Advertisement

Interactions of Oxygen and Sulfhydryls with Free Radicals in Irradiated Mammalian Cells

  • Kathryn D. Held
Part of the Basic Life Sciences book series (BLSC, volume 49)

Abstract

Studies on radiosensitization by oxygen and radioprotection by sulfhydryl-containing compounds have often directed attention to the importance of interactions of those two agents — oxygen and thiols — in determining radiation response. The so-called repair-fixation theory suggests radiation response is determined by a competition between damage fixation by oxidizing agents (e.g., oxygen) and damage repair by reducing species (e.g., sulfhydryls) 1,2: where T· represents an ionizing radiation-induced organic radical on a cellular “target” molecule, TH, such as DNA, and RSH is any thiol. This competition can be clearly demonstrated in simple chemical systems and in nucleic acids such as poly(A) and transforming DNA, and it has been shown that the damage fixation reaction is over 100 times faster than the H donation, chemical repair reaction (reviewed recently3). But the occurrence of this competition in mammalian cells is more difficult to demonstrate. This paper will review the current literature indicating the involvement of this chemical competition in determining radiation response in mammalian cells.

Keywords

Hypoxic Cell Glutathione Synthetase Buthionine Sulfoximine High Oxygen Level Diethyl Maleate 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    P. Alexander and A. Charlesby, Physiochemical methods of protection against ionizing radiations, in: “Radiobiology Symposium 1954,” Z.M. Bacq and P. Alexander, eds., Butterworths, London (1955).Google Scholar
  2. 2.
    T. Alper and P. Howard-Flanders, Role of oxygen in modifying the radiosensitivity of E. coli B, Nature 178:978 (1956).PubMedCrossRefGoogle Scholar
  3. 3.
    K.D. Held, Models for thiol protection of DNA in cells, Pharmac. Ther., in press.Google Scholar
  4. 4.
    O.W. Griffith and A. Meister, Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximide), J. Biol. Chem. 254:7558 (1982).Google Scholar
  5. 5.
    J.E. Biaglow, M.E. Varnes, M. Astor, and E.J. Hall, Non-protein thiols and cellular response to drugs and radiation. Int. J. Radiat. Oncol. Biol. Phys. 8:719 (1982).PubMedCrossRefGoogle Scholar
  6. 6.
    A. Larsson, 5-oxoprolinuria and other inborn errors related to the-glutamyl cycle, in: “Transport and Inherited Disease,” N.R. Belton and C. Toothill, ed., MTP Press, Lancaster (1981).Google Scholar
  7. 7.
    C.J. Koch, C.C. Stobbe, and E.A. Bump, The effect on the K for radiosensitization at 0° C of thiol depletion by diethylmaleate pretreatment: Quantitative differences found using the radiation sensitizing agent misonidazole or oxygen, Radiat. Res. 98:141 (1984).PubMedCrossRefGoogle Scholar
  8. 8.
    E.A. Bump, N.Y. Yu, and J.M. Brown, Radiosensitization of hypoxic tumor cells by depletion of intracellular glutathione, Science 217:544 (1982).PubMedCrossRefGoogle Scholar
  9. 9.
    J.B. Mitchell, A. Russo, J.E. Biaglow, and S. McPherson, Cellular depletion by diethyl maléate or buthionine sulfoximine: No effect of glutathione depletion on the oxygen enhancement ratio, Radiat. Res. 96:422 (1983).PubMedCrossRefGoogle Scholar
  10. 10.
    E.P. Clark, E.R. Epp, M. Morse-Gaudio, and J.E. Biaglow, The role of glutathione in the aerobic radioresponse. I. Sensitization and recovery in the absence of intracellular glutathione, Radiat. Res. 108:238 (1986).PubMedCrossRefGoogle Scholar
  11. 11.
    D.C. Shrieve, J. Denekamp, and A. I. Minchinton, Effects of glutathione depletion by buthionine sulfoximine on radiosensitization by oxygen and misonidazole in vitro, Radiat. Res. 102:283 (1985).PubMedCrossRefGoogle Scholar
  12. 12.
    R.J. Hodgkiss, N.R. Jones, M.E. Watts, and M. Woodcock, Glutathione depletion enhances the lifetime of oxygen-reactive radicals in mammalian cells, Int. J. Radiat. Biol. 46:673 (1984).CrossRefGoogle Scholar
  13. 13.
    P.J. Deschavanne, J. Midander, M. Edgren, A. Larsson, E.-P. Malaise, and L. Revesz, Oxygen enhancement of radiation induced lethality is greatly reduced in glutathione deficient human fibroblasts, Biomedicine 35:35 (1981).PubMedGoogle Scholar
  14. 14.
    M. Edgren, A. Larsson, and L. Revesz, Induction and repair of single strand DNA breaks after X-irradiation of human fibroblasts deficient in glutathione. Int. J. Radiat. Biol. 40:355 (1981).CrossRefGoogle Scholar
  15. 15.
    J. Midander, Oxygen enhancement ratios of glutathione-deficient fibroblasts determined from the frequency of radiation induced micronuclei. Int. J. Radiat. Biol. 42:195 (1982).CrossRefGoogle Scholar
  16. 16.
    D. Debieu, P.J. Deschavanne, J. Midander, A. Larsson, and E.P. Malaise, Survival curves of glutathione synthetase deficient human fibroblasts: correlation between radiosensitivity in hypoxia and glutathione synthetase activity, Int. J. Radiat. Biol. 48:525 (1985).CrossRefGoogle Scholar
  17. 17.
    E.-P. Malaise, Reduced oxygen enhancement of the radiosensitivity of glutathione-deficient fibroblasts, Radiat. Res. 95, 486 (1983).PubMedCrossRefGoogle Scholar
  18. 18.
    L. Revesz, The role of endogenous thiols in intrinsic radioprotection, Int. J. Radiat. Biol. 47:361 (1985).Google Scholar
  19. 19.
    L. Revesz and M. Edgren, Glutathione dependent yield and repair of single-strand DNA breaks in irradiated cells. Br. J. Cancer 49, Suppl. VI:55 (1984).Google Scholar
  20. 20.
    G. Solen, M. Edgren, O.C.A. Scott, and L. Revesz, Cellular glutathione content and K values, Int. J. Radiat. Biol. 51:39 (1987).CrossRefGoogle Scholar
  21. 21.
    B.D. Michael, S. Davies, and K.D. Held, Ultrafast chemical repair of DNA single and double strand break precursors in irradiated V79 cells, in: “Mechanisms of DNA Damage and Repair,” M.G. Simic, L. Grossman, and A.C. Upton, eds., Plenum Press, New York (1986).Google Scholar
  22. 22.
    B.M. Cullen and H.C. Walker, Variation of the radiobiological oxygen constant, K, with the proliferative activity of the cells, Int. J. Radiat. Biol. 38:513 (1980).CrossRefGoogle Scholar
  23. 23.
    B.M. Cullen, A. Michalowski, H.C. Walker, and L. Revesz, Correlation between the radiobiological oxygen constant, K, and the nonprotein sulphydryl content of mammalian cells, Int. J. Radiat. Biol. 38:525 (1980).CrossRefGoogle Scholar
  24. 24.
    H.C. Walker and B.M. Cullen, The importance of NPSH on the radio-sensitizing effect of oxygen in Chinese hamster V-79 cells, Int. J. Radiat. Biol. 51:19 (1987).CrossRefGoogle Scholar
  25. 25.
    A. Russo, J.B. Mitchell, E. Finkelstein, W.G. DeGraff, I.J. Spiro, and J. Gamson, The effects of cellular glutathione elevation on the oxygen enhancement ratio, Radiat. Res. 103:232 (1985).PubMedCrossRefGoogle Scholar
  26. 26.
    T. Alper, “Cellular Radiobiology,” Cambridge University Press, Cambridge (1979).Google Scholar
  27. 27.
    K.D. Held, Role of free radical scavengers in radiation protection of DNA, in: “Free Radicals, Aging, and Degenerative Diseases,” J.E. Johnson et al, eds., Alan R. Liss, New York (1986).Google Scholar
  28. 28.
    K.D. Held, Interactions of radioprotectors and oxygen in cultured mammalian cells. I. Dithiothreitol effects on radiation-induced cell killing, Radiat. Res. 101:424 (1985).PubMedCrossRefGoogle Scholar
  29. 29.
    J. Lunec, B. Cullen, H. Walker, and S. Hornsey, A cautionary note on the use of thiol compounds to protect normal tissues in radiotherapy, Br. J. Radiol. 54:428 (1981).PubMedCrossRefGoogle Scholar
  30. 30.
    J. Denekamp, B.D. Michael, A. Rojas, and F.A. Stewart, Thiol radio-protection in vivo: the critical role of tissue oxygen concentration, Br. J. Radiol. 54:1112 (1981).PubMedCrossRefGoogle Scholar
  31. 31.
    J. Denekamp, A. Rojas, and F.A. Stewart, Is radioprotection by WR-2721 restricted to normal tissues?, in: “Radioprotectors and Anticarcinogens,” O.F. Nygaard and M.G. Simic, eds., Academic Press, New York (1983).Google Scholar
  32. 32.
    C. Parkins, J.F. Fowler, and J. Denekamp, Low radioprotection by thiol in lung: The role of local tissue oxygenation, Eur. J. Cancer Clin. Oncol. 19:1169 (1983).PubMedCrossRefGoogle Scholar
  33. 33.
    M. Edgren, Nuclear glutathione and oxygen enhancement of radiosensitivity, Int. J. Radiat. Biol. 51:3 (1987).CrossRefGoogle Scholar
  34. 34.
    M. Edgren, T. Nishidai, O.C.A. Scott, and L. Revesz, Combined effect of misonidazole and glutathione depletion by buthionine sulphoximine on cellular radiation response, Int. J. Radiat. Biol. 47:463 (1985).Google Scholar
  35. 35.
    C.J. Koch and R.L. Howell, Combined radiation-protective and radiation-sensitizing agents. I. Radiosensitivity of hypoxic or aerobic Chinese hamster fibroblasts in the presence of cysteamine and misonidazole: Implications for the “oxygen effect,” Radiat. Res. 87:265 (1981).PubMedCrossRefGoogle Scholar
  36. 36.
    C.J. Koch, Competition between radiation portectors and radiation sensitizers in mammalian cells, in: “Radioprotectors and Anticarcinogens,” O.F. Nygaard and M.G. Simic, eds., Academic Press, New York (1983).Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Kathryn D. Held
    • 1
  1. 1.Department of Radiation Medicine, Massachusetts General Hospital Cancer CenterHarvard Medical SchoolBostonUSA

Personalised recommendations