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

Nature Reviews Cancer

Volumn 6, Issue 9, 2006, Pages 702-713

  Bentzen, Søren M ^a  

^a UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOVIRUS VECTOR; ALPHA TOCOPHEROL; AMIFOSTINE; ANGIOTENSIN II; ANTIOXIDANT; DIPEPTIDYL CARBOXYPEPTIDASE INHIBITOR; PENTOXIFYLLINE; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; TAMOXIFEN; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1; TRANSFORMING GROWTH FACTOR BETA1; TRANSFORMING GROWTH FACTOR BETA2; TRANSFORMING GROWTH FACTOR BETA3;

ALLERGIC REACTION; ATAXIA TELANGIECTASIA; CANCER INHIBITION; CELL DAMAGE; CELL KILLING; CLINICAL TRIAL; DNA REPAIR; FIBROGENESIS; FIBROSIS; GENE MAPPING; GENETIC VARIABILITY; GENOMICS; HEALTH CARE COST; HUMAN; HYPOTENSION; IONIZING RADIATION; LUNG INJURY; PATHOGENESIS; PRIORITY JOURNAL; RADIATION INJURY; RADIOBIOLOGY; RADIOSENSITIVITY; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; TARGET CELL; TISSUE REPAIR; TUMOR PROMOTION; VOMITING; XEROSTOMIA;

HUMANS; NEOPLASMS; RADIATION INJURIES; RADIATION PROTECTION; RADIATION-PROTECTIVE AGENTS; RADIOTHERAPY;

EID: 33747826874     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1950     Document Type: Review

References (162)

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. Center for Disease Control (USA). Cancer Survivorship - United States, 1971-2001. Center for Disease Control [online], http://www.cdc.gov/mmwr/preview/ mmwrhtml/mm5324a3.htm.
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. Hawkins, M. M. Long-term survivors of childhood cancers: what knowledge have we gained? Nature Clin. Pract. Oncol. 1, 26-31 (2004).
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. Bentzen, S. M. et al. Normal tissue effects: reporting and analysis. Semin. Radiat. Oncol. 13, 189-202 (2003).
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. Allan, J. M. & Travis, L. B. Mechanisms of therapy-related carcinogenesis. Nature Rev. Cancer. 5, 943-955 (2005).
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. Bentzen, S. M., Thames, H. D. & Overgaard, M. Latenttime estimation for late cutaneous and subcutaneous radiation reactions in a single-follow-up clinical study. Radiother. Oncol. 15, 267-274 (1989).
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. 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. 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. Burnet, N. G. et al. Prediction of normal-tissue tolerance to radiotherapy from in-vitro cellular radiation sensitivity. Lancet 339, 1570-1571 (1992).
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. 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. Peacock, J. et al. Cellular radiosensitivity and complication risk after curative radiotherapy. Radiother. Oncol. 55, 173-178 (2000).
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. 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. 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. 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. 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. 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. 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. 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. 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. Kelly, M., Kolb, M., Bonniaud, P. & Gauldie, J. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr. Pharm. Des. 9, 39-49 (2003).
28. Grose, R. & Werner, S. Wound-healing studies in transgenic and knockout mice. Mol. Biotechnol. 28, 147-166 (2004).
29. Border, W. A. & Noble, N. A. Transforming growth factor β in tissue fibrosis. N. Engl. J. Med. 331, 1286-1292 (1994).
30. Moussad, E. E. & Brigstock, D. R. Connective tissue growth factor: what's in a name? Mol. Genet. Metab. 71, 276-292 (2000).
31. Leask, A. & Abraham, D. J. TGFβ signaling and the fibrotic response. FASEB J. 18, 816-827 (2004).
32. Hatamochi, A., Mori, K. & Ueki, H. Role of cytokines in controlling connective tissue gene expression. Arch. Dermatol. Res. 287, 115-121 (1994).
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. 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. 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. 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. Eckes, B. et al. Fibroblast-matrix interactions in wound healing and fibrosis. Matrix Biol. 19, 325-332 (2000).
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. Dumont, N. & Arteaga, C. L. Targeting the TGF β signaling network in human neoplasia. Cancer Cell. 3, 531-536 (2003).
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. 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. 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. Wakefield, L. M. & Roberts, A. B. TGF-β signaling: positive and negative effects on tumorigenesis. Curr. Opin. Genet. Dev. 12, 22-29 (2002).
44. Lawrence, D. A. Latent-TGF-β: an overview. Mol. Cell Biochem. 219, 163-170 (2001).
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. 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. 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. Attisano, L. & Wrana, J. L. Signal transduction by the TGF-β superfamily. Science. 296, 1646-1647 (2002).
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. Herskind, C. & Rodemann, H. P. Spontaneous and radiation-induced differentiationof fibroblasts. Exp. Gerontol. 35, 747-755 (2000).
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. 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. Herskind, C. et al. Differentiation state of skin fibroblast cultures versus risk of subcutaneous fibrosis after radiotherapy. Radiother. Oncol. 47, 263-269 (1998).
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. Kalluri, R. & Neilson, E. G. Epithelial-mesenchymal transition and its implications for fibrosis. J. Clin. Invest. 112, 1776-1784 (2003).
56. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341-350 (2002).
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. 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. 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. 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. Delanian, S. & Lefaix, J. L. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother. Oncol. 73, 119-131 (2004).
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. Nangaku, M. Hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. Nephron Exp. Nephrol. 98, e8-e12 (2004).
64. Urquhart, D. S., Montgomery, H. & Jaffe, A. Assessment of hypoxia in children with cystic fibrosis. Arch. Dis. Child. 90, 1138-1143 (2005).
65. Siegmund, S. V. & Brenner, D. A. Molecular pathogenesis of alcohol-induced hepatic fibrosis. Alcohol Clin. Exp. Res. 29, 102S-109S (2005).
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. Cadenas, E. & Davies, K. J. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med. 29, 222-230 (2000).
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. Vaziri, N. D. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin. Nephrol. 24, 469-473 (2004).
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. 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. 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. 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. 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. 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. 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. Aziz, N. M. & Rowland, J. H. Trends and advances in cancer survivorship research: challenge and opportunity. Semin. Radiat. Oncol. 13, 248-266 (2003).
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. Bentzen, S. M. Potential clinical impact of normal-tissue intrinsic radiosensitivity testing. Radiother. Oncol. 43, 121-131 (1997).
80. Gatti, R. A. The inherited basis of human radiosensitivity. Acta Oncol. 40, 702-711 (2001).
81. Hall, J. The Ataxia-telangiectasia mutated gene and breast cancer: gene expression profiles and sequence variants. Cancer Lett. 227, 105-114 (2005).
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. 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. Gatti, R. A. et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. 336, 577-580 (1988).
85. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749-1753 (1995).
86. Zgheib, O. et al. ATM signaling and 53BP1. Radiother. Oncol. 76, 119-122 (2005).
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. Abadir, R. & Hakami, N. Ataxia telangiectasia with cancer. An indication for reduced radiotherapy and chemotherapy doses. Br. J. Radiol. 56, 343-345 (1983).
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. 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. 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. Broeks, A. et al. ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am. J. Hum. Genet. 66, 494-500 (2000).
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. 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. 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. 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. 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. 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. Dumitrescu, R. G. & Cotarla, I. Understanding breast cancer risk - where do we stand in 2005? J. Cell Mol. Med. 9, 208-221 (2005).
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. 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. 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. 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. 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. Houlston, R. S. & Peto, J. The search for low-penetrance cancer susceptibility alleles. Oncogene. 23, 6471-6476 (2004).
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. Ross, J. S. et al. Pharmacogenomics. Adv. Anat. Pathol. 11, 211-220 (2004).
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. Bahlo, M. et al. Detecting genome wide haplotype sharing using SNP or microsatellite haplotype data. Hum. Genet. 119, 38-50 (2006).
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. 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. Bentzen, S. M. Radiobiological considerations in the design of clinical trials. Radiother. Oncol. 32, 1-11 (1994).
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. 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. 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. 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. 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. 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. 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. 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. 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. Rades, D. et al. Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients. Radiother. Oncol. 70, 261-264 (2004).
123. Lindegaard, J. C. & Grau, C. Has the outlook improved for amifostine as a clinical radioprotector? Radiother. Oncol. 57, 113-118 (2000).
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. 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. 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. 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. 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. 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. 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. Roberts, A. B. et al. Is Smad3 a major player in signal transduction pathways leading to fibrogenesis? Chest. 120, 43S-47S (2001).
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. 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. 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. 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. 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. 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. 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. 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. 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. 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).
142. women with 29 fields of radiation fibrosis were randomized in a double-blind, placebo-controlled 2x2 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.
143. Ha, H. & Lee, H. B. Reactive oxygen species and matrix remodeling in diabetic kidney. J. Am. Soc. Nephrol. 14, S246-S249 (2003).
144. Rezvani, M. et al. Modification of radiation myelopathy by the transplantation of neural stem cells in the rat. Radiat. Res. 156, 408-412 (2001).
145. 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).
146. 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).
147. Bentzen, S. M. Radiation therapy: intensity modulated, image guided, biologically optimized and evidence based. Radiother. Oncol. 77, 227-230 (2005).
148. Baumann, M., Holscher, T. & Begg, A. C. Towards genetic prediction of radiation responses: ESTRO's GENEPI project. Radiother. Oncol. 69, 121-125 (2003).
149. Puck, T. T. & Marcus, P. I. Action of x-rays on mammalian cells. J. Exp. Med. 103, 653-666 (1956).
150. Thames, H. D. & Hendry, J. H. Fractionation in radiotherapy. Taylor & Francis, London (1987).
151. 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).
152. 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).
153. 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).
154. 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).
155. 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).
156. 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).
157. Bentzen, S. M. & Overgaard, M. Relationship between early and late normal-tissue injury after postmastectomy radiotherapy. Radiother. Oncol. 20, 159-165 (1991).
158. Baumann, M. in Radiation sequelae (eds Dunst, J. & Sauer, R.) 3-12 (Springer-Verlag, Berlin-Heidelberg, 1995).
159. 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).
160. Merrick, G. S. et al. Erectile function after permanent prostate brachytherapy. Int. J. Radiat. Oncol. Biol. Phys. 52, 893-902 (2002).
161. 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).
162. 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).