New Directions for Free Radical Cancer Research and Medical Applications

  • Stephen M. Hahn
  • C. Murali Krishna
  • James B. Mitchell
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 366)


The study of free radicals in biomedical research has dramatically increased in recent years. There is evidence that free radicals play a role in aging, chronic inflammatory or autoimmune diseases, atherosclerosis, and ischemia/reperfusion injury1. Free radicals may also play an important role in several areas of cancer research including the study of carcinogenesis, mechanisms of radiation and chemotherapy action, and the toxicity of therapies. As our knowledge of free radical mechanisms has grown, we have increased our ability to devise strategies in cancer prevention and in modifying the actions of chemotherapeutic agents and radiation. Concomitant with this increased knowledge base, has been the need for further study of free radicals as they relate to carcinogenesis and therapies based upon free radical damage.


Semiquinone Radical Free Radical Mechanism Differential Protection Radioprotective Property Nitroxide Spin Probe 
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. 1.
    B. Halliwell, and J. M. C. Gutteridge, “Free Radicals in Biology and Medicine,” Clarendon Press, Oxford, UK (1989).Google Scholar
  2. 2.
    P. Cerutti, G. Shah, A. Peskin, and P. Amstad, Oxidant carcinogenesis and antioxidant defense, Ann. N. Y. Acad. Sci. 663:158 (1992).PubMedCrossRefGoogle Scholar
  3. 3.
    P. A. Cerutti, Oxidant stress and carcinogenesis, Eur. J. Clin. Invest. 21:1 (1991).PubMedCrossRefGoogle Scholar
  4. 4.
    A. Russo, J. B. Mitchell, S. McPherson, and N. Friedman, Alteration of bleomycin cytotoxicity by glutathione depletion or elevation, Int. J. Radiat. Oncol. Biol. Phys. 10:1675 (1984).PubMedCrossRefGoogle Scholar
  5. 5.
    C. Borek, and W. Troll, Modifiers of free radicals inhibit in vitro the oncogenic actions of x-rays, bleomycin, and the tumor promoter 12-O-tetradecanoylphorbol 13-acetate, Proc. Natl. Acad. Sci. USA 80:1304 (1983).PubMedCrossRefGoogle Scholar
  6. 6.
    T. Komiyama, T. Kikuchi, and Y. Sugiura, Generation of hydroxyl radical by anticancer quinone drugs, carbazilquinone, mitomycin C, aclacinomycin A and adriamycin, in the presence of NADPH-cytochrome P-450 reductase, Biochem. Pharmacol. 31:3651 (1982).PubMedCrossRefGoogle Scholar
  7. 7.
    C. M. Krishna, W. DeGraff, S. Tamura, F. Gonzalez, A. Samuni, A. Russo, and J. B. Mitchell, Mechanisms of hypoxic and aerobic cytotoxicity of Mitomycin C in Chinese hamster V79 cells, Cancer Res. 51:6622 (1991).PubMedGoogle Scholar
  8. 8.
    B. B. Hasinoff, The interaction of the cardioprotective agent ICRF-187 [+]-1,2-bis(3,5-dioxopiperazinyl-1-yl) propane; its hydrolysis product (ICRF-198; and other chelating agents with the Fe(III) and Cu(II) complexes of adriamycin, Agents Actions 26:378 (1989).PubMedCrossRefGoogle Scholar
  9. 9.
    G. F. Vile, and C. C. Winterbourn, dl-N,N’-dicarboxcamidomethyl-N,N’-dicarboxymethyl-l, 2-diaminopropane (ICRF-198) and d-l,2-bis(3,5-dioxopiperazine-1-yl) propane (ICRF-187) inhibition of Fe3+ reduction, lipid peroxidation, and CaATPase inactivation in heart microsomes exposed to adriamycin, Cancer Res. 50:2307 (1990).PubMedGoogle Scholar
  10. 10.
    H. F. Bennett, H. M. Swartz, R. D. Brown III, and S. H. Koenig, Modification of relaxation of lipid protons by molecular oxygen and nitroxides, Invest. Radiol. 22:502 (1987).PubMedCrossRefGoogle Scholar
  11. 11.
    H. M. McConnell, “Spin Labelling: Theory and Applications,” C.C. Thomas Publ., Springfield, IL (1965).Google Scholar
  12. 12.
    H. M. Swartz, Interactions between cells and nitroxides and their implications for their uses as biophysical probes and as metabolically responsive contrast agents for in vivo NMR, Bull. Mag. Res. 8:172 (1983).Google Scholar
  13. 13.
    S. Belkin, R. J. Mehlhorn, K. Hideg, O. Hankovsky, and L. Packer, Reduction and destruction of nitroxide spin probes, Arch. Biochem. Biophys. 256:232 (1987).PubMedCrossRefGoogle Scholar
  14. 14.
    J. Chateauneuf, J. Lusztyk, and K. U. Ingold, Absolute rate constants for the reactions of some carbon-centered radicals with 2,2,6,6-tetramethylpiperidine-N-oxyl, J. Org.Chem. 53:1629 (1988).CrossRefGoogle Scholar
  15. 15.
    R. J. Mehlhorn, and L. Packer, Electron paramagnetic resonance spin destruction methods for radical detection, Methods in Enzymology 105:215 (1984).PubMedCrossRefGoogle Scholar
  16. 16.
    U. A. Nilsson, L. I. Olsson, G. Carlin, and A. C. Bylund-Fellenius, Inhibition of lipid peroxidation by spin labels. Relationships between structure and function, J. Biol. Chem. 264:11131 (1989).PubMedGoogle Scholar
  17. 17.
    A. Samuni, C. M. Krishna, P. Riesz, E. Finkelstein, and A. Russo, Superoxide reaction with nitroxide spin-adducts, Free Radic. Biol. Med. 6:141 (1989).PubMedCrossRefGoogle Scholar
  18. 18.
    A. Samuni, C. M. Krishna, P. Riesz, E. Finkelstein, and A. Russo, A novel metal-free low molecular weight superoxide dismutase mimic, J. Biol. Chem. 263:17921 (1988).PubMedGoogle Scholar
  19. 19.
    A. Samuni, C. M. Krishna, J. B. Mitchell, C. R. Collins, and A. Russo, Superoxide reaction with nitroxides., Free Rad. Res. Comms. 9:241 (1990).CrossRefGoogle Scholar
  20. 20.
    M. C. Krishna, D. A. Grahame, A. Samuni, J. B. Mitchell, and A. Russo, Oxoammonium cation intermediate in the nitroxide-catalyzed dismutation of superoxide, Proc. Natl. Acad. Sci. 89:5537 (1992).PubMedCrossRefGoogle Scholar
  21. 21.
    R. J. Mehlhorn, and C. E. Swanson, Nitroxide-mediated H202 decomposition by peroxidases and pseudoperoxidases, Free Radic. Res. Comm. 17:157 (1992).CrossRefGoogle Scholar
  22. 22.
    J. B. Mitchell, A. Samuni, M. C. Krishna, W. G. DeGraff, M. S. Ahn, U. Samuni, and A. Russo, Biologically active metal-independent superoxide dismutase mimics, Biochemistry 29:2802 (1990).PubMedCrossRefGoogle Scholar
  23. 23.
    A. Samuni, D. Winkelsberg, A. Pinson, S. M. Hahn, J. B. Mitchell, and A. Russo, Nitroxide stable radicals protect beating cardiomyocytes against oxidative damage, J. Clin. Invest 87:1526 (1991).PubMedCrossRefGoogle Scholar
  24. 24.
    D. Gelvan, P. Saultman, and S. Powell, Cardiac reperfusion damage prevented by a stable nitroxide free radical, Proc. Natl. Acad. Sci. USA 88:4680 (1991).PubMedCrossRefGoogle Scholar
  25. 25.
    E. J. Hall, “Radiobiology for the Radiologist,” J. B. Lippincott Co., Philadelphia, PA (1994).Google Scholar
  26. 26.
    J. B. Mitchell, W. DeGraff, D. Kaufman, M. C. Krishna, A. Samuni, E. Finkelstein, M. S. Ahn, S. M. Hahn, J. Gamson, and A. Russo, Inhibition of oxygen-dependent radiation-induced damage by the nitroxide superoxide dismutase mimic, Tempol, Arch. Biochem. Biophys. 289:62 (1991).PubMedCrossRefGoogle Scholar
  27. 27.
    B. C. Millar, E. M. Fielden, and C. E. Smithen, Polyfunctional radiosensitizers IV. The effect of contact time and temperature on sensitization of hypoxic Chinese hamster cells in vitro by bifunctional nitroxyl compounds, Br. J. Cancer 37:73 (1978).Google Scholar
  28. 28.
    P. T. Emmerson, and P. Howard-Flanders, Preferential sensitization of anoxic bacteria to X-rays by organic nitroxide-free radicals, Radiat. Res. 23:54 (1965).CrossRefGoogle Scholar
  29. 29.
    S. M. Hahn, L. Wilson, C. M. Krishna, J. Liebmann, W. DeGraff, J. Gamson, A. Samuni, D. Venzon, and J. B. Mitchell, Identification of nitroxide radioprotectors, Radiat. Res. 132:87 (1992).PubMedCrossRefGoogle Scholar
  30. 30.
    W. G. DeGraff, M. C. Krishna, D. Kaufman, and J. B. Mitchell, Nitroxide-mediated protection against x-ray-and neocarzinostatin-induced DNA damage, Free Radic. Biol. Med. 13:479 (1992).PubMedCrossRefGoogle Scholar
  31. 31.
    S. M. Hahn, Z. Tochner, C. M. Krishna, J. Glass, L. Wilson, A. Samuni, M. Sprague, D. Venzon, E. Glatstein, J. B. Mitchell, and A. Russo, Tempol, a stable free radical, is a novel murine radiation protector, Cancer Res. 52:1750 (1992).PubMedGoogle Scholar
  32. 32.
    J. M. Yuhas, and J. B. Storer, The effect of age on two modes of radiation death and on hematopoietic cell survival in the mouse, Radiat. Res. 32:596 (1969).CrossRefGoogle Scholar
  33. 33.
    K. A. Kennedy, B. A. Teicher, S. Rockwell, and A. C. Sartorelli, The hypoxic tumor cell: a target for selective cancer chemotherapy, Biochem. Pharmacol. 29:1 (1980).PubMedCrossRefGoogle Scholar
  34. 34.
    T. Goffman, D. Cuscela, J. Glass, S. Hahn, C. M. Krishna, G. Lupton, and J. B. Mitchell, Topical application of nitroxide protects radiation induced alopecia in guinea pigs, Int. J. Radiat. Oncol. Biol. Phys. 22:803 (1992).PubMedCrossRefGoogle Scholar
  35. 35.
    R. T. Dorr, G. T. Bowden, D. S. Alberts, and J. D. Liddil, Interactions of mitomycin C with mammalian DNA detected by alkaline elution, Cancer Res. 45:3510 (1985).PubMedGoogle Scholar
  36. 36.
    N. R. Bachur, S. L. Gordon, M. V. Gee, and H. Kon, NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals, Proc. Natl. Acad. Sci. USA 76:954 (1979).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Stephen M. Hahn
    • 1
  • C. Murali Krishna
    • 1
  • James B. Mitchell
    • 1
  1. 1.Radiation Biology Branch National Cancer InstituteNational Institutes of HealthBethesdaUSA

Personalised recommendations