In Vivo Stimulation of Oxy Radicals by Mouse Skin Tumor Promoters

  • G. Witz
  • B. Czerniecki
  • S. C. Gad
  • Bernard D. Goldstein


Our original suggestion in 1980 (1,2). that free radicals may be involved in tumor promotion was based on linkage of a number of puzzling observations about tumor promoters with newer insights into the biological and pathological role of free radicals. Of note was that the then known skin tumor promoters in the classic two-stage mouse skin tumor promotion system were all inflammatory agents. However, the lack of correlation among phorbol esters of tumor promoting ability with inflammation, as measured by standard techniques such as number of infiltrating inflammatoiy cells, seemed to preclude a role for inflammation in tumor promotion. Yet it was hard to ignore the many clinical observations, dating back to the nineteenth century, that inferentially seemed to point to chronic inflammation having some role in tumor development, observations ranging from the frequency of basal cell tumors on the bridge of the nose of eye glass wearers, to colorectal carcinoma in patients with ulcerative colitis. Our first approach to a possible role for free radicals in tumor promotion was to consider that the source of such free radicals in the mouse skin tumor initiation-promotion model might be derived from the activation of phagocytic cells, a known source of free radicals and active states of oxygen. Further, hepatic models of tumor promotion tend to feature compounds that are powerful inducers of cytochrome P-450 or of peroxisomes, both conceivably sources of free radicals or other active states of oxygen.


Peritoneal Macrophage Phorbol Myristate Acetate Phorbol Ester Phagocytic Cell Tumor Promotion 
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  1. 1.
    G. Witz, B. D. Goldstein, M. A. Amoruso, D. S. Stone, and W. Troll, Stimulation of human polymorphonuclear leukocyte (PMN) superoxide anion radical (O2) production by tumor pronoters. Proc. Am. Assoc. Cancer Res. 21, 112 (1980).Google Scholar
  2. 2.
    B. D. Goldstein, G. Witz, J. Zimmerman and C. Gee, Free radicals and reactive oxygen species in tumor promotion. In: Oxy Radicals and Their Scavenger Systems, Vol. 2: Cellular and Medical Aspects. (R. A. Greenwald and G. Cohen, Eds.) pp. 321–325. Elsevier, New York (1983).Google Scholar
  3. B. M. Babior, Oxidants from phagocytes: Agents of defense and destruction. Blood 64, 959–966 (1984).PubMedGoogle Scholar
  4. 4.
    B. D. Goldstein, G. Witz, M. A. Amoruso and W. Troll, Protease inhibitors antagonize the activation of polymorphonuclear leukocyte oxygen consumption. Biochem. Biophys. Res. Commun. 88, 854–860 (1979).PubMedCrossRefGoogle Scholar
  5. 5.
    W. Troll, A. Klassen and A. Janoff, Tumorigenesis in mouse skin: Inhibition by synthetic inhibitors of proteases. Science 169. 1211–1213 (1970).PubMedCrossRefGoogle Scholar
  6. 6.
    B. D. Goldstein, G. Witz, M. A. Amoruso, D. S. Stone and W. Troll, Stimulation of human polymorphonuclear leukocyte superoxide anion radical production by tumor promoters. Cancer Lett. 11, 257–262 (1981).PubMedCrossRefGoogle Scholar
  7. 7.
    G. Witz, B. D. Goldstein, M. A. Amoruso, D. S. Stone and W. Troll, Retinoid inhibition of superoxide anion radical production by human polymorphonuclear leukocytes stimul ated with tumor promoters. Res. Commun, 97, 883–888 (1980).Google Scholar
  8. 8.
    A. K. Verma, B. G. Shapas, H. M. Rice and R. K. Boutwell, Correlation of the inhibition by retinoids of tumor promoter-induced mouse epidermal ornithine decarboxylase activity and of skin tumor promotion. Cancer Res. 39, 419–425 (1979).PubMedGoogle Scholar
  9. 9.
    R. A. Floyd and J. J. Watson, Sensitive assay of hydroxyl free radical formation utilizing high pressure liquid chrcmatography with electrochemical detection of phenol and salicylate hydroxylation products. J. Biochem. Biophys. Methods 10, 221–235 (1985).CrossRefGoogle Scholar
  10. 10.
    B. Czerniecki, S. C. Gad, C. Reilly, A. C. Smith and G. Witz, Phorbol diacetate inhibits superoxide anion radical production and tumor promotion by mezerein. Carcinogenesis 7, 1637–1641 (1986).PubMedCrossRefGoogle Scholar
  11. 11.
    T. J. Slaga, S. M. Fischer, K. Nel son and G. L. Gleason, Studies on the mechanism of skin tumor promotion: Evidence for several stages in promotion. Proc. Natl. Acad. U.S.A. 77, 3659–3663 (1980).CrossRefGoogle Scholar
  12. 12.
    A. J. Klein-Szanto, S. M. Major and T. J. Slaga, Induction of dark keratinocytes by 12-Otetradecanoyl phorbol-13-acetate and mezerein as an indicator of tumor promoting efficiency. Carcinogenesis 1, 399–403 (1980).PubMedCrossRefGoogle Scholar
  13. 13.
    R. K. Boutwell, The function and mechanism of promoters of carcinogenesis. CRC Crit. Rev. Toxicol. 2, 419–443 (1974).PubMedCrossRefGoogle Scholar
  14. 14.
    P. M. Blumberg, In vitro studies on the mode of action of the phorbol esters, potent tumor promoters. CRC Crit. Rev. Toxicol. 8, 153–193 (1980).CrossRefGoogle Scholar
  15. 15.
    R. Schmidt and E. Hecker, Simple phorbol esters as inhibitors of tumor promotion by TPA in mouse skin. In: Carcinogenesis. Vol. 7. (E. Hecker et al., Eds.) pp. 57–63. Raven Press, New York (1982).Google Scholar
  16. 16.
    G. Witz and B. Czerniecki, In vivo inhibition by phorbol esters of oxy radical production by mouse preritoneal exudate cells stimulated with phorbol myristate acetate. Ann. N.Y. Acad. Sci. 7 36. in press.Google Scholar
  17. 17.
    P. A. Cerutti, Prooxidant states and tumor promotion. Science 277, 375–381 (1985).CrossRefGoogle Scholar
  18. 18.
    T. W. Kensler and B. G. Taffe. Free radicals in tumor promotion. Adv.Free Radical Biol. Med. 2, 347–387, 1986.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • G. Witz
    • 1
  • B. Czerniecki
    • 1
  • S. C. Gad
    • 1
    • 2
  • Bernard D. Goldstein
    • 1
  1. 1.UMDNJ-Robert Wood Johnson Medical SchoolPiscatawayUSA
  2. 2.G. D. SearleSkokieUSA

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