Experimental Models for Ionizing Radiation Research

  • Kristin Fabre
  • William DeGraff
  • John A. Cook
  • Murali C. KrishnaEmail author
  • James B. Mitchell
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


Ionizing radiation is a valuable tool used for cancer treatment as well as for basic molecular research. More recent interest stems from a need to provide countermeasures against accidental or intentional exposure to radiation through nuclear devices. This chapter provides an overview of the biological effects of radiation and highlights models used to study radiation-induced damage and repair. In vitro and in vivo endpoints including DNA damage, cell survival, apoptosis, cytogenetic aberrations, oxidative stress, tumor response, and genomic instability are discussed. Appropriate use of these models will facilitate the advancement of radiation research as novel molecular mechanisms are elucidated.


Cell killing DNA damage DNA repair IR protectors Radiation Radiosensitizers ROS 



Ataxia telangectasia mutant


Astrazeneca Chk1 inhibitor


B-cell lymphoma 2


Breast cancer associated 1/2


Bystander effect




Checkpoint kinase 1/2


Chinese hamster ovary cell line






5-Ethyl-5,6-dihydro-6-phenyl-3,8-diaminophenanthridine, hydroethidine


3,3′-Dihexyloxacarbocyanine iodide


Dose modifying factor


DNA-dependent protein kinase catalytic subunit


Double-strand break


Epidermal growth factor receptor


Enzyme-linked immunosorbent assay


Fluorescence plus Giemsa


Fractionated IR


Genomic instability




Histone H2A




Histone deactetylase


Hypoxanthine–guanine phosphoribosyltransferase


High performance liquid chromatography


Homologous recombination


Heat-shock protein 90


Ionizing radiation




Microtubule-associated protein 1 light chain 3


Lethal dose for 50% at 30 days


Linear energy transfer






Mammalian target of rapamycin




3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide


Nuclear factor kappa-light-chain-enhancer of activated B cells


Nonhomologous end-joining


Poly (ADP-ribose) polymerase-1


Protector factor


Pulse field gel electrophoresis


Phosphoinositide 3-kinases


Permeability transition pores


Reactive oxygen species


Replication protein A


Sister chromatid exchange


Single nucleotide polymorphism


Single strand break


Single strand DNA


Tumor control dose for 50%




Terminal deoxynucleotidyl transferase dUTP nick end labeling


Vascular endothelial growth factor


X-linked Inhibitor of apoptosis protein


X-ray repair complementing defective repair in CHO 4




Gamma (phosphorylated) H2AX

Δy  m

Membrane potential difference


  1. 1.
    Hall, E.J. and A.J. Giaccia, Radiobiology for the Radiologist. 6th ed. 2006, Philadelphia: Lippincott Williams & Wilkins.Google Scholar
  2. 2.
    Steel, G.G., Basic Clinincal Radiobiology. 3rd ed. 2002, New York: Hodder Arnold.Google Scholar
  3. 3.
    von-Sonntag, C., The Chemical Basis of Radiation Biology. 1987, Philadelphia: Taylor & Francis.Google Scholar
  4. 4.
    Munro, T.R., The relative radiosensitivity of the nucleus and cytoplasm of Chinese hamster fibroblasts. Radiat Res, 1970. 42(3): p. 451–  70.PubMedCrossRefGoogle Scholar
  5. 5.
    Ward, J.F., DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol, 1988. 35:p. 95–125.PubMedCrossRefGoogle Scholar
  6. 6.
    Cornforth, M.N. and J.S. Bedford, A quantitative comparison of potentially lethal damage repair and the rejoining of interphase chromosome breaks in low passage normal human fibroblasts. Radiat Res, 1987. 111(3): p. 385–405.PubMedCrossRefGoogle Scholar
  7. 7.
    Pfeiffer, P., et al., DNA lesions and repair. Mutat Res, 1996. 366(2): p. 69–80.CrossRefGoogle Scholar
  8. 8.
    Duggan, D.E., A.W. Anderson, and P.R. Elliker, Inactivation of the Radiation-Resistant Spoilage Bacterium Micrococcus Radiodurans. Ii. Radiation Inactivation Rates as Influenced by Menstruum Temperature, Preirradiation Heat Treatment, and Certain Reducing Agents. Appl Microbiol, 1963. 11: p. 413–7.PubMedGoogle Scholar
  9. 9.
    Blasius, M., S. Sommer, and U. Hubscher, Deinococcus radiodurans: what belongs to the survival kit? Crit Rev Biochem Mol Biol, 2008. 43(3): p. 221–38.PubMedCrossRefGoogle Scholar
  10. 10.
    Pass, H.I., et al., Lung Cancer: Principles and Practice. 2nd ed. 2000, Philadelphia, PA: Lippencott Williams & Wilkins.Google Scholar
  11. 11.
    Savage, J.R., Update on target theory as applied to chromosomal aberrations. Environ Mol Mutagen, 1993. 22(4): p. 198–207.PubMedCrossRefGoogle Scholar
  12. 12.
    Minton, K.W., DNA repair in the extremely radioresistant bacterium Deinococcus radiodurans. Mol Microbiol, 1994. 13(1): p. 9–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Brown, J.M. and L.D. Attardi, The role of apoptosis in cancer development and treatment response. Nat Rev Cancer, 2005. 5(3): p. 231–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Puck, T.T. and P.I. Marcus, Action of x-rays on mammalian cells. J Exp Med, 1956. 103(5): p. 653–66.PubMedCrossRefGoogle Scholar
  15. 15.
    Puck, T.T. and P.I. Marcus, A Rapid Method for Viable Cell Titration and Clone Production with Hela Cells in Tissue Culture: The Use of X-Irradiated Cells to Supply Conditioning Factors. Proc Natl Acad Sci USA, 1955. 41(7): p. 432–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Albright, N., Computer programs for the analysis of cellular survival data. Radiat Res, 1987. 112(2): p. 331–40.PubMedCrossRefGoogle Scholar
  17. 17.
    Hahn, S.M., et al., Identification of nitroxide radioprotectors. Radiat Res, 1992. 132(1): p. 87–93.CrossRefGoogle Scholar
  18. 18.
    Thotala, D.K., et al., A new class of molecular targeted radioprotectors: GSK-3beta inhibitors. Int J Radiat Oncol Biol Phys, 2010. 76(2): p. 557–65.PubMedCrossRefGoogle Scholar
  19. 19.
    Mitchell, J.B., et al., Differing sensitivity to fluorescent light in Chinese hamster cells containing equally incorporated quantities of BUdR versus IUdR. Int J Radiat Oncol Biol Phys, 1984. 10(8): p. 1447–51.PubMedCrossRefGoogle Scholar
  20. 20.
    Kerr, J.F., History of the events leading to the formulation of the apoptosis concept. Toxicology, 2002. 181–182: p. 471–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Castedo, M., et al., Quantitation of mitochondrial alterations associated with apoptosis. J Immunol Methods, 2002. 265(1-2): p. 39–47.PubMedCrossRefGoogle Scholar
  22. 22.
    Huerta, S., et al., Screening and detection of apoptosis. J Surg Res, 2007. 139(1):p. 143–56.PubMedCrossRefGoogle Scholar
  23. 23.
    Brown, J.M. and B.G. Wouters, Apoptosis, p53, and tumor cell sensitivity to anticancer agents. Cancer Res, 1999. 59(7): p. 1391–9.PubMedGoogle Scholar
  24. 24.
    Brown, J.M. and G. Wilson, Apoptosis genes and resistance to cancer therapy: what does the experimental and clinical data tell us? Cancer Biol Ther, 2003. 2(5): p. 477–90.PubMedGoogle Scholar
  25. 25.
    Dewey, W.C., C.C. Ling, and R.E. Meyn, Radiation-induced apoptosis: relevance to radiotherapy. Int J Radiat Oncol Biol Phys, 1995. 33(4): p. 781–96.PubMedCrossRefGoogle Scholar
  26. 26.
    Verheij, M., Clinical biomarkers and imaging for radiotherapy-induced cell death. Cancer Metastasis Rev, 2008. 27(3): p. 471–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Hotchkiss, R.S., et al., Cell death. N Engl J Med, 2009. 361(16): p. 1570–83.CrossRefGoogle Scholar
  28. 28.
    Yang, Z. and D.J. Klionsky, An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol, 2009. 335: p. 1–32.PubMedCrossRefGoogle Scholar
  29. 29.
    Nelson, D.A. and E. White, Exploiting different ways to die. Genes Dev, 2004. 18(11): p. 1223–6.PubMedCrossRefGoogle Scholar
  30. 30.
    White, E. and R.S. DiPaola, The double-edged sword of autophagy modulation in cancer. Clin Cancer Res, 2009. 15(17): p. 5308–16.PubMedCrossRefGoogle Scholar
  31. 31.
    Kroemer, G. and E. White, Autophagy for the avoidance of degenerative, inflammatory, infectious, and neoplastic disease. Curr Opin Cell Biol, 2010. 22(2): p. 121–3.PubMedCrossRefGoogle Scholar
  32. 32.
    Barth, S., D. Glick, and K.F. Macleod, Autophagy: assays and artifacts. J Pathol, 2010.Google Scholar
  33. 33.
    Komatsu, M., et al., Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell, 2007. 131(6): p. 1149–63.PubMedCrossRefGoogle Scholar
  34. 34.
    Jin, S., et al., Metabolic catastrophe as a means to cancer cell death. J Cell Sci, 2007. 120(Pt 3): p. 379–83.PubMedCrossRefGoogle Scholar
  35. 35.
    Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 1983. 65(1-2): p. 55–63.PubMedCrossRefGoogle Scholar
  36. 36.
    Marshall, N.J., C.J. Goodwin, and S.J. Holt, A critical assessment of the use of microculture tetrazolium assays to measure cell growth and function. Growth Regul, 1995. 5(2): p. 69–84.PubMedGoogle Scholar
  37. 37.
    Carmichael, J., et al., Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res, 1987. 47(4): p. 936–42.PubMedGoogle Scholar
  38. 38.
    Carmichael, J., et al., Chemosensitivity testing of human lung cancer cell lines using the MTT assay. Br J Cancer, 1988. 57(6): p. 540–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Carmichael, J., et al., Radiation sensitivity of human lung cancer cell lines. Eur J Cancer Clin Oncol, 1989. 25(3): p. 527–34.PubMedCrossRefGoogle Scholar
  40. 40.
    Ishikawa, K., H. Ishii, and T. Saito, DNA damage-dependent cell cycle checkpoints and genomic stability. DNA Cell Biol, 2006. 25(7): p. 406–11.PubMedCrossRefGoogle Scholar
  41. 41.
    Sancar, A., et al., Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem, 2004. 73: p. 39–85.PubMedCrossRefGoogle Scholar
  42. 42.
    Hartlerode, A.J. and R. Scully, Mechanisms of double-strand break repair in somatic mammalian cells. Biochem J, 2009. 423(2): p. 157–68.PubMedCrossRefGoogle Scholar
  43. 43.
    Ma, Y., et al., Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell, 2002. 108(6): p. 781–94.PubMedCrossRefGoogle Scholar
  44. 44.
    Buck, D., et al., Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell, 2006. 124(2): p. 287–99.PubMedCrossRefGoogle Scholar
  45. 45.
    Hanakahi, L.A., et al., Binding of inositol phosphate to DNA-PK and stimulation of double-strand break repair. Cell, 2000. 102(6): p. 721–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Block, W.D., et al., Autophosphorylation-dependent remodeling of the DNA-dependent protein kinase catalytic subunit regulates ligation of DNA ends. Nucleic Acids Res, 2004. 32(14): p. 4351–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Auckley, D.H., et al., Reduced DNA-dependent protein kinase activity is associated with lung cancer. Carcinogenesis, 2001. 22(5): p. 723–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Lavin, M.F., Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol, 2008. 9(10): p. 759–69.PubMedCrossRefGoogle Scholar
  49. 49.
    Han, J., et al., Polymorphisms in DNA double-strand break repair genes and breast cancer risk in the Nurses’ Health Study. Carcinogenesis, 2004. 25(2): p. 189–95.PubMedCrossRefGoogle Scholar
  50. 50.
    Kuschel, B., et al., Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet, 2002. 11(12): p. 1399–407.PubMedCrossRefGoogle Scholar
  51. 51.
    Rafii, S., et al., A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer. Hum Mol Genet, 2002. 11(12): p. 1433–8.PubMedCrossRefGoogle Scholar
  52. 52.
    Roddam, P.L., et al., Genetic variants of NHEJ DNA ligase IV can affect the risk of developing multiple myeloma, a tumour characterised by aberrant class switch recombination. J Med Genet, 2002. 39(12): p. 900–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Bhatti, P., et al., Polymorphisms in DNA repair genes, ionizing radiation exposure and risk of breast cancer in U.S. Radiologic technologists. Int J Cancer, 2008. 122(1): p. 177–  82.Google Scholar
  54. 54.
    Helleday, T., Pathways for mitotic homologous recombination in mammalian cells. Mutat Res, 2003. 532(1-2): p. 103–15.PubMedGoogle Scholar
  55. 55.
    Jeggo, P. and M.F. Lavin, Cellular radiosensitivity: how much better do we understand it? Int J Radiat Biol, 2009. 85(12): p. 1061–81.PubMedCrossRefGoogle Scholar
  56. 56.
    Venkitaraman, A.R., Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J Cell Sci, 2001. 114(Pt 20): p. 3591–8.PubMedGoogle Scholar
  57. 57.
    Wenham, R.M., et al., Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer. Clin Cancer Res, 2003. 9(12): p. 4396–403.PubMedGoogle Scholar
  58. 58.
    Elkind, M.M. and C. Kamper, Two forms of repair of DNA in mammalian cells following irradiation. Biophys J, 1970. 10(3): p. 237–45.PubMedCrossRefGoogle Scholar
  59. 59.
    Zwelling, L.A., et al., Protein-associated deoxyribonucleic acid strand breaks in L1210 cells treated with the deoxyribonucleic acid intercalating agents 4-(9-acridinylamino) methanesulfon-m-anisidide and adriamycin. Biochemistry, 1981. 20(23): p. 6553–63.PubMedCrossRefGoogle Scholar
  60. 60.
    Geigl, E.M. and F. Eckardt-Schupp, The repair of double-strand breaks and S1 nuclease-sensitive sites can be monitored chromosome-specifically in Saccharomyces cerevisiae using pulse-field gel electrophoresis. Mol Microbiol, 1991. 5(7): p. 1615–20.PubMedCrossRefGoogle Scholar
  61. 61.
    Okayasu, R., et al., A deficiency in DNA repair and DNA-PKcs expression in the radiosensitive BALB/c mouse. Cancer Res, 2000. 60(16): p. 4342–5.PubMedGoogle Scholar
  62. 62.
    Stamato, T.D. and N. Denko, Asymmetric field inversion gel electrophoresis: a new method for detecting DNA double-strand breaks in mammalian cells. Radiat Res, 1990. 121(2):p. 196–205.PubMedCrossRefGoogle Scholar
  63. 63.
    Olive, P.L., Impact of the comet assay in radiobiology. Mutat Res, 2009. 681(1): p. 13–23.PubMedCrossRefGoogle Scholar
  64. 64.
    Olive, P.L., J.P. Banath, and R.E. Durand, Detection of etoposide resistance by measuring DNA damage in individual Chinese hamster cells. J Natl Cancer Inst, 1990. 82(9): p. 779–83.PubMedCrossRefGoogle Scholar
  65. 65.
    Pilch, D.R., et al., Characteristics of gamma-H2AX foci at DNA double-strand breaks sites. Biochem Cell Biol, 2003. 81(3): p. 123–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Rogakou, E.P., et al., DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem, 1998. 273(10): p. 5858–68.PubMedCrossRefGoogle Scholar
  67. 67.
    Mitchell, J.B., et al., In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762. Clin Cancer Res, 2010. 16(7): p. 2076–84.PubMedCrossRefGoogle Scholar
  68. 68.
    Banath, J.P., et al., Explanation for excessive DNA single-strand breaks and endogenous repair foci in pluripotent mouse embryonic stem cells. Exp Cell Res, 2009. 315(8):p. 1505–20.PubMedCrossRefGoogle Scholar
  69. 69.
    Kinner, A., et al., Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res, 2008. 36(17): p. 5678–94.PubMedCrossRefGoogle Scholar
  70. 70.
    Rothkamm, K. and S. Horn, gamma-H2AX as protein biomarker for radiation exposure. Ann Ist Super Sanita, 2009. 45(3): p. 265–71.PubMedGoogle Scholar
  71. 71.
    Smith, L.E., et al., Radiation-induced genomic instability: radiation quality and dose response. Health Phys, 2003. 85(1): p. 23–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Morgan, W.F., Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation? Oncogene, 2003. 22(45): p. 7094–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Little, J.B., Lauriston S. Taylor lecture: nontargeted effects of radiation: implications for low-dose exposures. Health Phys, 2006. 91(5): p. 416–26.PubMedCrossRefGoogle Scholar
  74. 74.
    Morgan, W.F., Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiat Res, 2003. 159(5): p. 581–96.PubMedCrossRefGoogle Scholar
  75. 75.
    Hei, T.K., et al., Advances in radiobiological studies using a microbeam. J Radiat Res (Tokyo), 2009. 50 Suppl A: p. A7–A12.Google Scholar
  76. 76.
    Nagasawa, H. and J.B. Little, Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Cancer Res, 1992. 52(22): p. 6394–6.PubMedGoogle Scholar
  77. 77.
    Mothersill, C. and C. Seymour, Medium from irradiated human epithelial cells but not human fibroblasts reduces the clonogenic survival of unirradiated cells. Int J Radiat Biol, 1997. 71(4): p. 421–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Hagelstrom, R.T., et al., DNA-PKcs and ATM influence generation of ionizing radiation-induced bystander signals. Oncogene, 2008. 27(53): p. 6761–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Harada, T., et al., Different involvement of radical species in irradiated and bystander cells. Int J Radiat Biol, 2008. 84(10): p. 809–14.PubMedCrossRefGoogle Scholar
  80. 80.
    Ponnaiya, B., M.N. Cornforth, and R.L. Ullrich, Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white. Radiat Res, 1997. 147(2): p. 121–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Perry, P. and S. Wolff, New Giemsa method for the differential staining of sister chromatids. Nature, 1974. 251(5471): p. 156–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Fenech, M., The in vitro micronucleus technique. Mutat Res, 2000. 455(1-2): p. 81–95.PubMedGoogle Scholar
  83. 83.
    Han, W., et al., Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation. Mutat Res, 2010. 684(1-2): p. 81–9.PubMedGoogle Scholar
  84. 84.
    Bailey, S.M. and J.S. Bedford, Studies on chromosome aberration induction: what can they tell us about DNA repair? DNA Repair (Amst), 2006. 5(9-10): p. 1171–81.Google Scholar
  85. 85.
    Sankaranarayanan, K., Ionizing radiation and genetic risks. III. Nature of spontaneous and radiation-induced mutations in mammalian in vitro systems and mechanisms of induction of mutations by radiation. Mutat Res, 1991. 258(1): p. 75–97.Google Scholar
  86. 86.
    Zhou, H., et al., Quantification of CD59- mutants in human-hamster hybrid (AL) cells by flow cytometry. Mutat Res, 2006. 594(1-2): p. 113–9.PubMedGoogle Scholar
  87. 87.
    Little, J.B., et al., Bystander effects: intercellular transmission of radiation damage signals. Radiat Prot Dosimetry, 2002. 99(1-4): p. 159–62.PubMedCrossRefGoogle Scholar
  88. 88.
    Nagasawa, H. and J.B. Little, Unexpected sensitivity to the induction of mutations by very low doses of alpha-particle radiation: evidence for a bystander effect. Radiat Res, 1999. 152(5): p. 552–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Kinashi, Y., et al., Bystander effect-induced mutagenicity in HPRT locus of CHO cells following BNCT neutron irradiation: characteristics of point mutations by sequence analysis. Appl Radiat Isot, 2009. 67(7-8 Suppl): p. S325–7.PubMedCrossRefGoogle Scholar
  90. 90.
    Waldren, C., C. Jones, and T.T. Puck, Measurement of mutagenesis in mammalian cells. Proc Natl Acad Sci U S A, 1979. 76(3): p. 1358  –  62.PubMedCrossRefGoogle Scholar
  91. 91.
    Jones, C., P. Wuthier, and T.T. Puck, Genetics of somatic cell surface antigens. III. Further analysis of the AL marker. Somatic Cell Genet, 1975. 1(3): p. 235–46.CrossRefGoogle Scholar
  92. 92.
    Puck, T.T., et al., Genetics of somatic mammalian cells: lethal antigens as genetic markers for study of human linkage groups. Proc Natl Acad Sci USA, 1971. 68(12): p. 3102–6.PubMedCrossRefGoogle Scholar
  93. 93.
    Persaud, R., et al., Assessment of low linear energy transfer radiation-induced bystander mutagenesis in a three-dimensional culture model. Cancer Res, 2005. 65(21): p. 9876–82.PubMedCrossRefGoogle Scholar
  94. 94.
    Wu, L.J., et al., Targeted cytoplasmic irradiation with alpha particles induces mutations in mammalian cells. Proc Natl Acad Sci USA, 1999. 96(9): p. 4959–64.PubMedCrossRefGoogle Scholar
  95. 95.
    Hei, T.K., et al., Mutagenic effects of a single and an exact number of alpha particles in mammalian cells. Proc Natl Acad Sci USA, 1997. 94(8): p. 3765–70.PubMedCrossRefGoogle Scholar
  96. 96.
    Zielonka, J. and B. Kalyanaraman, Hydroethidine- and MitoSOX-derived red fluorescence is not a reliable indicator of intracellular superoxide formation: another inconvenient truth. Free Radic Biol Med, 2010. 48(8): p. 983–1001.PubMedCrossRefGoogle Scholar
  97. 97.
    Zhao, H., et al., Detection and characterization of the product of hydroethidine and intracellular superoxide by HPLC and limitations of fluorescence. Proc Natl Acad Sci USA, 2005. 102(16): p. 5727–32.PubMedCrossRefGoogle Scholar
  98. 98.
    Stone, H.B., et al., Effects of radiation on normal tissue: consequences and mechanisms. Lancet Oncol, 2003. 4(9): p. 529–36.PubMedCrossRefGoogle Scholar
  99. 99.
    Stone, H.B., W.H. McBride, and C.N. Coleman, 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, 2002. 157(2): p. 204  –23.PubMedCrossRefGoogle Scholar
  100. 100.
    Dutreix, J., M. Tubiana, and A. Dutreix, An approach to the interpretation of clinical data on the tumour control probability-dose relationship. Radiother Oncol, 1988. 11(3): p. 239–48.PubMedCrossRefGoogle Scholar
  101. 101.
    McNally, N.J. and P.W. Sheldon, The effect of radiation on tumour growth delay, cell survival and cure of the animal using a single tumour system. Br J Radiol, 1977. 50(593): p. 321–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Hahn, S.M., et al., Evaluation of tempol radioprotection in a murine tumor model. Free Radic Biol Med, 1997. 22(7): p. 1211–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Ellington, O.B., Cis-platinum: a brief review of its use, and nursing guidelines. Cancer Nurs, 1978. 1(5): p. 403–6.PubMedGoogle Scholar
  104. 104.
    Evseenko, L.S., et al., [5-fluorouracil in the chemotherapy of malignant neoplasms]. Vopr Onkol, 1966. 12(1): p. 92–106.PubMedGoogle Scholar
  105. 105.
    Erlichman, C., Novel chemotherapeutic agents in clinical development. Curr Opin Oncol, 1991. 3(6): p. 1037–42.PubMedCrossRefGoogle Scholar
  106. 106.
    Dumont, F., A. Altmeyer, and P. Bischoff, Radiosensitising agents for the radiotherapy of cancer: novel molecularly targeted approaches. Expert Opin Ther Pat, 2009. 19(6):p. 775–99.PubMedCrossRefGoogle Scholar
  107. 107.
    Sarkaria, J.N. and J.S. Eshleman, ATM as a target for novel radiosensitizers. Semin Radiat Oncol, 2001. 11(4): p. 316–27.PubMedCrossRefGoogle Scholar
  108. 108.
    Ortiz, T., et al., Radiosensitizer effect of wortmannin in radioresistant bladder tumoral cell lines. Int J Oncol, 2004. 24(1): p. 169–75.PubMedGoogle Scholar
  109. 109.
    Khan, K., et al., Head and neck cancer radiosensitization by the novel poly(ADP-ribose) polymerase inhibitor GPI-15427. Head Neck, 2010. 32(3): p. 381–91.PubMedGoogle Scholar
  110. 110.
    Janetka, J.W., et al., Inhibitors of checkpoint kinases: from discovery to the clinic. Curr Opin Drug Discov Devel, 2007. 10(4): p. 473–86.PubMedGoogle Scholar
  111. 111.
    Harari, P.M. and S. Huang, Radiation combined with EGFR signal inhibitors: head and neck cancer focus. Semin Radiat Oncol, 2006. 16(1): p. 38–  44.PubMedCrossRefGoogle Scholar
  112. 112.
    Prevo, R., et al., Class I PI3 kinase inhibition by the pyridinylfuranopyrimidine inhibitor PI-103 enhances tumor radiosensitivity. Cancer Res, 2008. 68(14): p. 5915–23.PubMedCrossRefGoogle Scholar
  113. 113.
    Diaz, R., et al., The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer. Br J Cancer, 2009. 100(6): p. 932–  40.PubMedCrossRefGoogle Scholar
  114. 114.
    Ahmed, K.M. and J.J. Li, NF-kappa B-mediated adaptive resistance to ionizing radiation. Free Radic Biol Med, 2008. 44(1): p. 1–13.PubMedCrossRefGoogle Scholar
  115. 115.
    Capalbo, G., et al., The role of survivin for radiation therapy. Prognostic and predictive factor and therapeutic target. Strahlenther Onkol, 2007. 183(11): p. 593–9.CrossRefGoogle Scholar
  116. 116.
    Bristow, R.G., S. Benchimol, and R.P. Hill, The p53 gene as a modifier of intrinsic radiosensitivity: implications for radiotherapy. Radiother Oncol, 1996. 40(3): p. 197–223.PubMedCrossRefGoogle Scholar
  117. 117.
    An, J., et al., Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor. Oncogene, 2007. 26(5): p. 652–61.PubMedCrossRefGoogle Scholar
  118. 118.
    Karikari, C.A., et al., Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. Mol Cancer Ther, 2007. 6(3): p. 957–66.PubMedCrossRefGoogle Scholar
  119. 119.
    Bozec, A., et al., Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model. Br J Cancer, 2008. 99(1): p. 93–9.PubMedCrossRefGoogle Scholar
  120. 120.
    Camphausen, K. and P.J. Tofilon, Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J Clin Oncol, 2007. 25(26): p. 4051–6.PubMedCrossRefGoogle Scholar
  121. 121.
    Camphausen, K. and P.J. Tofilon, Inhibition of Hsp90: a multitarget approach to radiosensitization. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4326–30.PubMedCrossRefGoogle Scholar
  122. 122.
    Patt, H.M., et al., Cysteine Protection against X Irradiation. Science, 1949. 110(2852): p. 213–214.Google Scholar
  123. 123.
    Rasey, J.S., et al., Radioprotection of normal tissues against gamma rays and cyclotron neutrons with WR-2721: LD50 studies and 35S-WR-2721 biodistribution. Radiat Res, 1984. 97(3): p. 598–607.PubMedCrossRefGoogle Scholar
  124. 124.
    Spalding, A.C. and T.S. Lawrence, New and emerging radiosensitizers and radioprotectors. Cancer Invest, 2006. 24(4): p. 444–56.PubMedCrossRefGoogle Scholar
  125. 125.
    Mitchell, J.B. and M.C. Krishna, Nitroxides as radiation protectors. Mil Med, 2002. 167(2 Suppl): p. 49–50.PubMedGoogle Scholar
  126. 126.
    Stone, H.B., et al., Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003. Radiat Res, 2004. 162(6): p. 711–28.PubMedCrossRefGoogle Scholar
  127. 127.
    Coleman, C.N., et al., Molecular and cellular biology of moderate-dose (1-10 Gy) radiation and potential mechanisms of radiation protection: report of a workshop at Bethesda, Maryland, December 17-18, 2001. Radiat Res, 2003. 159(6): p. 812–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Kristin Fabre
  • William DeGraff
  • John A. Cook
  • Murali C. Krishna
    • 1
    Email author
  • James B. Mitchell
  1. 1.Radiation Biology Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaUSA

Personalised recommendations