International Journal of Radiation Oncology * Biology * Physics
Volume 49, Issue 2 , Pages 379-389 , 1 February 2001

Low-dose hypersensitivity: current status and possible mechanisms

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

  • Michael C Joiner, Ph.D.

      Affiliations

    • Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK
    • Corresponding Author InformationAddress reprint requests to: Michael Joiner, Ph.D., Experimental Oncology Group, Gray Laboratory Cancer Research Trust, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR, U.K. Tel: +44 192 382 8611; Fax: +44 192 383 5210
    • ,
  • Brian Marples, Ph.D.

      Affiliations

    • Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK
    • ,
  • Philippe Lambin, M.D., Ph.D.

      Affiliations

    • Department of Radiation Oncology, University of Maastricht, Maastricht, The Netherlands
    • ,
  • Susan C Short, Ph.D. (M.B.)

      Affiliations

    • Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK
    • ,
  • Ingela Turesson, M.D., Ph.D.

      Affiliations

    • Department of Oncology, Academic Hospital, Uppsala, Sweden

,Accepted 31 August 2000.

References 

  1. Chadwick KH, Leenhouts HP. The effect of an asynchronous population of cells on the initial slope of dose-effect curves. In:  Alper T editors. Cell survival after low doses of radiation (Theoretical and clinical implications). London: The Institute of Physics and John Wiley & Sons; 1975;p. 57–63
  2. Eriksson G. Induction of waxy mutants in maize by acute and chronic gamma irradiation. Hereditas. 1963;50:161–178
  3. Calkins J. An unusual form of response in X-irradiated protozoa and a hypothesis as to its origin. Int J Radiat Biol. 1967;12:297–301
  4. Beam CA, Mortimer RK, Wolfe RG, et al.  The relation of radioresistance to budding in Saccharomyces cerevisiae. Arch Biochem Biophys. 1954;49:110–122
  5. Horsley RJ, Pujara CM. Study of the inflexion of X-radiation survival curves for synchronized cell populations of the green alga (Oedogonium cardiacum). Radiat Res. 1969;40:440–449
  6. Hillova J, Drasil V. The inhibitory effect of iodoacetamide on recovery from sub-lethal damage in Chlamydomonas reinhardti. Int J Radiat Biol. 1967;12:201–208
  7. Hendry JH. Radioresistance induced in fern spores by prior irradiation. Radiat Res. 1986;106:396–400
  8. Boreham DR, Mitchel RE. DNA lesions that signal the induction of radioresistance and DNA repair in yeast. Radiat Res. 1991;128:19–28
  9. Joiner MC, Lambin P, Marples B. Adaptive response and induced resistance. C R Acad Sci III. 1999;322:167–175
  10. Howard A, Cowie FG. Induced resistance in a desmid Closterium moniliferum. Radiat Res. 1976;65:540–549
  11. Howard A, Cowie FG. Induced resistance in Closterium (Indirect evidence for the induction of repair enzyme). Radiat Res. 1978;75:607–616
  12. Horsley RJ, Laszlo A. Unexpected additional recovery following a first X-ray dose to a synchronous cell culture. Int J Radiat Biol. 1971;20:593–596
  13. Horsley RJ, Laszlo A. Additional recovery in X-irradiated Oedogonium cardiacum can be suppressed by cycloheximide. Int J Radiat Biol. 1973;23:201–204
  14. Bryant PE. Changes in sensitivity of cells during exposure to radiation at low dose-rate. Int J Radiat Biol. 1972;22:67–73
  15. Santier S, Gilet R, Malaise EP. Induced radiation resistance during low-dose-rate gamma irradiation in plateau-phase Chlorella cells. Radiat Res. 1985;104:224–233
  16. Koval TM. Multiphasic survival response of a radioresistant lepidopteran insect cell line. Radiat Res. 1984;98:642–648
  17. Koval TM. Inducible repair of ionizing radiation damage in higher eukaryotic cells. Mutat Res. 1986;173:291–293
  18. Koval TM. Enhanced recovery from ionizing radiation damage in a lepidopteran insect cell line. Radiat Res. 1988;115:413–420
  19. Palcic B, Faddegon B, Jaggi B, et al.  Automated low dose assay system for survival measurements of mammalian cells in vitro. J Tiss Cult Meth. 1983;8:103–107
  20. Palcic B, Jaggi B. The use of solid-state image sensor technology to detect and characterize live mammalian cells growing in tissue culture. Int J Radiat Biol. 1986;50:345–352
  21. Spadinger I, Palcic B. The relative biological effectiveness of 60Co gamma-rays, 55 kVp X-rays, 250 kVp X-rays, and 11 MeV electrons at low doses. Int J Radiat Biol. 1992;61:345–353
  22. Spadinger I, Palcic B. Cell survival measurements at low doses using an automated image cytometry device. Int J Radiat Biol. 1993;63:183–189
  23. Spadinger I, Poon SS, Palcic B. Automated detection and recognition of live cells in tissue culture using image cytometry. Cytometry. 1989;10:375–381
  24. Spadinger I, Poon SS, Palcic B. Effect of focus on cell detection and recognition by the Cell Analyzer. Cytometry. 1990;11:460–467
  25. Wouters BG, Skarsgard LD. The response of a human tumor cell line to low radiation doses (Evidence of enhanced sensitivity). Radiat Res. 1994;138:S76–S80
  26. Marples B, Joiner MC. The response of Chinese hamster V79 cells to low radiation doses (Evidence of enhanced sensitivity of the whole cell population). Radiat Res. 1993;133:41–51
  27. Marples B, Joiner MC, Skov KA. An X-ray inducible repair response (Evidence from high resolution survival measurements in air and hypoxia). In:  Sugahara T,  Sagan LA,  Aoyama T editor. Low dose irradiation and biological defense mechanisms. Amsterdam: Elsevier; 1992;p. 295–298
  28. Lambin P, Coco Martin J, Legal JD, et al.  Intrinsic radiosensitivity and chromosome aberration analysis using fluorescence in situ hybridization in cells of two human tumor cell lines. Radiat Res. 1994;138:S40–S43
  29. Lambin P, Fertil B, Malaise EP, et al.  Multiphasic survival curves for cells of human tumor cell lines (Induced repair or hypersensitive subpopulation?). Radiat Res. 1994;138:S32–S36
  30. Lambin P, Malaise EP, Joiner MC. The effect of very low radiation doses on the human bladder carcinoma cell line RT112. Radiother Oncol. 1994;32:63–72
  31. Lambin P, Malaise EP, Joiner MC. Might intrinsic radioresistance of human tumour cells be induced by radiation?. Int J Radiat Biol. 1996;69:279–290
  32. Lambin P, Marples B, Fertil B, et al.  Hypersensitivity of a human tumour cell line to very low radiation doses. Int J Radiat Biol. 1993;63:639–650
  33. Short S, Mayes C, Woodcock M, et al.  Low dose hypersensitivity in the T98G human glioblastoma cell line. Int J Radiat Biol. 1999;75:847–855
  34. Short SC, Mitchell SA, Boulton P, et al.  The response of human glioma cell lines to low-dose radiation exposure. Int J Radiat Biol. 1999;75:1341–1348
  35. Wouters BG, Sy AM, Skarsgard LD. Low-dose hypersensitivity and increased radioresistance in a panel of human tumor cell lines with different radiosensitivity. Radiat Res. 1996;146:399–413
  36. Joiner MC, Denekamp J, Maughan RL. The use of ‘top-up’ experiments to investigate the effect of very small doses per fraction in mouse skin. Int J Radiat Biol. 1986;49:565–580
  37. Joiner MC, Johns H. Renal damage in the mouse (The response to very small doses per fraction). Radiat Res. 1988;114:385–398
  38. Parkins CS, Fowler JF. The linear quadratic fit for lung function after irradiation with X-rays at smaller doses per fraction than 2 Gy. Br J Cancer Suppl. 1986;7:320–323
  39. Lambin P, Malaise EP, Joiner MC. Megafractionnement (Une methode pour agir sur les tumeurs intrinsequement radioresistantes?). Bull Cancer Radiother. 1993;80:417–423
  40. Marples B, Joiner MC. The elimination of low-dose hypersensitivity in Chinese hamster V79-379A cells by pretreatment with X rays or hydrogen peroxide. Radiat Res. 1995;141:160–169
  41. Short SC, Kelly J, Woodcock M; et al. Low dose hypersensitivity after fractionated low-dose irradiation in vitro. Int J Radiat Biol; in press.
  42. Wouters BG, Skarsgard LD. Low-dose radiation sensitivity and induced radioresistance to cell killing in HT-29 cells is distinct from the “adaptive response” and cannot be explained by a subpopulation of sensitive cells. Radiat Res. 1997;148:435–442
  43. Wolff S. Failla memorial lecture. Is radiation all bad? The search for adaptation. Radiat Res. 1992;131:117–123
  44. Marples B, Lambin P, Skov KA, et al.  Low dose hyper-radiosensitivity and increased radioresistance in mammalian cells. Int J Radiat Biol. 1997;71:721–735
  45. Eady JJ, Peacock JH, McMillan TJ. Host cell reactivation of gamma-irradiated adenovirus 5 in human cell lines of varying radiosensitivity. Br J Cancer. 1992;66:113–118
  46. Jeeves WP, Rainbow AJ. U.V. enhanced reactivation of U.V.- and gamma-irradiated adenovirus in normal human fibroblasts. Int J Radiat Biol. 1983;43:599–623
  47. Jeeves WP, Rainbow AJ. Gamma-ray enhanced reactivation of gamma-irradiated adenovirus in human cells. Biochem Biophys Res Commun. 1979;90:567–574
  48. Francis MA, Rainbow AJ. UV-enhanced reactivation of a UV-damaged reporter gene suggests transcription-coupled repair is UV-inducible in human cells. Carcinogenesis. 1999;20:19–26
  49. Mitchel RE, Morrison DP. Inducible DNA-repair systems in yeast (Competition for lesions). Mutat Res. 1987;183:149–159
  50. Skov K, Marples B, Matthews JB, et al.  A preliminary investigation into the extent of increased radioresistance or hyper-radiosensitivity in cells of hamster cell lines known to be deficient in DNA repair. Radiat Res. 1994;138:S126–S129
  51. Jeggo PA. DNA-PK (At the cross-roads of biochemistry and genetics). Mutat Res. 1997;384:1–14
  52. Wojewodzka M, Wojcik A, Szumiel I; et al. Faster DNA damage repair in adapted human lymphocytes. In: Hagen U, Jung H, Streffer C, editors. Radiation research 1895–1995, congress abstracts. Wurzburg: 10th ICRR Society; 1995. p. 307.
  53. Ikushima T, Aritomi H, Morisita J. Radioadaptive response (Efficient repair of radiation-induced DNA damage in adapted cells). Mutat Res. 1996;358:193–198
  54. Robson T, Joiner MC, Wilson GD, et al.  A novel human stress response-related gene with a potential role in induced radioresistance. Radiat Res. 1999;152:451–461
  55. Vaganay-Juéry S, Muller C, Abdulkarim B, et al.  Decreased DNA-PK activity in human cancer cells exhibiting hypersensitivity to low-dose irradiation. Brit J Cancer. 2000;83:514–518
  56. Power OM. Cellular and molecular mechanisms affecting tumour radiosensitivity: An in vitro study [Ph.D. Thesis]. University of London, 1998.
  57. Song Q, Lees Miller SP, Kumar S, et al.  DNA-dependent protein kinase catalytic subunit (A target for an ICE-like protease in apoptosis). Embo J. 1996;15:3238–3246
  58. Azzam EI, de Toledo SM, Raaphorst GP, et al.  Radiation-induced resistance in a normal human skin fibroblast line. In:  Sugahara T,  Sagan LA,  Aoyama T editor. Low dose irradiation and biological defence mechanisms. Amsterdam: Elsevier; 1992;p. 291–294
  59. Marples B, Lam GK, Zhou H, et al.  The response of Chinese hamster V79-379A cells exposed to negative pi-mesons (Evidence that increased radioresistance is dependent on linear energy transfer). Radiat Res. 1994;138:S81–S84
  60. Marples B, Skov KA. Small doses of high-linear energy transfer radiation increase the radioresistance of Chinese hamster V79 cells to subsequent X irradiation. Radiat Res. 1996;146:382–387
  61. Gupta SS, Bhattacharjee SB. Induction of repair functions by hydrogen peroxide in Chinese hamster cells. Int J Radiat Biol. 1988;53:935–942
  62. Caney C, Bulmer JT, Singh G, et al.  Pre-exposure of human squamous carcinoma cells to low-doses of gamma-rays leads to an increased resistance to subsequent low-dose cisplatin treatment. Int J Radiat Biol. 1999;75:963–972
  63. Elledge SJ. Cell cycle checkpoints (Preventing an identity crisis). Science. 1996;274:1664–1672
  64. Murnane JP. Cell cycle regulation in response to DNA damage in mammalian cells (A historical perspective). Cancer Metastasis Rev. 1995;14:17–29
  65. Seeberg E, Eide L, Bjoras M. The base excision repair pathway. Trends Biochem Sci. 1995;20:391–397
  66. Hoeijmakers JH. Nucleotide excision repair. II (From yeast to mammals). Trends Genet. 1993;9:211–217
  67. Jeggo PA. Identification of genes involved in repair of DNA double-strand breaks in mammalian cells. Radiat Res. 1998;150:S80–S91
  68. Thacker J. Repair of ionizing radiation damage in mammalian cells. Alternative pathways and their fidelity. C R Acad Sci Paris. 1999;322:103–108
  69. Lieber MR, Grawunder U, Wu X, et al.  Tying loose ends (Roles of Ku and DNA-dependent protein kinase in the repair of double-strand breaks). Curr Opin Genet Dev. 1997;7:99–104
  70. Marples B, Joiner MC. The modification of survival by inhibitors of DNA repair: An explanation for the phenomenon of increased radioresistance. Int J Radiat Biol 2000;in press.
  71. Lee SE, Mitchell RA, Cheng A, et al.  Evidence for DNA-PK-dependent and -independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle. Mol Cell Biol. 1997;17:1425–1433
  72. Salles-Passador I, Fotedar A, Fotedar R. Cellular response to DNA damage. Link between p53 and DNA-PK. C R Acad Sci Paris. 1999;322:113–120
  73. Critchlow SE, Bowater RP, Jackson SP. Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV. Curr Biol. 1997;7:588–598
  74. Getts RC, Stamato TD. Absence of a Ku-like DNA end binding activity in the xrs double-strand DNA repair-deficient mutant. J Biol Chem. 1994;269:15981–15984
  75. Gu Y, Jin S, Gao Y, et al.  Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc Natl Acad Sci U S A. 1997;94:8076–8081
  76. Lees Miller SP, Godbout R, Chan DW, et al.  Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line. Science. 1995;267:1183–1185
  77. Allalunis Turner MJ, Barron GM, Day RSd, et al.  Isolation of two cell lines from a human malignant glioma specimen differing in sensitivity to radiation and chemotherapeutic drugs. Radiat Res. 1993;134:349–354
  78. Thacker J, Ganesh AN. DNA-break repair, radioresistance of DNA synthesis, and camptothecin sensitivity in the radiation-sensitive irs mutants (Comparisons to ataxia-telangiectasia cells). Mutat Res. 1990;235:49–58
  79. Britten RA, Murray D. Constancy of the relative biological effectiveness of 42 MeV (p->Be+) neutrons among cell lines with different DNA repair proficiencies. Radiat Res. 1997;148:308–316
  80. Marples B, Adomat H, Koch CJ, et al.  Response of V79 cells to low doses of X-rays and negative pi-mesons (Clonogenic survival and DNA strand breaks). Int J Radiat Biol. 1996;70:429–436
  81. Chiu SM, Xue LY, Friedman LR, et al.  Chromatin compaction and the efficiency of formation of DNA-protein crosslinks in γ-irradiated mammalian cells. Radiat Res. 1992;129:184–191
  82. Elia MC, Bradley MO. Influence of chromatin structure on the induction of DNA double strand breaks by ionising radiation. Cancer Res. 1992;52:1580–1586
  83. Nackerdien Z, Michie J, Bohm L. Chromatin decondensed by acetylation shows an elevated radiation response. Radiat Res. 1989;117:234–244
  84. Olive PL, Banath JP. Radiation-induced DNA double-strand breaks produced in histone-depleted tumor cell nuclei measured using the neutral comet assay. Radiat Res. 1995;142:144–152
  85. Holley WR, Chatterjee A. Clusters of DNA induced by ionizing radiation (Formation of short DNA fragments. I. Theoretical modeling). Radiat Res. 1996;145:188–199
  86. Rydberg B. Clusters of DNA damage induced by ionizing radiation (Formation of short DNA fragments. II. Experimental detection). Radiat Res. 1996;145:200–209
  87. Ward JF, Blakely WF, Joner EI. Mammalian cells are not killed by DNA single-strand breaks caused by hydroxyl radicals from hydrogen peroxide. Radiat Res. 1985;103:383–392
  88. Dewey WC, Noel JS, Dettor CM. Changes in radiosensitivity and dispersion of chromatin during the cell cycle of synchronous chinese hamster cells. Radiat Res. 1972;52:373–394
  89. Iliakis G, Okayasu R, Varlotto J, et al.  Hypertonic treatment during premature chromosome condensation allows visualization of interphase chromosome breaks repaired with fast kinetics in irradiated CHO cells. Radiat Res. 1993;135:160–170
  90. Metzger L, Iliakis G. Kinetics of DNA double-strand break repair throughout the cell cycle as assayed by pulsed field gel electrophoresis in CHO cells. Int J Radiat Biol. 1991;59:1325–1339
  91. Okayasu R, Varlotto J, Iliakis G. Hypertonic treatment does not affect the radiation yield of interphase chromosome breaks in DNA double-strand break repair-deficient xrs-5 cells. Radiat Res. 1993;135:171–177
  92. Raaphorst GP, Azzam EI. Fixation of potentially lethal radiation damage in Chinese hamster cells by anisotonic solutions, polyamines and DMSO. Radiat Res. 1981;86:52–66
  93. Bunch RT, Gewirtz DA, Povirk LF. Ionizing radiation-induced DNA strand breakage and rejoining in specific genomic regions as determined by an alkaline unwinding/Southern blotting method. Int J Radiat Biol. 1995;68:553–562
  94. Leadon SA, Cooper PK. Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome. Proc Natl Acad Sci U S A. 1993;90:10499–10503
  95. Puerto S, Surralles J, Ramirez MJ, et al.  Analysis of bleomycin- and cytosine arabinoside-induced chromosome aberrations involving chromosomes 1 and 4 by painting FISH. Mutat Res. 1999;439:3–11
  96. Sak A, Stuschke M. Repair of ionizing radiation induced DNA double-strand breaks (dsb) at the c-myc locus in comparison to the overall genome. Int J Radiat Biol. 1998;73:35–43
  97. Martinez-Lopez W, Boccardo EM, Folle GA, et al.  Intrachromosomal localization of aberration breakpoints induced by neutrons and gamma rays in Chinese hamster ovary cells. Radiat Res. 1998;150:585–592
  98. Radford IR, Hodgson GS, Matthews JP. Critical DNA target size model of ionizing radiation-induced mammalian cell death. Int J Radiat Biol. 1988;54:63–79
  99. Slijepcevic P, Natarajan AT. Distribution of radiation-induced G1 exchange and terminal deletion breakpoints in Chinese hamster chromosomes as detected by G banding. Int J Radiat Biol. 1994;66:747–755
  100. Malyapa RS, Wright WD, Roti Roti JL. Radiation sensitivity correlates with changes in DNA supercoiling and nucleoid protein content in cells of three Chinese hamster cell lines. Radiat Res. 1994;140:312–320
  101. Schwartz JL, Shadley J, Jaffe DR, et al.  Association between radiation sensitivity, DNA repair, and chromosome organisation in the Chinese hamster ovary cell line xrs 5. In:  Mendelsohn ML,  Albertini RJ editor. Mutation and the environment part a (Basic mechanisms). New York: Wiley-Liss; 1990;p. 255–264
  102. Schwartz JL, Vaughan ATM. Association among DNA/chromosome break rejoining rates, chromatin structure alterations, and radiation sensitivity in human tumour cell lines. Cancer Res. 1989;49:5054–5057
  103. Wlodek D, Olive PL. Neutral filter elution detects differences in chromatin organization which can influence cellular radiosensitivity. Radiat Res. 1992;132:242–247
  104. Yasui LS, Ling-Indeck L, Johnson-Wint B, et al.  Changes in the nuclear structure in the radiation-sensitive CHO mutant, xrs-5. Radiat Res. 1991;127:269–277
  105. Amundson SA, Chen DJ. Inverse dose-rate effect for mutation induction by gamma-rays in human lymphoblasts. Int J Radiat Biol. 1996;69:555–563
  106. Colussi N, Lohman PH. Low dose-rate X-irradiation induces larger deletions at the human HPRT locus than high dose-rate X-irradiation. Int J Radiat Biol. 1997;72:531–536
  107. Furuno Fukushi I, Tatsumi K, Takahagi M, et al.  Quantitative and qualitative effect of gamma-ray dose-rate on mutagenesis in human lymphoblastoid cells. Int J Radiat Biol. 1996;70:209–217
  108. Rigaud O, Moustacchi E. Radioadaptation for gene mutation and the possible molecular mechanisms of the adaptive response. Mutat Res. 1996;358:127–134
  109. Marples B, Joiner MC, Skov KA. The effect of oxygen on low-dose hypersensitivity and increased radioresistance in Chinese hamster V79-379A cells. Radiat Res. 1994;138:S17–S20
  110. Wolff S, Afzal V, Wiencke JK, et al.  Human lymphocytes exposed to low doses of ionizing radiations become refractory to high doses of radiation as well as to chemical mutagens that induce double-strand breaks in DNA. Int J Radiat Biol. 1988;53:39–47
  111. Wolff S, Wiencke JK, Afzal V, et al.  The adaptive response of human lymphocytes to very low doses of ionizing radiation (A case of induced chromosomal repair with the induction of specific proteins). In:  Baverstock KF,  Stather JW editor. Low dose radiation (Biological bases of risk assessment). London: Taylor & Francis; 1989;p. 446–454

PII: S0360-3016(00)01471-1

International Journal of Radiation Oncology * Biology * Physics
Volume 49, Issue 2 , Pages 379-389 , 1 February 2001

Article Tools

* Image Usage & Resolution