Adaptation to Ionizing Radiation in Mammalian Cells

  • R. E. J. Mitchel
  • E. I. Azzam
  • S. M. De Toledo


The concept of an ionizing radiation-induced increase in resistance against the effects of a subsequent exposure is an accepted and reasonably well-understood process in both prokaryotes (Walker, 1984, 1985) and nonmammalian eukaryotes (Calkins, 1967; Boreham et al., 1990, 1991; Boreham and Mitchel, 1991, 1993, 1994; Mitchel and Morrison, 1982, 1984, 1987; Koval, 1986, 1988). Such processes however, have been more difficult to demonstrate in mammalian cells, where their existence and/or significance have been very controversial (Olivieri et al., 1984; Olivieri and Bosi, 1990; Wiencke et al., 1987, Wilson, 1989; Wojcik et al., 1992a,b; Wolff, 1992 a,b). This lack of general acceptance, while reflecting the lack of volume of the data as well as the variability noted above and a lack of direct evidence of an influence on whole animal risk, also reflects the fact that the concept challenges long entrenched and widely held beliefs and practices, both scientific and public, on which all radiation protection programs and cancer risk estimates are based. Consequently, demonstration of the existence and quantification of the significance of adaptation to radiation in mammalian cells has, potentially, large social and economic implications.


Adaptive Response Ionize Radiation Human Lymphocyte Human Skin Fibroblast Acute Dose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Azzam, E. I., de Toledo, S. M., Raaphorst, G. P. and Mitchel, R. E. J., 1992, Radiation-induced radioresistance in a normal human skin fibroblast cell line, in: Low Dose Irradiation and Biological Defense Mechanisms ( T. Sugahara, L. A. Sagan, T. Aoyama, eds.), Elsevier, Amsterdam, pp. 291–294.Google Scholar
  2. Azzam, E. I., Raaphorst, G. P., and Mitchel, R. E. J., 1994a, Radiation-induced adaptive response for protection against micronucleus formation and neoplastic transformation in C3H 10T1/2 mouse embryo cells, Radiat. Res. 138: S28 - S31.PubMedCrossRefGoogle Scholar
  3. Azzam, E. I., de Toledo, S. M., Raaphorst, G. P., and Mitchel, R. E. J., 1994b, Réponse adaptative au rayonnement ionisant des fibroblastes de peau humaine Augmentation de la vitesse de réparation de l’ADN et variations de l’expression des génes, J. Chim. Phys. Phys. Chim. Biol. 91: 931–936.Google Scholar
  4. Azzam, E. I., de Toledo, S. M., Raaphorst, G. P., and Mitchel, R. E. J., 1996, Low-dose ionizing radiation decreases the frequency of neoplastic transformation to a level below the spontaneous rate in C3H 10T’ cells, Radiat. Res. 146: 369–373.PubMedCrossRefGoogle Scholar
  5. Boreham, D. R., and Mitchel, R. E. J., 1991, DNA lesions that signal the induction of radioresistance and DNA repair in yeast, Radiat. Res. 128: 19–28.PubMedCrossRefGoogle Scholar
  6. Boreham, D. R, and Mitchel, R. E. J., 1993, DNA repair in Chlamydomonas reinhardtii induced by heat shock and gamma radiation, Radiat. Res. 135: 365–371.PubMedCrossRefGoogle Scholar
  7. Boreham, D. R., and Mitchel, R. E. J., 1994, Regulation of heat and radiation stress responses in yeast by hsp-104, Radiat. Res. 137: 190–195.PubMedCrossRefGoogle Scholar
  8. Boreham, D. R., Trivedi, A., Weinberger, P. and Mitchel, R. E. J.,1990, The involvement of topoisomerases and DNA polymerase I in the mechanism of induced thermal and radiation resistance in yeast, Radiat. Res. 123: 203–212.Google Scholar
  9. Boreham, D. R., Trivedi, A., and Mitchel, R. E. J., 1991, Radiation and stress response in Saccharomyces cerevisiae, in: Molecular Biology of Yeast in Relation to Biotechnology ( R. Prasad, ed.), Omega Scientific, New Delhi, India, pp. 295–314.Google Scholar
  10. Boreham, D. R., Walker, J.-A., Mayes, S. R, Greiner, K., Mitchel, R. E. J., and Lucas, J. N., 1994, Mild hyperthermia-induced modification of radiation induced chromosomal aberrations. A comparison of micronuclei and translocations, Proceedings of the 42nd Annual Meeting of the Radiation Research Society, Abstract P03–51, p. 119.Google Scholar
  11. Boreham, D. R., Mayes, S. R., Miller, S., Morrison, D. P., and Mitchel, R. E. J., 1996, Heat induced thermal tolerance and radiation resistance to apoptosis in human lymphocytes, Proceedings of the 44th Annual Meeting of the Radiation Research Society, Abstract P19–328, p. 156.Google Scholar
  12. Calkins, J., 1967, An unusual form of response in x-irradiated protozoa and a hypothesis as to its origin, Int. J. Radiat. Biol. 4: 297–301.CrossRefGoogle Scholar
  13. Cregan, S. P., Boreham, D. R., Walker, J.-A., Brown, D. L., and Mitchel, R. E. J., 1994, Modification of radiation-induced apoptosis in radiation or hyperthermiaadapted human lymphocytes, Biochem. Cell Biol. 72: 475–482.PubMedCrossRefGoogle Scholar
  14. de Toledo, S. M., Azzam, E. I., Gasmann, M. K., and Mitchel, R. E. J., 1995, Use of semi-quantitative reverse transcription-polymerase chain reaction to study gene expression in normal skin fibroblasts following low dose-rate irradiation, Int. J. Radiat. Biol. 67: 135–142.PubMedCrossRefGoogle Scholar
  15. Doffing, J.-A., Boreham, D. R., Brown, D. L., Raaphorst, G. P., and Mitchel, R. E. J., 1997, Rearrangement of human cell homologous chromosome domains in response to ionizing radiation, Int. J. Radiat. Biol. 72: 303–311.CrossRefGoogle Scholar
  16. Dulic, V., Kaufmann, W. K., Wilson, S. J., Tisty, T. D., Lees, E., Wade Harper, J., Elledge, S. J., and Reed, S. I., 1994, P53-dependent inhibition of cyclindependent kinase activities in human fibroblasts during radiation-induced G1 arrest, Cell 76: 1013–1023.PubMedCrossRefGoogle Scholar
  17. Gordon-Smith, E. C., and Rutherford, T. R., 1991, Fanconi anemia: Constitutional aplastic-anemia, Semin. Hematol. 28: 104–112.PubMedGoogle Scholar
  18. ICRP, 1991, 1990 Recommendations of the International Commission on Radiological Protection, Publication 60, Annals of the ICRP, 21, Pergamon Press, London.Google Scholar
  19. Kastan, M. B., Zhan, Q., El-Deity, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Volgestein, B., and Fornace A. J., Jr., 1992, A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxiatelangiectasia, Cell 71: 587–597.PubMedCrossRefGoogle Scholar
  20. Koval, T. M., 1986, Inducible repair of ionizing radiation damage in higher eukaryotic cells, Mutat. Res. 173: 291–293.PubMedCrossRefGoogle Scholar
  21. Koval, T. M., 1988, Enhanced recovery from ionizing radiation damage in a lepidopteran insect cell line, Radiat. Res. 115: 413–420.PubMedCrossRefGoogle Scholar
  22. Lambin, P., Marples, B., Malaise, E. P., Fertil, B., and Joiner, M. C., 1993, Hypersensitivity of a human tumour cell line to very low radiation doses, Int. J. Radiat. Biol. 63: 639–650.Google Scholar
  23. Lambin, P., Fertil, B., Malaise, E. P., and Joiner, M. C., 1994, Multiphasic survival curves for cells of human tumor cell lines: Induced repair or hypersensitive subpopulation? Radiat. Res. 138: S32 - S36.PubMedCrossRefGoogle Scholar
  24. Lehnert, S., and Chow, T. Y. K., 1996, Low doses of ionizing radiation induce nuclear activity catalyzing double strand homologous DNA recombination, Proceedings of the 44th Annual Meeting of the Radiation Research Society, Abstract P14–262, p. 140.Google Scholar
  25. Marples, B., and Joiner, M. C., 1993, The response of Chinese hamster V79 cells to low radiation doses: evidence of enhanced sensitivity of the whole population, Radiat. Res. 133: 41–51.PubMedCrossRefGoogle Scholar
  26. Marples, B., Joiner, M. C., and Skov, K., 1994, The effect of oxygen on low-dose hypersensitivity and increased radioresistance in Chinese hamster V79–379A cells, Radiat. Res. 138: S17 - S20.PubMedCrossRefGoogle Scholar
  27. Mitchel, R. E. J., 1995, Mechanisms for the adaptive response in irradiated mammalian cells, Radiat. Res. 141: 117–118.Google Scholar
  28. Mitchel, R. E. J., and Morrison, D. P., 1982, Heat shock induction of ionizing radiation resistance in Saccharomyces cerevisiae. Transient changes in growth cycle distribution and recombinational ability, Radiat. Res. 92: 182–187.PubMedCrossRefGoogle Scholar
  29. Mitchel, R. E. J., and Morrison, D. P., 1984, An oxygen effect for gamma-radiation induction of radiation resistance in yeast, Radiat. Res. 100: 205–210.PubMedCrossRefGoogle Scholar
  30. Mitchel, R. E. J., and Morrison, D. P., 1987, Inducible DNA-repair systems in yeast: Competition for lesions, Mutat. Res. 183: 149–159.Google Scholar
  31. Mushel, R. J., Zhang, H. B., Iliakis G, and McKenna, W. G., 1991, Cyclin B expression in HeLa cells during the G2 block induced by ionizing radiation, Cancer Res. 51: 5113–5117.Google Scholar
  32. Nelson, W. G., and Kastan, M. B., 1994, DNA strand breaks: The DNA template alterations that trigger p53-dependent DNA damage response pathways, Mol. Cell. Biol. 14: 1815–1823.PubMedGoogle Scholar
  33. Olivieri, G., and Bosi, A., 1990, Possible causes of variability of the adaptive response in human lymphocytes, in: Chromosomal Aberrations: Basic and Applied Aspects ( G. Obe andA.T. Natarajan, eds.), Springer-Verlag, Berlin, pp. 130–139.CrossRefGoogle Scholar
  34. Olivieri, G., Bodycote, J., and Wolff, S., 1984, Adaptive response of human lympho- cytes to low concentration of radioactive thymidine, Science 23: 594–597.CrossRefGoogle Scholar
  35. Pagano, M., Pepperkok, P., Verde, F., Ansorge, W., and Draetta, G., 1992, CyclinA is required at two points in the human cell cycle, EMBO J. 11: 961–971.Google Scholar
  36. Papathanasiou, M. A., Kerr, N. C. K., Robbins, J. H., McBride, O. W., Alamo, I., Jr., Barret, S. F., Hickson, I. D., and Fornace, A. J., Jr., 1991, Induction by ionizing radiation of the GADD45 gene in cultured human cells: Lack of mediation by protein kinase C, Moi. Cell. Biol. 11: 1009–1016.Google Scholar
  37. Resnitzky, D., Gossen, M., Bujard, H., and Reed, S. I., 1994, Acceleration of the G1/S transition by expression of cyclins D1 and E using an inducible system, MoL Cell. Biol. 14: 1669–1679.Google Scholar
  38. Shadley, J. D., and Wiencke, J. K., 1989, Induction of the adaptive response by x-rays is dependent on radiation intensity, Int. J. Radiat. Biol. 56: 107–118.PubMedCrossRefGoogle Scholar
  39. Sherr, C. J., 1993, Mammalian G1 cyclins, Cell 73: 1059–1065.PubMedCrossRefGoogle Scholar
  40. Spadinger, I., Marples, B., Mathews, J., and Skov, K., 1994, Can colony size be used to detect low-dose effects? Radiat. Res. 138: S21 - S24.PubMedCrossRefGoogle Scholar
  41. Stevnsner, T., and Bohr, V., 1993, Studies on the role of topoisomerases in general, gene-and strand-specific DNA repair, Carcinogenesis 14: 1841–1850.PubMedCrossRefGoogle Scholar
  42. Strathdee, C. A., and Buchwald, M., 1992, Molecular and cellular biology of Fanconi anemia, Am. J. Pediatr. Hematol. Oncol. 14: 177–185.PubMedCrossRefGoogle Scholar
  43. Strathdee, C. A., Gavish, H., Shannon, W. R, and Buchwald, M., 1992, Cloning of cDNAs for Fanconi’s anaemia by functional complementation, Nature 356: 763–767.PubMedCrossRefGoogle Scholar
  44. Walker, G. C., 1984, Mutagenesis and inducible responses to deoxyribonucleic acid damage in Escherichia coli, Microbioi. Rey. 48: 60–93.Google Scholar
  45. Walker, G. C., 1985, Inducible DNA repair systems, Annu. Rey. Biochem. 54: 425–457.CrossRefGoogle Scholar
  46. Wiencke, J. K., Afzal, V., Olivieri, G., and Wolff, S., 1986, Evidence that the [3H1thymidine-induced adaptive response of human lymphocytes to subsequent doses of X-rays involves the induction of a chromosomal repair mechanism, Mutagenesis 1: 375–380.PubMedCrossRefGoogle Scholar
  47. Wiencke, J. K., Shadley, J. D., Kelsey, K. T., Kronenberg, A., and Little, J. B., 1987, Failure of high intensity X-ray treatments or densely ionizing fast neutrons to induce the adaptive response in human lymphocytes, in: Proceedings of the 8th International Congress of Radiation Research (E. M. Fielden, J. F. Fowler, J. H. Hendry, and D. Scott, eds.), Taylor Francis, London, Vol. 1, p. 212.Google Scholar
  48. Wilson, A., 1989, Meeting report: The effects of small doses of radiation, Int. J. Radiat. Biol. 56: 203–206.Google Scholar
  49. Woessner, R. D., Mattern, M. R, Mirabelli, C. K., Johnson, R. K., and Drake, F. H., 1991, Proliferation-and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells, Cell Growth Differ 2: 209–214.PubMedGoogle Scholar
  50. Wojcik, A., and Tuschl, H., 1990, Indications of an adaptive response in C57BL mice pre-exposed in vivo to low doses of ionizing radiation, Mutat. Res. 243: 67–73.PubMedCrossRefGoogle Scholar
  51. Wojcik, A., Bonk, K., Müller, W.-U., Streffer, C., Weissenborn, U., and Obe, G., 1992a, Absence of adaptive response to low doses of X-rays in preimplantation embryos and spleen lymphocytes of an inbred mouse strain as compared to human peripheral lymphocytes: A cytogenetic study, Int. J. Racifiat. Biol. 62: 177–186.CrossRefGoogle Scholar
  52. Wojcik, A., Bonk, K., Müller, W.-U., and Streffer, C., 1992b, Indications of strain specificity for the induction of adaptive response to ionizing radiation in mice, in: Low Dose Irradiation and Biological Defense Mechanisms ( T. Sugahara, L. A. Sagan, and T. Aoyama, eds.), Elsevier, Amsterdam, pp. 311–314.Google Scholar
  53. Wolff, S., 1992a, Failla Memorial Lecture: Is radiation all bad? The search for adaptation, Radiat. Res. 131: 117–123.PubMedCrossRefGoogle Scholar
  54. Wolff, S., 1992b, Low dose exposure and the induction of adaptation, in: Low Dose Irradiation and Biological Defense Mechanisms ( T. Sugahara, L. A. Sagan, and T. Aoyama, eds.), Elsevier, Amsterdam, pp. 21–28.Google Scholar
  55. Wolff, S., Afzal, V., Wiencke, J. K., Olivieri, G. and Micheali, A., 1988, Human lymphocytes exposed to low doses of ionizing radiations become refractory to high doses of radiation as well as chemical mutagens that induce double-strand breaks in DNA, Int. J. Radiat. Biol. 53: 39–48.Google Scholar
  56. Wolff, S., Wiencke, J. K., Afzal, V., Youngblom, J., and Cortés, F., 1989, 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: Low Dose Radiation: Biological Bases of Risk Assessment ( K. F. Baverstock and J. W. Stather, eds.), Taylor Francis, London, pp. 446–454.Google Scholar
  57. Wouters, B. G., and Skarsgard, L. D., 1994, The response of a human tumor cell line to low radiation doses: Evidence for enhanced sensitivity, Radiat. Res. 138: S76 - S80.PubMedCrossRefGoogle Scholar
  58. Xiong, Y., and Beach, D., 1991, Population explosion in the cyclin family, Curr. Biol. 1: 362–364.PubMedCrossRefGoogle Scholar
  59. Xu, Y., Greenstock, C. L., Trivedi, A., and Mitchel, R. E. J., 1996, Occupational levels of radiation exposure induce surface expression of interleukin-2 receptors in stimulated human peripheral blood lymphocytes, Radiat. Environ. Biophys. 35: 89–93.PubMedCrossRefGoogle Scholar
  60. Zhan, Q., Carrier, F., and Fornace, A. J., Jr., 1993, Induction of cellular p53 activity by DNA-damaging agents and growth arrest, Mol. Cell. Biol. 13: 4242–4250.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • R. E. J. Mitchel
    • 1
  • E. I. Azzam
    • 1
  • S. M. De Toledo
    • 1
  1. 1.Radiation Biology and Health Physics Branch, Chalk River LaboratoriesAtomic Energy of Canada LimitedChalk RiverCanada

Personalised recommendations