International Journal of Radiation Oncology * Biology * Physics
Volume 49, Issue 2 , Pages 353-365 , 1 February 2001

Normal tissue radiobiology: from the laboratory to the clinic

Presented at ICTR 2000, Lugano, Switzerland, March 5–8, 2000.

  • R.P Hill, Ph.D.

      Affiliations

    • Ontario Cancer Institute, Toronto, Ontario, Canada
    • Corresponding Author InformationReprint requests to: Dr. R. P. Hill, Research Division, Ontario Cancer Institute/Princess Margaret Hospital, 610, University Avenue, Toronto, Ontario, Canada M5G 2M9
  • ,
  • H.-P Rodemann, Ph.D.

      Affiliations

    • Department of Radio-Oncology, Eberhard-Karls-University Tubingen, Tubingen, Germany
  • ,
  • J.H Hendry, Ph.D. (D.Sc.)

      Affiliations

    • Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK
  • ,
  • S.A Roberts, Ph.D.

      Affiliations

    • Paterson Institute for Cancer Research, Christie Hospital, Manchester, UK
  • ,
  • M.S Anscher, M.D.

      Affiliations

    • Department of Radiation Oncology, Duke University Medical School, Durham, NC, USA

,Accepted 31 August 2000.

References 

  1. Budach W, Classen J, Belka C, et al.  Clinical impact of predictive assays for acute and late radiation morbidity. Strahlenther Onkol. 1998;174(Suppl. 3):20–24
  2. Moulder JE, Robbins ME, Cohen EP, et al.  Pharmacologic modification of radiation-induced late normal tissue injury. Cancer Treat Res. 1998;93:129–151
  3. Withers HR. Failla Memorial Lecture. Contrarian concepts in the progress of radiotherapy. Radiat Res. 1989;119:395–412
  4. Travis EL, Tucker SL. The relationship between functional assays of radiation response in the lung and target cell depletion. Br J Cancer Suppl. 1986;7:304–319
  5. Thames HD, Hendry JH. Fractionation in radiotherapy. London, UK: Taylor and Francis Ltd; 1987;
  6. Rubin P, Caserett GW. Clinical radiation pathology. Philadelphia: WB Saunders; 1968;
  7. Hopewell JW, Calvo W, Jaenke R, et al.  Microvasculature and radiation damage. Rec Results Cancer Res. 1993;130:1–16
  8. Ellis F. Dose, time and fractionation (A clinical hypothesis). Clin Radiol. 1969;20(1):1–7
  9. Weeks DE, Paterson MC, Lange K, et al.  Assessment of chronic gamma radiosensitivity as an in vitro assay for heterozygote identification of ataxia-telangiectasia. Radiat Res. 1991;128(1):90–99
  10. Deschavanne PJ, Fertil B. A review of human cell radiosensitivity in vitro. Int J Radiat Oncol Biol Phys. 1996;1:1–274
  11. Norman A, Kagan AR, Chan SL. The importance of genetics for the optimization of radiation therapy. Am J Clin Oncol. 1988;11:84–88
  12. Peters LJ. The ESTRO Regaud lecture (Inherent radiosensitivity of tumor and normal tissue cells as a predictor of human tumor response). Radiother Oncol. 1990;17:177–190
  13. Tucker SL, Geara FB, Peters LJ, et al.  How much could the radiotherapy dose be altered for individual patients based on a predictive assay of normal-tissue radiosensitivity?. Radiother Oncol. 1996;38:103–113
  14. Mackay RI, Hendry JH. The modelled benefits of individualizing radiotherapy patients dose using cellular radiosensitivity assays with inherent variability. Radiother Oncol. 1999;50(1):67–75
  15. Russell NS, Grummels A, Hart AA, et al.  Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer. Int J Radiat Biol. 1998;73(6):661–670
  16. Bentzen SM, Hendry JH. Variability in the radiosensitivity of normal cells and tissues. Report from a workshop organised by the European Society for Therapeutic Radiology and Oncology in Edinburgh, UK, 19 September 1998. Int J Radiat Biol. 1999;75(4):513–517
  17. Brock WA, Tucker SL, Geara FB, et al.  Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer. Int J Radiat Oncol Biol Phys. 1995;32:1371–1379
  18. Hendry JH, Jiang TN. Differential radiosensitising effect of the scid mutation among tissues, studied using high and low dose rates (Implications for prognostic indicators in radiotherapy). Radiother Oncol. 1994;33(3):209–216
  19. Kiltie AE, Barber JB, Swindell R, et al.  Lack of correlation between residual radiation-induced DNA damage, in keratinocytes assayed directly from skin, and late radiotherapy reactions in breast cancer patients. Int J Radiat Oncol Biol Phys. 1999;43(3):481–487
  20. Steel GG. The radiobiology of human tumour cells. Br J Radiol Suppl. 1988;22:116–120
  21. Sproston AR, Boyle JM, Heighway J, et al.  Fibroblasts from Li-Fraumeni patients are resistant to low dose-rate irradiation. Int J Radiat Biol. 1996;70(2):145–150
  22. LENT SOMA scales for all anatomic sites. Int J Radiat Oncol Biol Phys. 1995;31:1049–1091
  23. Rubin P, Finkelstein JN, Shapiro D. Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes (Interrelationship between the alveolar macrophage and the septal fibroblast). Int J Radiat Oncol Biol Phys. 1992;24:93–101
  24. Rubin P, Johnston CJ, Williams JP, et al.  A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995;33(1):99–109
  25. Epperly MW, Bray JA, Krager S, 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. 1999;43(1):169–181
  26. Epperly MW, Travis EL, Sikora C, et al.  Manganese superoxide dismutase plasmid/liposome pulmonary radioprotective gene therapy (Modulation of irradiation-induced mRNA for IL-I, TNF-alpha, and TGF-beta correlates with delay of organizing alveolitis/fibrosis). Biol Blood Marrow Transplant. 1999;5(4):204–214
  27. Khan MA, Hill RP, Van Dyk J. Partial volume rat lung irradiation (An evaluation of early DNA damage). Int J Radiat Oncol Biol Phys. 1998;40(2):467–476
  28. Travis EL, Liao ZX, Tucker SL. Spatial heterogeneity of the volume effect for radiation pneumonitis in mouse lung. Int J Radiat Oncol Biol Phys. 1997;38(5):1045–1054
  29. Tucker SL, Liao ZX, Travis EL. Estimation of the spatial distribution of target cells for radiation pneumonitis in mouse lung. Int J Radiat Oncol Biol Phys. 1997;38(5):1055–1066
  30. Franko AJ, Sharplin J, Ward WF, et al.  Evidence for two patterns of inheritance of sensitivity to induction of lung fibrosis in mice by radiation, one of which involves two genes. Radiat Res. 1996;146:68–74
  31. Haston CK, Travis EL. Murine susceptibility to radiation-induced pulmonary fibrosis is influenced by a genetic factor implicated in susceptibility to bleomycin-induced pulmonary fibrosis. Cancer Res. 1997;57(23):5286–5291
  32. Dileto CL, Travis EL. Fibroblast radiosensitivity in vitro and lung fibrosis in vivo (Comparison between a fibrosis-prone and fibrosis-resistant mouse strain). Radiat Res. 1996;146(1):61–67
  33. Johnston CJ, Piedboeuf B, Baggs R, et al.  Differences in correlation of mRNA gene expression in mice sensitive and resistant to radiation-induced pulmonary fibrosis. Radiat Res. 1995;142(2):197–203
  34. Franko AJ, Sharplin J, Ghahary A, et al.  Immunohistochemical localization of transforming growth factor beta and tumor necrosis factor alpha in the lungs of fibrosis-prone and non-fibrosing mice during the latent period and early phase after irradiation. Radiat Res. 1997;147(2):245–256
  35. Li C, Wilson PB, Levine E, et al.  TGF-beta1 levels in pre-treatment plasma identify breast cancer patients at risk of developing post-radiotherapy fibrosis. Int J Cancer. 1999;84(2):155–159
  36. Wang J, Zheng H, Sung CC, et al.  Cellular sources of transforming growth factor-beta isoforms in early and chronic radiation enteropathy. Am J Pathol. 1998;153(5):1531–1540
  37. Rubin P, Finkelstein JN, Williams JP. Paradigm shifts in the radiation pathophysiology of late effects in normal tissues (Molecular vs. classic concepts). Curr Radiat Oncol. 1997;3:1–26
  38. Gorodetsky R, McBride WH, Withers HR, et al.  Effect of fibroblast implants on wound healing of irradiated skin (Assay of wound strength and quantitative immunohistology of collagen). Radiat Res. 1991;125(2):181–186
  39. Ferguson PC, Boynton EL, Wunder JS, et al.  Intradermal injection of autologous dermal fibroblasts improves wound healing in irradiated skin. J Surg Res. 1999;85:331–338
  40. Guha C, Sharma A, Gupta S, et al.  Amelioration of radiation-induced liver damage in partially hepatectomized rats by hepatic transplantation. Cancer Res. 1999;59:5871–5874
  41. Shi Q, Rafii S, Hong-De Wu M, et al.  Evidence for circulating bone-marrow derived endothelial cells. Blood. 1998;92:362–367
  42. Takahashi T, Kalka C, Masuda H, et al.  Ischaemic and cytokine-induced mobilization of bone-marrow derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5:434–438
  43. Rodemann HP. Differential degradation of intracellular proteins in human skin fibroblasts of mitotic and mitomycin C-induced postmitotic differentiation states. Differentiation. 1989;42:37–43
  44. Bayreuther K, Rodemann HP, Francz PI, et al.  Differentiation of fibroblast stem cells. J Cell Sci. 1988;10(Suppl.):115–130
  45. Rodemann HP, Bayreuther K, Dittmann K, et al.  Selective enrichment of and biochemical characterization of 7 human skin fibroblast cell types in vitro. Exp Cell Res. 1989;180:84–93
  46. Hakenjos L, Bamberg M, Rodemann HP. TGF-β1-mediated alterations of rat lung fibroblast differentiation resulting in the radiation-induced fibrotic phenotype. Int J Radiat Biol. 2000;76:503–509
  47. Bayreuther K, Rodemann HP, Hommel R, et al.  Human skin fibroblasts in vitro differentiate along a terminal cell lineage. Proc Natl Acad Sci USA. 1988;85:5112–5116
  48. Rodemann HP, Bamberg M. Cellular basis of radiation-induced fibrosis. Radiother Oncol. 1995;35:83–90
  49. Yi ES, Bedoya A, Lee H, et al.  Radiation-induced lung injury in vivo (Expression of transforming growth factor β precedes fibrosis). Inflammation. 1996;20:339–352
  50. Lafuma C, El Nabout R, Crechet F, et al.  Expression of 72-kDa gelatinase, collagenase, and tissue metallo-proteinase inhibitor (TIMP) in primary pig skin fibroblast cultures derived from radiation-induced skin fibrosis. J Invest Dermatol. 1994;102:945–950
  51. Gartel AL, Serfas MS, Tyner AL. Negative regulator of the cell cycle. Proc Soc Exp Biol Med. 1996;213:138–149
  52. Rodemann HP, Binder A, Bamberg M. Radiation-induced fibrosis (Experimental studies). In:  Dunst J,  Sauer R editor. Medical radiology. Heidelberg: Springer-Verlag; 1995;p. 93–99
  53. Lara PC, Russell NS, Smolders IJH, et al.  Radiation-induced differentiation of human skin fibroblasts (Relationship with cell survival and collagen production). Int J Radiat Biol. 1996;70:683–692
  54. Burger A, Löffler H, Bamberg M, et al.  Molecular and cellular basis of radiation fibrosis. Int J Radiat Biol. 1998;73(4):401–408
  55. Johansen J, Bentzen SM, Overgaard J, et al.  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. 1994;66(4):407–412
  56. Herskind C, Bentzen SM, Overgaard J, et al.  Differentiation state of skin fibroblast cultures versus risk of subcutaneous fibrosis after radiotherapy. Radiother Oncol. 1998;47(3):263–269
  57. West CM. Predictive assays in radiation therapy. Adv Radiat Biol. 1994;18:149–180
  58. Brock WA, Tucker SL, Geara FB. Fibroblast radiosensitivity versus acute and late normal skin responses in patients treated for breast cancer. Int J Radiat Oncol Biol Phys. 1995;32:1371–1379
  59. Burnet NG, Wurm R, Peacock JH. Low does-rate fibroblast radiosensitivity and the prediction of patient response to radiotherapy. Int J Radiat Biol. 1996;70:289–300
  60. Ramsay J, Birrell G. Normal tissue radiosensitivity in breast cancer patients. Int J Radiat Oncol Biol Phys. 1995;31:339–344
  61. Wurm R, Burnet NG, Duggal N, et al.  Cellular radiosensitivity and DNA damage in primary human fibroblasts. Int J Radiat Oncol Biol Phys. 1994;30:625–633
  62. Scott D, Hu Q, Roberts SA. Dose-rate sparing for micronucleus induction in lymphocytes of controls and ataxia telangiectasia heterozygotes exposed to 60Co γ-irradiation in vitro. Int J Radiat Biol. 1996;70:521–527
  63. Maciejewski B, Withers HR, Taylor JM, et al.  Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx. Part 2. Normal tissue responses (Acute and late effects). Int J Radiat Oncol Biol Phys. 1990;18(1):101–111
  64. Hendry JH, Jen YM. The time factor for late reactions in radiotherapy (Repopulation or intracellular repair?). Rec Results Cancer Res. 1993;130:17–26
  65. Trott K, Kummermehr J. The time factor and repopulation in tumours and normal tissues. Semin Radiat Oncol. 1993;3:115–125
  66. Hendry JH, Bentzen SM, Dale RG, et al.  A modelled comparison of the effects of using different ways to compensate for missed treatment days in radiotherapy. Clin Oncol R Coll Radiol. 1996;8(5):297–307
  67. Bentzen SM, Overgaard J. Clinical normal-tissue radiobiology. In: Tobias JS, Thomas PRM, editors. Current Radiation Oncology. Vol. 2. London: Arnold; 1996. p. 37–67
  68. Dische S, Saunders MI. The CHART regimen and morbidity. Acta Oncol. 1999;38(2):147–152
  69. Turesson I, Thames HD. Repair capacity and kinetics of human skin during fractionated radiotherapy (Erythema, desquamation, and telangiectasia after 3 and 5 years’ follow-up). Radiother Oncol. 1989;15(2):169–188
  70. Bentzen SM, Turesson I, Thames HD. Fractionation sensitivity and latency of telangiectasia after postmastectomy radiotherapy (a graded-response analysis). Radiother Oncol. 1990;18(2):95–106
  71. Bentzen SM, Overgaard M. Relationship between early and late normal-tissue injury after postmastectomy radiotherapy. Radiother Oncol. 1991;20(3):159–165
  72. Hendry JH. Response of human organs to single (or fractionated equivalent) doses of irradiation. Int J Radiat Biol. 1989;56:691–700
  73. Stewart JG, Jackson AW. The steepness of the dose response curve both for tumor cure and normal tissue injury. Laryngoscope. 1975;85(7):1107–1111
  74. Withers HR, Peters LJ, Taylor JM, et al.  Late normal tissue sequelae from radiation therapy for carcinoma of the tonsil (Patterns of fractionation study of radiobiology). Int J Radiat Oncol Biol Phys. 1995;33(3):563–568
  75. Brown DQ, Graham WJ, MacKenzie LJ, et al.  Can WR-2721 be improved upon?. Pharmacol Ther. 1988;39:157–168
  76. Hospers GA, Eisenhauer EA, de Vries EG. The sulfhydryl containing compounds WR-2721 and glutathione as radio- and chemoprotective agents. A review, indications for use and prospects. Br J Cancer. 1999;80(5–6):629–638
  77. Horiot JC, Le Fur R, N′Guyen T, et al.  Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma (Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy). Radiother Oncol. 1992;25(4):231–241
  78. Hendry JH. Treatment acceleration in radiotherapy (The relative time factors and dose-response slopes for tumours and normal tissues). Radiother Oncol. 1992;25(4):308–312
  79. Hopewell JW. The volume effect in radiotherapy—Its biological significance. Br J Radiol. 1997;70(Spec No):S32–S40
  80. Emami B, Lyman J, Brown A, et al.  Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21(1):109–122
  81. Dearnaley DP, Khoo VS, Norman AR, et al.  Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer (A randomised trial). Lancet. 1999;353(9149):267–272
  82. Tait DM, Nahum AE, Meyer LC, et al.  Acute toxicity in pelvic radiotherapy; a randomised trial of conformal versus conventional treatment. Radiother Oncol. 1997;42(2):121–136
  83. Perks JR, Jalali R, Cosgrove VP, et al.  Optimization of stereotactically-guided conformal treatment planning of sellar and parasellar tumors, based on normal brain dose volume histograms. Int J Radiat Oncol Biol Phys. 1999;45(2):507–513
  84. Hopewell JW, van den Aardweg GJ, Morris GM, et al.  Amelioration of both early and late radiation-induced damage to pig skin by essential fatty acids. Int J Radiat Oncol Biol Phys. 1994;30(5):1119–1125
  85. Mahler PA, Rasey JS, Yatvin MB. Influence of protein nutrition on dose-survival relationship following rat kidney irradiation. Radiat Res. 1987;109(2):238–244
  86. Robbins ME, Bywaters T, Jaenke RS, et al.  Influence of a low protein diet on radiation nephropathy in the pig. Int J Radiat Biol. 1993;64(4):407–416
  87. Trott KR, Breiter N, Spiethoff A. Experimental studies on the pathogenesis of the chronic radiation ulcer of the large bowel in rats. Int J Radiat Oncol Biol Phys. 1986;12(9):1637–1643
  88. MacKay RI, Niemierko A, Goitein M, et al.  Potential clinical impact of normal-tissue intrinsic radiosensitivity testing. Radiother Oncol. 1998;46(2):215–216
  89. Anscher MS, Kong FM, Andrews K, et al.  Plasma transforming growth factor beta1 as a predictor of radiation pneumonitis. Int J Radiat Oncol Biol Phys. 1998;41(5):1029–1035
  90. Anscher MS, Crocker IR, Jirtle RL. Transforming growth factor-β1 expression in irradiated liver. Radiat Res. 1990;122:77–85
  91. Broekelmann TJ, Limper AH, Colby TV, et al.  Transforming growth factor beta-1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci USA. 1991;88:6642–6646
  92. Castilla A, Prieto J, Fausto N. Transforming growth factors beta-1 and alpha in chronic liver disease—Effects of interferon alpha therapy. N Engl J Med 1991;324:993–940.
  93. Postlewaite AE, Keski-Oja J, Moses HL, et al.  Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exper Med. 1987;165:251–256
  94. Cromack DT, Sporn MB, Roberts AB, et al.  Transforming growth factor beta levels in rat wound chambers. J Surg Res. 1987;42:622–628
  95. Mustoe TA, Pierce GF, Thomason A, et al.  Accelerated healing of incisional wounds in rats induced by transforming growth factor beta. Science. 1987;235:1333–1336
  96. Roberts A, Sporn M, Assoian R, et al.  Transforming growth factor type-beta (Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro). Proc Natl Acad Sci USA. 1986;83:4167–4171
  97. Sporn MB, Roberts AB, Shull JH, et al.  Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science. 1983;219:1329–1331
  98. Fine A, Goldstein RH. The effect of transforming growth factor beta on cell proliferation and collagen formation by lung fibroblasts. J Biol Chem. 1987;262:3897–3902
  99. Lund LR, Riccio A, Andreasen PA, et al.  TGFβ is a strong and fast-acting positive regulator of the level of Type 1 plasminogen activator inhibitor mRNA in WI-38 lung fibroblast. EMBO J. 1987;6:1281–1286
  100. Jirtle RL, Anscher MS, Alati T. Radiation sensitivity of the liver. In: Lett JT, Altman KI, editors. Advances in radiation biology. Relative radiation sensitivities of human organ systems, Part II. Vol. 14. San Diego, CA: Academic Press; 1990. p. 269–312.
  101. Lawrence TS, Robertson JN, Anscher MS, et al.  Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys. 1995;31:1237–1248
  102. Hackman R, Madtes D, Petersen F, et al.  Pulmonary venoocclusive disease following marrow transplantation. Transplantation. 1989;47:989–992
  103. Shulman HM, Gown AM, Nugent BJ. Hepatic venoocclusive disease after bone marrow transplantation (Immunohistochemical identification of the material within occluded central venules). Am J Pathol. 1987;127:549–558
  104. Hoyt B, Lazo J. Alterations in pulmonary mRNA encoding procollagens, fibronectin, and transforming growth factor beta precede bleomycin-induced pulmonary fibrosis. J Pharmacol Exper Ther. 1988;246:765–771
  105. Hoyt B, Laso J. Early increases in pulmonary mRNA encoding procollagens and transforming growth factor beta in mice sensitive to cyclophosphamide-induced pulmonary fibrosis. J Pharmacol Exper Ther. 1989;249:38–43
  106. Giri S, Hyde D, Hollinger M. Effect of antibody to transforming growth factor β on bleomycin induced accumulation of lung collagen in mice. Thorax. 1993;48:959–966
  107. Gurujeyalakshmi G, Hollinger M, Giri S. Regulation of transforming growth factor-β1 mRNA expression by taurine and niacin in the bleomycin hamster model of lung fibrosis. Am J Respir Cell Mol Biol. 1998;18:334–342
  108. Delgado-Rizo V, Salazar A, Panduro A, et al.  Treatment with anti-transforming growth factor β antibodies influences an altered pattern of cytokines gene expression in injured rat liver. Biochem Biophys Acta. 1998;1442:20–27
  109. Chandrasekar B, Troyer D, Venkatraman J, et al.  Dietary omega-3 lipids delay the onset and progression of autoimmune lupus nephritis by inhibiting transforming growth factor β mRNA and protein expression. J Autoimmun. 1995;8:381–393
  110. Ali S, Laping N, Fredrickson T, et al.  Angiotensin-converting enzyme inhibition attenuates proteinuria and renal TGF-β1 mRNA expression in rats with chronic renal disease. Pharmacol. 1998;57:20–27
  111. Iyer S, Gurujeyalakshmi G, Giri S. Effects of pirfenidone on transforming growth factor-β gene expression at the transcriptional level in bleomycin hamster model of fibrosis. J Pharmacol Exper Ther. 1999;291:367–373
  112. Datta P, Moulder J, Fish B, et al.  TGF-β1 production in radiation nephropathy (Role of angiotensin II). Int J Radiat Biol. 1999;75(4):473–479
  113. Cohen E, Molteni A, Hill P, et al.  Captopril preserves function and ultrastructure in experimental radiation nephropathy. Lab Invest. 1996;75:349–360
  114. Ward W, Molteni A, Ts’ao C-H, et al.  Radiation pneumotoxicity in rats (modification by inhibitors of angiotensin converting enzyme). Int J Radiat Oncol Biol Phys. 1992;22:623–625
  115. Wang L, Fu X, Clough R, et al.  Can angiotensin converting enzyme inhibitors protect against symptomatic radiation pneumonitis?. Radiat Res. 2000;153:405–410

PII: S0360-3016(00)01484-X

International Journal of Radiation Oncology * Biology * Physics
Volume 49, Issue 2 , Pages 353-365 , 1 February 2001