Cancer and Free Radicals

  • William A. Pryor
Part of the Basic Life Sciences book series (BLSC, volume 39)


It is now clear that free radical Intermediates often are involved in the activation of many types of procarcinogens and promutagens to their active forms as well as in the binding of these activated species to DNA. In this chapter, a general introduction to free radical chemistry is presented, with some discussion of radical lifetimes and reactivities. Potential biological targets of radical attack include lipids, proteins, and nucleic acids, and the reactions of all three of these target molecules with radicals are discussed. Finally, the evidence linking free radical reactions with chemical carcinogenesis is reviewed. A mechanistic scheme that divides the mechanisms for activating procarcinogens into 5 types is suggested; of these, 3 types of mechanisms involve free radicals, either in the activation of the carcinogen or in its binding to DNA or both. It also is suggested that a “reverse binding” can occur in which radicals produced on the DNA backbone attack and bond to unactivated substrates, rather than activated substrates (such as radicals) attacking unactivated DNA. It is known that systems that produce superoxide can lead to the production of hydroxyl radicals and that these HO· radicals form radical sites on DNA; thus, reverse binding could occur when any species that can add to a free radical is in the vicinity of the radical-damaged DNA.


Free Radical Linoleic Acid Peroxyl Radical Free Radical Reaction Hydroxyl Radical Scavenger 
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.


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  1. 1.
    Adelman, R.C., and E.E. Dekker, eds. (1985) Modification of Proteins During Aging, Alan R. Liss, Inc., New York, 120 pp.Google Scholar
  2. 2.
    Ames, B.N., R.L. Saul, E. Schwiers, R. Adelman, and R. Cathcart (1984) Oxidative DNA damage as related to cancer and aging: The assay of thymine glycol, thymidine glycol, and hydroxymethyluracil in human and rat urine. In Proceedings of the Symposium on Molecular Biology of Aging: Gene Stability and Gene Expression, Raven Press, New York.Google Scholar
  3. 3.
    Armstrong, D., ed. (1984) Free Radicals in Molecular Biology, Aging, and Disease, Raven Press, New York, 412 pp.Google Scholar
  4. 4.
    Aust, S.D., and B.A. Svingen (1982) The role of iron in enzymatic lipid peroxidation. In Free Radicals in Biology, Vol. V, W.A. Pryor, ed. Academic Press, New York, pp. 1–28.Google Scholar
  5. 4a.
    Bachur, N.R., S.L. Gordon, and M.V. Gee (1978) A general mechanism for microsomal activation of quinone anticancer agents to free radicals. Cancer Res. 38:1745–1750.Google Scholar
  6. 5.
    Bernstein, L., L.S. Gold, B.N. Ames, M.C. Pike, and D.G. Hoel (1985) Totologenic aspects of the comparison of carcinogenic potency in rats and mice. Fund. Appl. Tox. 5:79–86.CrossRefGoogle Scholar
  7. 6.
    Birnboim, H.C. (1982) DNA strand breakage in human leukocytes exposed to a tumor promoter, phorbol myristate acetate. Science 215:1247–1249.CrossRefGoogle Scholar
  8. 7.
    Birnboim, H.C. (1983) Importance of DNA strand-break damage in tumor promotion. In Radioprotectors and Anticarcinogens, O.F. Nygaard and M.G. Simic, eds. Academic Press, New York, pp. 539–556.Google Scholar
  9. 8.
    Borg, D.C., and K.M. Schaich (1984) Cytotoxicity from coupled redox cycling of autoxidizing xenobiotics and metals. Israel J. Chem. 24: 38–53.Google Scholar
  10. 9.
    Borish, E.T., J.P. Cosgrove, D.F. Church, W.A. Deutsch, and W.A. Pryor (1985) Cigarette tar causes single strand breaks in DNA. Biochem. Biophys. Res. Commun. (in press).Google Scholar
  11. 10.
    Brot, N., and H. Weissbach (1983) Biochemistry and physiological role of methionine sulfoxide residues in proteins. Arch. Biochem. Biophys. 223:271–281.CrossRefGoogle Scholar
  12. 11.
    Burka, L.T., F.P. Guengerich, R.J. Willard, and T.L. Macdonald (1985) Mechanism of cytochrome P-450 catalysis. Mechanism of n-dealkylation and amine oxide deoxygenation. J. Am. Chem. Soc. 107:2549–2551.CrossRefGoogle Scholar
  13. 12.
    Burkey, T., D.F. Church, and W.A. Pryor (1986) Initiation of lipid peroxidation by gas phase cigarette smoke models. (To be submitted).Google Scholar
  14. 13.
    Burton, G.W., L. Hughes, and K.U. Ingold (1983) Antioxidant activity of phenols related to vitamin E, Are there chain-breaking antioxidants better than alpha-tocopherol. J. Am. Chem. Soc. 105:5950–5951.CrossRefGoogle Scholar
  15. 14.
    Burton, G.W., K.H. Cheesman, K.U. Ingold, and T.F. Slater (1983) Lipid antioxidants and products of lipid peroxidation as potential tumour protective agents. Biochem. Soc. Trans. 11:261–262.Google Scholar
  16. 15.
    Cathcart, R., E. Schwiers, R.L. Saul, and B.N. Ames (1984) Thymine glycol and thymidine glycol in human and rat urine: A possible assay for oxidative DNA damage. Proc. Natl. Acad. Sci., USA 81:5633–5637.CrossRefGoogle Scholar
  17. 16.
    Cavalieri, E.L., and E.G. Rogan (1984) One-electron and two-electron oxidation in aromatic hydrocarbon carcinogenesis. In Free Radicals in Biology, Vol. VI, W.A. Pryor, ed. Academic Press, New York, pp. 323–369.Google Scholar
  18. 17.
    Gerutti, P.A. (1985) Prooxidant states and tumor promotion. Science 227:375–381.CrossRefGoogle Scholar
  19. 18.
    Chesis, P.L., D.E. Levin, M.T. Smith, L. Ernster, and B.N. Ames (1984) Mutagenicity of quinones: Pathways of metabolic activation and detoxification. Proc. Natl. Acad. Sei., USA 81:1696–1700.CrossRefGoogle Scholar
  20. 19.
    Church, D.F., and W.A. Pryor (1985) The free radical chemistry of cigarette smoke and its toxicological implications. Env. Health Perspect. (in press).Google Scholar
  21. 20.
    Coon, M.J., et al., eds. (1980) Microsomes, Drug Oxidations, and Chemical Carcinogens, Vol. I, Academic Press, New York.Google Scholar
  22. 21.
    Cosgrove, J.P., E.T. Borish, D.F. Church, and W.A. Pryor (1985) The metal-mediated formation of hydroxyl radical by aqueous extracts of cigarette tar. Biochem. Biophys. Res. Commun. 132:390–396.CrossRefGoogle Scholar
  23. 21a.
    Dipple, A., R.C. Moschell, and C.A.H. Bigger (1984) Polynuclear aromatic carcinogens. In Chemical Carcinogens (second edition, revised and expanded). Vol. 2, C.E. Searle, ed, American Chemical Society, Washington, D.C., 163 pp.Google Scholar
  24. 22.
    Dix, T.A., R. Fontana, A. Panthani, and L.J. Marnett (1985) Hematincatalyzed epoxidation of 7,8-dihydroxyl-7,8-dihydrobenzo[a]pyrene by polyunsaturated fatty acid hydroperoxides. J. Biol. Chem. 260:5358–5365.Google Scholar
  25. 23.
    Dunford, H.B., and W.A. Pryor, in collaboration with S. Aust, W. Bors, I. Fridovich, W.H. Koppenol, T. Traylor, and V. Ullrich (1981) A list of recommended names and possible structures for various iron-oxygen complexes. In Oxygen and Oxy-radicals in Chemistry and Biology, M.A.J. Rogers and E.L. Powers, eds. Academic Press, New York, p. 196.Google Scholar
  26. 24.
    Emerit, I., and P. Gerutti (1984) Icosanoids and chromosome damage. In Icosanoids and Cancer, H. Thaler-Dao, A. Crastes de Paulet, and R. Paoletti, eds. Raven Press, New York, pp. 127–138.Google Scholar
  27. 25.
    Fitchett, M., and B.C. Gilbert (1985) ESR studies of the reactions of OH with carbohydrates, sugar-phosphates and other nucleotide components. Life Chem. Rep. 3:57–61.Google Scholar
  28. 26.
    Fucci, L., C.N. Oliver, M.J. Coon, and E.R. Stadtman (1983) Inactivation of key metabolic enzymes by mixed-function oxidation reactions: Possible implication in protein turnover and aging. Proc. Natl. Acad. Sei., USA 80:1521–1525.CrossRefGoogle Scholar
  29. 27.
    Gale, P.H., and R.W. Egan (1984) Prostaglandin endoperoxide synthetase-catalyzed oxidation reactions. In Free Radicals in Biology, Vol. VI, W.A. Pryor, ed. Academic Press, New York, pp. 1–38.Google Scholar
  30. 28.
    Ghezzi, P., M. Bianchi, L. Gianera, S. Landolfo, and M. Salmona (1985) Role of reactive oxygen intermediates in the interferon-mediated depression of hepatic drug metabolism and protective effect of n-acetylcysteine in mice. Cancer Res. 45:3444–3447.Google Scholar
  31. 29.
    Grollman, A.P., M. Takeshita, D.M.R. Pillai, and Francis Johnson (1985) Origin and cytotoxic properties of base propenals derived from DNA. Cancer Res. 45:1127–1131.Google Scholar
  32. 30.
    Groves, J.T., and D.V. Subramanian (1984) Hydroxylation by cytochrome P-450 and metalloporphyrin models. Evidence for allylic rearrangement. J. Am. Chem. Soc. 106:2177–2181.CrossRefGoogle Scholar
  33. 31.
    Gutteridge, J.M.C. (1982) Iron-dependent free radical damage to DNA and deoxyribose. Separation of TBA-reactive intermediates. Int. J. Biochem. 14:891–893.CrossRefGoogle Scholar
  34. 32.
    Gutteridge, J.M.C. (1984) Reactivity of hydroxyl and hydroxy1-like radicals discriminated by release of thiobarbituric acid-reactive material from deoxy sugars, nucleosides and benzoate. Biochem. J. 224: 761–767.Google Scholar
  35. 33.
    Huttermann, J., W. Kohnlein, and R. Teoule, eds.; A.J. Bertinchamps, coordinating ed. (1978) Effects of Ionizing Radiation on DNA, Springer-Verlag, Berlin, Heidelberg, New York, 650 pp.Google Scholar
  36. 34.
    Janoff, A., H. Capp, P. Laurent, and L. Raju (1983) The role of oxidative processes in emphysema. Am. Rev. Respir. Dis. 127:531–538.Google Scholar
  37. 35.
    Kalyanaraman, B., and K. Sivarajah (1984) The electron spin resonance study of free radicals formed during the archidonic acid cascade and cooxidation of xenobiotics by prostaglandin synthase. In Free Radicals in Biology, Vol. VI, W.A. Pryor, ed. Academic Press, New York, pp. 149–198.Google Scholar
  38. 36.
    Kennedy, K.A., E.G. Mimnaugh, M.A. Trush, and B.K. Sinha (1985) Effects of glutathione and ethylxanthate on mitomycin C activation by isolated rat hepatic or EMT6 mouse mammary tumor nuclei. Cancer Res. 45:4071–4076.Google Scholar
  39. 37.
    Kensler, T.W., and M.A. Trush (1984) Role of oxygen radicals in tumor promotion. Environ. Mutag. 6:593–616.CrossRefGoogle Scholar
  40. 38.
    Kensler, T.W., D.M. Bush, and W.J. Kozumbo (1983) Inhibition of tumor promotion by a biomimetic superoxide dismutase. Science 221:75–77.CrossRefGoogle Scholar
  41. 39.
    Korzekwa, K., W. Trager, M. Gouterman, D. Spangler, and G.H. Loew (1985) Cytochrome P450 mediated aromatic oxidation: A theoretical study. J. Am. Chem. Soc. 107:4273–4279.CrossRefGoogle Scholar
  42. 40.
    Kozumbo, W.J., M.A. Trush, and T.W. Kensler (1985) Poly(adenosine diphosphate-ribosylation) of nuclear matrix proteins in alkylating agent resistant and sensitive cell lines. Chem. Biol. Interact. 54:199–208.CrossRefGoogle Scholar
  43. 41.
    Lands, W.E.M. (1985) Interactions of lipid hydroperoxides with eicosanoid biosynthesis. J. Free Radicals Biol. Med. 1:97–101.CrossRefGoogle Scholar
  44. 42.
    Lands, W.E.M., R.J. Kulmacz, and P.J. Marshall (1984) Lipid peroxide actions in the regulation of prostaglandin biosynthesis. In Free Radicals in Biology, Vol. VI, W.A. Pryor, ed. Academic Press, New York, pp. 39–61.Google Scholar
  45. 43.
    Laughrea, M. (1982) On the error theories of aging. Exp. Gerontology 17:305–317.CrossRefGoogle Scholar
  46. 44.
    Lazo, J.S., and M.P. Hacker (1985) Organ-directed toxicology of antitumor agents. Fed. Proc. 44:2335–2338.Google Scholar
  47. 45.
    Lesko, S.A., R.J. Lorentzen, and P.O.P. Ts’o (1980) Role of superoxide in deoxyribonucleic acid strand scission. Biochemistry 19:3023–3028.CrossRefGoogle Scholar
  48. 46.
    Lin, S.W., and K.J.A. Davies (1985) General aspects of protein damage by oxygen radicals. Fed. Proc. Vol. 44 (abstract of paper no. 3990).Google Scholar
  49. 47.
    Lown, J.W. (1985) Molecular mechanisms of action of anticancer agents involving free radicals. Adv. Free Radical Biol. Med, (in press).Google Scholar
  50. 48.
    McBrien, D.C.H., and T.F. Slater, eds. (1982) Free Radicals, Lipid Peroxidation and Cancer, Academic Press, New York.Google Scholar
  51. 49.
    McNeill, J.M., and E.D. Wills (1985) The formation of mutagenic derivatives of benzo[a]pyrene by peroxidising fatty acids. Chem. Biol. Interact. 53:197–207.CrossRefGoogle Scholar
  52. 50.
    Man, E.H. (1983) Accumulation of d-aspartic acid with age in the human brain. Science 220:1407–1408.CrossRefGoogle Scholar
  53. 51.
    Marnett, L.J. (1984) Hydroperoxide-dependent oxidations during prostaglandin biosyntheses. In Free Radicals in Biology, Vol. VI, W.A. Pryor, ed. Academic Press, New York, pp. 63–94.Google Scholar
  54. 52.
    Mead, J.F. (1976) Free radical mechanisms of lipid damage and consequences for cellular membranes. In Free Radicals in Biology, Vol. I, W.A. Pryor, ed. Academic Press, New York, pp. 51–67.Google Scholar
  55. 53.
    Morisaki, N., J.A. Lindsey, J.M. Stitts, H. Zhang, and D.G. Cornwell (1984) Fatty acid metabolism and cell proliferation. V. Evaluation of pathways for the generation of lipid peroxides. Lipids 19:381–394.CrossRefGoogle Scholar
  56. 54.
    Myers, G.G., W.P. McGuire, R.H. Liss, L. Ifrim, K. Grotzinger, and R.G. Young (1977) Adriamycin. The role of lipid peroxidation in cardiac toxicity and tumor response. Science 197:165–167.CrossRefGoogle Scholar
  57. 55.
    Oliver, G.N., R. Fulks, R.L. Levine, L. Fucci, A.J. Rivett, J.E. Rose- man, and E.R. Stadtman (1984) Oxidative inactivation of key metabolic enzymes during aging. In Molecular Basis of Aging, A.K. Roy and B. Ghatterjee, eds. Academic Press, New York, pp. 235–260.Google Scholar
  58. 56.
    Phillips, G.O., ed. (1968) Energetics and Mechanisms in Radiation Biology, Academic Press, New York, 527 pp.Google Scholar
  59. 57.
    Pryor, W.A. (1980) Mechanisms and detection of pathology caused by free radicals: Tobacco smoke, nitrogen dioxide, and ozone. In Environmental Health Chemistry, J.U. McKinney, ed. Ann Arbor Science Publishers, Ann Arbor, Michigan, pp. 445–467.Google Scholar
  60. 58.
    Pryor, W.A. (1980) Methods of detecting free radicals and free radical-mediated pathology in environmental toxicology. In Molecular Basis of Environmental Toxicity, R.S. Bhatnagar, ed. Ann Arbor Science Publishers, Ann Arbor, Michigan, pp. 3–36.Google Scholar
  61. 59.
    Pryor, W.A. (1982) Free radical biology: Xenobiotics, cancer and aging. In Vitamin E: Biochemical, Hematological and Clinical Aspects, B. Lubin and L.J. Machlin, eds. New York Academy of Sciences, New York, pp. 1–22.Google Scholar
  62. 60.
    Pryor, W.A. (1984) Free radicals in autoxidation and in aging. Part I. Kinetics of the autoxidation of linoleic acid in SDS micelles: Calculations of radical concentrations, kinetic chain lengths, and the effects of vitamin E. Part II. The role of radicals in chronic human diseases and in aging. In Free Radicals in Molecular Biology, Aging, and Disease, D. Armstrong, R.S. Sohal, R.G. Cutler, and T.F. Slater, eds. Raven Press, New York, pp. 13–41.Google Scholar
  63. 61.
    Pryor, W.A. (1986) Oxy-radicals and related species: Their formation, their lifetimes, and their reactions. Ann. Rev. Phys. 48:657–667.CrossRefGoogle Scholar
  64. 61.
    a. Pryor, W.A. (1986) Free radicals in cigarette smoke. In Oxidative and Proteolytic Damage to the Lung; Second International Symposium, C. Mittman and J.G. Taylor, eds. Academic Press, New York (in press).Google Scholar
  65. 62.
    Pryor, W.A., and M.M. Dooley (1985) Inactivation of human alpha-l-proteinase inhibitor by cigarette smoke: Effect of smoke phase and buffer. Am. Rev. Respir. Dis. 131:941–943.Google Scholar
  66. 63.
    Pryor, W.A., M.M. Dooley, and D.F. Church (1984) Inactivation of human alpha-1-proteinase inhibitor by gas-phase cigarette smoke. Biochem. Biophys. Res. Gommun. 122:676–681.CrossRefGoogle Scholar
  67. 64.
    Pryor, W.A., M.M. Dooley, and D.F. Church (1986) The mechanisms of the inactivation of human alpha-l-proteinase inhibitor by gas-phase cigarette smoke. Adv. Free Radical Biol. Med, (in press).Google Scholar
  68. 65.
    Pryor, W.A., M.J. Kaufman, and D.F. Church (1985) Autoxidation of micelle-solubilized linoleic acid. Relative inhibitory efficiencies of ascorbate and ascorbyl palmitate. J. Org. Chem. 50:281–283.CrossRefGoogle Scholar
  69. 66.
    Pryor, W.A., J.P. Stanley, and E. Blair (1976) Autoxidation of polyunsaturated fatty acids: II. A suggested mechanism for the formation of TBA-reactive materials from prostaglandin-like endoperoxides. Lipids 11:370–379.CrossRefGoogle Scholar
  70. 67.
    Pryor, W.A., M. Tamura, and D.F. Church (1984) ESR spon-trapping study of the radicals produced in NOx/olefin reactions: A mechanism for the production of the apparently long-lived radicals in gas-phase cigarette smoke. J. Am. Chem. Soc. 106:5073–5079.CrossRefGoogle Scholar
  71. 68.
    Pryor, W.A., K. Uehara, and D.F. Church (1984) The chemistry and biochemistry of the radicals in cigarette smoke: ESR evidence for the binding of the tar radical to DNA and polynucleotides. In Oxygen Radicals in Chemistry and Biology, W. Bors, M. Saran, and D. Tait, eds. Walter de Gruyter & Co., Berlin, pp. 193–201.CrossRefGoogle Scholar
  72. 69.
    Pryor, W.A., B.J. Hales, P.I. Premovic, and D. F. Church (1983) The radicals in cigarette tar: Their nature and suggested physiological implications. Science 220:425–427.CrossRefGoogle Scholar
  73. 70.
    Slaga, T.J., ed. (1980) Modifiers of Chemical Carcinogenesis: An Approach to the Biochemical Mechanism and Cancer Prevention, Raven Press, New York, 275 pp.Google Scholar
  74. 71.
    Slaga, T.J., A.J.P. Klein-Szanto, L.L. Triplett, L.P. Yotti, and J.E. Trosko (1981) Skin tumor-promoting activity of benzoyl peroxide, a widely-used free radical-generating compound. Science 213:1023–1025.CrossRefGoogle Scholar
  75. 72.
    Smith, C.V., H. Hughes, B.C. Lauterburg, and J.R. Mitchell (1983) Chemical nature of reactive metabolites determines their biological interactions with glutathione. In Functions of Glutathione: Biochemical, Physiological, Toxicological, and Clinical Aspects, A. Larsson, ed. Raven Press, New York, pp. 125–137.Google Scholar
  76. 72a.
    Steenken, S., and V. Jagannadham (1985) Reaction of 6-yl radicals of uracil, thymine, and cytosine and their nucleosides and nucleotides with nitrobenzenes via addition to give nitroxide radicals. OH -catalyzed nitroxide hetrolysis. J. Am. Chem. Soc. 107:6818–6826.CrossRefGoogle Scholar
  77. 73.
    Troll, W., G. Witz, B. Goldstein, D. Stone, and T. Sugimura (1982) The role of free oxygen radicals in tumor promotion and carcinogenesis. In Carcinogenesis: A Comprehensive Survey, Vol. 7, E. Hecker, N.E. Fusenig, W. Kunz, F. Marks, and H.W. Thielmann, eds. Raven Press, New York, pp. 593–597.Google Scholar
  78. 74.
    Ts’o, P.O.P., W.J. Caspary, and R.J. Lorentzen (1977) The involvement of free radicals in chemical carcinogenesis. In Free Radicals in Biology, Vol. III, W.A. Pryor, ed. Academic Press, New York, pp. 251–303.Google Scholar
  79. 75.
    Tsuruta, Y., P.D. Josephy, A.D. Rahimtula, and P.J. O’Brien (1985) Peroxidase-catalyzed benzidine binding to DNA and other macromolecules. Chem. Biol. Interact. 54:143–158.CrossRefGoogle Scholar
  80. 76.
    Wattenberg, L.W. (1980) Inhibitors of chemical carcinogens. In Cancer and the Environment, H.B. Demopoulos and M.A. Mehlman, eds. Pathotox Publishers, Inc., Park Forest South, Illinois, pp. 35–52.Google Scholar
  81. 77.
    Wattenberg, L.W., and L.D.T. Lam (1983) Phenolic antioxidants as protective agents in chemical carcinogenesis. In Radioprotectors and An- ticarcinogens, O.F. Nygaard and M.G. Simic, eds. Academic Press, New York, pp. 461–469.Google Scholar
  82. 78.
    Weinstein, I.B. (1980) Evaluating substances for promotion, cofactor effects and synergy in the carcinogenic process. In Cancer and the Environment, H.B. Demopoulos and M.A. Mehlman, eds. Pathotox Publishers, Inc., Park Forest South, Illinois, pp. 89–101.Google Scholar
  83. 79.
    Weitzman, S.A., and T. P. Stossel (1981) Mutation caused by human phagocytes. Science 212:546–547.CrossRefGoogle Scholar
  84. 80.
    Weitzman, S.A., and T.P. Stossel (1982) Effects of oxygen radical scavengers and antioxidants on phagocyte-induced mutagenesis. J. Immun. 128:2770–2778.Google Scholar
  85. 81.
    Yamasaki, E., and B.N. Ames (1977) Concentration of mutagens from urine by adsorption with the nonpolar resin XAD-2: Cigarette smokers have mutagenic urine. Proc. Natl. Acad. Sci., USA 74:3555–3559.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • William A. Pryor
    • 1
  1. 1.Biodynamics InstituteLouisiana State UniversityBaton RougeUSA

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