryland, September 6–8, 2000. Radiat. Res. 157, 204–223 (2002).

  125. 125

    Anscher, M. S. et al. Recent progress in defining mechanisms and potential targets for prevention of normal tissue injury after radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 62, 255–259 (2005).

  126. 126

    Iyer, S., Wang, Z. G., Akhtari, M., Zhao, W. & Seth, P. Targeting TGFβ signaling for cancer therapy. Cancer Biol. Ther. 4, 261–266 (2005).

  127. 127

    Yingling, J. M., Blanchard, K. L. & Sawyer, J. S. Development of TGF-β signalling inhibitors for cancer therapy. Nature Rev. Drug Discov. 3, 1011–1022 (2004).

  128. 128

    Giri, S. N., Hyde, D. M. & Hollinger, M. A. Effect of antibody to transforming growth factor β on bleomycin induced accumulation of lung collagen in mice. Thorax 48, 959–966 (1993).

  129. 129

    Rabbani, Z. N. et al. Soluble TGFβ type II receptor gene therapy ameliorates acute radiation-induced pulmonary injury in rats. Int. J. Radiat. Oncol. Biol. Phys. 57, 563–572 (2003).

  130. 130

    Wang, Q., Hyde, D. M., Gotwals, P. J. & Giri, S. N. Effects of delayed treatment with transforming growth factor-beta soluble receptor in a three-dose bleomycin model of lung fibrosis in hamsters. Exp. Lung Res. 28, 405–417 (2002).

  131. 131

    Roberts, A. B. et al. Is Smad3 a major player in signal transduction pathways leading to fibrogenesis? Chest. 120, 43S–47S (2001).

  132. 132

    Ishida, W. et al. Intracellular TGF-β receptor blockade abrogates Smad-dependent fibroblast activation in vitro and in vivo. J. Invest. Dermatol. 126, 1733–1744 (2006).

  133. 133

    Xavier, S. et al. Amelioration of radiation-induced fibrosis: inhibition of transforming growth factor-β signaling by halofuginone. J. Biol. Chem. 279, 15167–15176 (2004).

  134. 134

    Prosser, C. C., Yen, R. D. & Wu, J. Molecular therapy for hepatic injury and fibrosis: where are we? World J. Gastroenterol. 12, 509–515 (2006).

  135. 135

    Epperly, M. W. et al. Intratracheal injection of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis. Int. J. Radiat. Oncol. Biol. Phys. 43, 169–181 (1999).

  136. 136

    Giri, S. N., Biring, I., Nguyen, T., Wang, Q. & Hyde, D. M. Abrogation of bleomycin-induced lung fibrosis by nitric oxide synthase inhibitor, aminoguanidine in mice. Nitric. Oxide. 7, 109–118 (2002).

  137. 137

    Gurujeyalakshmi, G., Wang, Y. & Giri, S. N. Suppression of bleomycin-induced nitric oxide production in mice by taurine and niacin. Nitric Oxide 4, 399–411 (2000).

  138. 138

    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).

  139. 139

    Delanian, S. et al. Successful treatment of radiation-induced fibrosis using liposomal Cu/Zn superoxide-dismutase-clinical-trial. Radiother. Oncol. 32, 12–20 (1994).

  140. 140

    Delanian, S., Porcher, R., Rudant, J. & Lefaix, J. L. Kinetics of response to long-term treatment combining pentoxifylline and tocopherol in patients with superficial radiation-induced fibrosis. J. Clin. Oncol. 23, 8570–8579 (2005).

  141. 141

    Delanian, S., Porcher, R., Balla-Mekias, S. & Lefaix, J. L. Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J. Clin. Oncol. 21, 2545–2550 (2003). 24 women with 29 fields of radiation fibrosis were randomized in a double-blind, placebo-controlled 2×2 clinical trial design of pentoxifylline and/or vitamin E. Regression of fibrosis was significantly greater in the combined therapy group than in any of three other groups.

  142. 142

    Ha, H. & Lee, H. B. Reactive oxygen species and matrix remodeling in diabetic kidney. J. Am. Soc. Nephrol. 14, S246–S249 (2003).

  143. 143

    Rezvani, M. et al. Modification of radiation myelopathy by the transplantation of neural stem cells in the rat. Radiat. Res. 156, 408–412 (2001).

  144. 144

    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).

  145. 145

    Moran, J. M., Elshaikh, M. A. & Lawrence, T. S. Radiotherapy: what can be achieved by technical improvements in dose delivery? Lancet Oncol. 6, 51–58 (2005).

  146. 146

    Bentzen, S. M. Radiation therapy: intensity modulated, image guided, biologically optimized and evidence based. Radiother. Oncol. 77, 227–230 (2005).

  147. 147

    Baumann, M., Holscher, T. & Begg, A. C. Towards genetic prediction of radiation responses: ESTRO's GENEPI project. Radiother. Oncol. 69, 121–125 (2003).

  148. 148

    Puck, T. T. & Marcus, P. I. Action of x-rays on mammalian cells. J. Exp. Med. 103, 653–666 (1956).

  149. 149

    Thames, H. D. & Hendry, J. H. Fractionation in radiotherapy. Taylor & Francis, London (1987).

  150. 150

    Meistrich, M. L., Hunter, N. R., Suzuki, N., Trostle, P. K. & Withers, H. R. Gradual regeneration of mouse testicular stem cells after exposure to ionizing radiation. Radiat. Res. 74, 349–362 (1978).

  151. 151

    Judas, L., Bentzen, S. M., Hansen, P. V. & Overgaard, J. Proliferative response of mouse spermatogonial stem cells after irradiation: a quantitative model analysis of experimental data. Cell Proliferation 29, 73–87 (1996).

  152. 152

    Bernier, J. Alteration of radiotherapy fractionation and concurrent chemotherapy: a new frontier in head and neck oncology? Nature Clinical Practice Oncology 2, 305–314 (2005).

  153. 153

    Bernier, J. & Bentzen, S. M. Altered fractionation and combined radio-chemotherapy approaches. Pioneering new opportunities in head and neck oncology. Eur. J. Cancer 39, 560–571 (2003).

  154. 154

    Bentzen, S. M., Overgaard, M. & Overgaard, J. Clinical correlations between late normal-tissue endpoints after radiotherapy: implications for predictive assays of radiosensitivity. Eur. J. Cancer 29A, 1373–1376 (1993).

  155. 155

    Tucker, S. L., Turesson, I. & Thames, H. D. Evidence for individual differences in the radiosensitivity of human skin. Eur. J. Cancer 28A, 1783–1791 (1992).

  156. 156

    Bentzen, S. M. & Overgaard, M. Relationship between early and late normal-tissue injury after postmastectomy radiotherapy. Radiother. Oncol. 20, 159–165 (1991).

  157. 157

    Baumann, M. in Radiation sequelae (eds Dunst, J. & Sauer, R.) 3–12 (Springer-Verlag, Berlin-Heidelberg, 1995).

  158. 158

    Holscher, T., Bentzen, S. M. & Baumann, M. Influence of connective tissue diseases on the expression of radiation side effects: A systematic review. Radiother. Oncol. 78, 123–130 (2006).

  159. 159

    Merrick, G. S. et al. Erectile function after permanent prostate brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 52, 893–902 (2002).

  160. 160

    Honore, H. B., Bentzen, S. M., Moller, K. & Grau, C. Sensori-neural hearing loss after radiotherapy for nasopharyngeal carcinoma: individualized risk estimation. Radiother. Oncol. 65, 9–16 (2002).

  161. 161

    Pignon, T. et al. Age has no impact on acute and late toxicity of curative thoracic radiotherapy [see comments]. Radiother. Oncol. 46, 239–248 (1998).

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S.B. is supported by the University of Wisconsin Comprehensive Cancer Center.

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Cytokine cascade

Cytokines, low-molecular-weight intercellular messenger proteins, are often produced in a cascade: one cytokine stimulates its target cell to secrete additional cytokines.


Small secreted cytokines that signal for various cell types to move in a specific direction, typically up the gradient of chemokine concentration.


A chemotherapeutic antibiotic that functions by inducing DNA strand breaks, and which is therefore seen as a radiation-mimetic drug. Although the initial damage induction differs from that of radiation, it is probable that the mesenchymal-response pathway is similar for the two agents. It is often used to induce lung fibrosis in mouse models.

Tissue hypoxia

A pathological condition in which a tissue region is deprived of the normal physiological oxygen concentration.

Reactive oxygen and nitrogen species

Highly reactive molecules that include oxygen or nitrogen, such as free radicals or other highly reactive forms (for example, singlet oxygen, a meta-stable state of oxygen with higher energy than the triplet ground state).


The visible dilation of small vessels under the skin or a mucosal surface that can occur after radiation therapy, perhaps as a result of radiation-induced cell killing and the loss of other small vessels in the area.

Nijmegen breakage syndrome

A rare heritable disease characterized by an abnormally small head and underdeveloped brain, associated with chromosomal instability and a predisposition to cancer, especially lymphomas.

Fanconi anaemia

A rare heritable disease in which the bone marrow fails to produce platelets, red or white blood cells or a combination of the three. It is associated with a predisposition to cancer, particularly leukaemia.

Ataxia telangiectasia

A rare heritable disease characterized by progressive dysfunction of the cerebellum, the part of the brain that coordinates voluntary motion, and a predisposition to cancer, particularly lymphomas and leukaemia.

Single nucleotide polymorphisms

(SNP) An inter-individual variation in the DNA sequence that involves the substitution of a single nucleotide that occurs in more than 1% of the population.

Candidate gene

A gene whose function indicates that it could be mechanistically involved in a specific process, such as radiation-damage repair or tissue remodelling.

Genome-wide SNP genotyping

A strategy for trying to discover associations between SNPs in any human gene and a specific phenotype; for example, patients showing atypically strong side effects after radiotherapy.

Bonferroni correction

A multiple-comparisons correction that is applied to reduce the chance of spurious ('false-positive') findings when several statistical tests are conducted to analyse a data set.


Dryness of mouth caused by reduction in the secretion of saliva, a possible side effect of radiation therapy for cander of the head and neck region.

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