Studies on the Mode of Action of Chemical Carcinogens in Cultured Mammalian Cells

  • Carol Jones
  • Eliezer Huberman
Part of the Basic Life Sciences book series


Researchers estimate that environmental chemicals are responsible for a portion of human cancers. These chemicals, identified as potential carcinogens by epidemiology or experimental studies, constitute a very diverse group and thus are likely to interact in the carcinogenic process at different stages and to varying degrees.


Polycyclic Aromatic Hydrocarbon Phorbol Ester Tumor Promoter Mouse Skin Ornithine Decarboxylase 
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.
    Miller, J.A. 1970. Carcinogenesis by chemicals: An overview - G.H.A. Clowes memorial lecture. Cancer Res. 30: 559–576.Google Scholar
  2. 2.
    Brookes, P., and P.D. Lawley. 1964. Evidence for the binding of polynuclear aromatic hydrocarbons to the nucleic acids of mouse skin: Relation between carcinogenic power of hydrocarbons and their binding to deoxyribonucleic acid. Nature 202: 781–784.Google Scholar
  3. 3.
    Essigmann, J.M., R.G. Croy, A.M. Hadzan, W.F. Busby, V.N. Reinhold, G. Buchi, and G.N. Wogan. 1977. Structural identification of the major DNA adduct formed by aflatoxin B1 in vitro. Proc. Natl. Acad. Sci. USA 74: 1870–1874.Google Scholar
  4. 4.
    Huberman, E., and L. Sachs. 1977. DNA binding and its relationship to carcinogenesis by different polycyclic hydrocarbons. Int. J. Cancer 19: 122–127.Google Scholar
  5. 5.
    Jeffrey, A.M., I.B. Weinstein, K.W. Jenette, K. Grzeskowiak, K. Nakahishi, R.G. Harvey, M. Authrup, and C. Harris. 1977. Structures of benzo[a]pyrene-nucleic acid adducts formed in human and bovine bronchial explants. Nature 269: 348–350.PubMedCrossRefGoogle Scholar
  6. 6.
    Newbold, R.F., C.B. Wigley, M.H. Thompson, and P. Brookes. 1977. Cell-mediated mutagenesis in cultured Chinese hamster cells by carcinogenic hydrocarbons: Nature and extent of the associated hydrocarbon-DNA reaction. Mutat. Res. 43: 101–116.Google Scholar
  7. 7.
    Ames, B.N. 1979. Identifying environmental chemicals causing mutations and cancer. Science 204: 587–593.PubMedCrossRefGoogle Scholar
  8. 8.
    Bouck, N., and G. DiMayorca. 1976. Somatic mutation as the basis for malignant transformation of BHK cells by chemical carcinogens. Nature (London) 264–360–361.Google Scholar
  9. 9.
    Heidelberger, C. 1970. Chemical carcinogenesis. Ann. Rev. Biochem. 44: 78–121.Google Scholar
  10. 10.
    Huberman, E. 1977. Viral antigen induction and mutability of different genetic loci by metabolically activated carcinogenic polycyclic hydrocarbons in cultured mammalian cells. In: The Origins of Human Cancer, Book C. H.H. Hiatt, J.D. Watson, and J.A. Winston, eds. Cold Spring Harbor Laboratory Publications: Cold Spring Harbor, New York. pp. 1521–1535.Google Scholar
  11. 11.
    Huberman, E. 1978. Mutagens and cell transformation of mammalian cells in culture by chemical carcinogens. J. Environ. Pathol. Toxicol. 2: 29–42.Google Scholar
  12. 12.
    Huberman, E., R. Mager, and L. Sachs. 1976. Mutagenesis and transformation of normal cells by chemical carcinogens. Nature 264: 360–361.PubMedCrossRefGoogle Scholar
  13. 13.
    Kao, F.T., and T.T. Puck. 1971. Genetics of somatic mammalian cells. XII: Mutagenesis by carcinogenic nitroso compounds. J. Cell. Physiol. 78: 139–144.Google Scholar
  14. 14.
    Knudsen, A.G., Jr., H.W. Hetchcote, and B.W. Brown. 1975. Mutation and childhood cancer: A probabilistic model for the incidence of retinoblastoma. Proc. Natl. Acad. Sci. US 72: 5116–5120.Google Scholar
  15. 15.
    Berenblum, I. 1969. A re-evaluation of the concept of cocarcinogenesis. Prog. Exp. Tumoir Res. 11: 21–30.Google Scholar
  16. 16.
    Boutwell, R.K. 1974. Function and mechanism of promoters of carcinogenesis. CRC Crit. Rev. Toxicol. 2: 419–447.Google Scholar
  17. 17.
    Van Duuren, B.L. 1969. Tumor-promoting agents in two stage carcinogenesis. Prog. Exp. Tumor Res. 11: 31–38.Google Scholar
  18. 18.
    Diamond, L., T.G. O’Brien, and W.M. Baird. 1980. Tumor promoters and the mechanism of tumor promotion. Adv. Cancer Res. 32: 1–63.Google Scholar
  19. 19.
    McCann, J.B., and B.N. Ames. 1976. Detection of carcinogens as mutagens in the Salmonella microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. USA 73: 950–954.Google Scholar
  20. 20.
    Meselson, M., and K. Ruseell. 1977. Comparisons ofGoogle Scholar
  21. carcinogenic and mutagenic potency. In: The Origins of Human Cancer, Book C. H.H. Hiatt, J.D. Watson, andGoogle Scholar
  22. J.A. Winston, eds. Cold Spring Harbor Laboratory Publications: Cold Spring Harbor, New York. pp. 1473–1482.Google Scholar
  23. 21.
    Scribner, N.K. B. Woodworth, G.P. Ford, and J.D. Scribner. 1980. The influence of molecular size and partition coefficients on the predictability of tumor initiation in mouse skin from mutagenicity in Salmonella typhimurium. Carcinogenesis 1: 715–719.PubMedCrossRefGoogle Scholar
  24. 22.
    Malling, H.V., and L.R. Valcovic. 1977. Gene mutation in mammals. In: Progress in Genetic Toxicology. D. Scott, B.A. Bridges, and F.H. Sobels, eds. Elsevier/North-Holland Biomedical Press: New York. pp. 155–164.Google Scholar
  25. 23.
    Bigger, C.A.H., J.E. Tomaszewski, and A. Dipple. 1978. Differences between products of binding of 7,12-dimethylbenz[a]anthracene to DNA in mouse skin and in a rat liver microsomal system. Biochem. Biophys. Res. Comm. 80: 229–235.Google Scholar
  26. 24.
    Selkirk, J.K. 1977. Benzo[a]pyrene carcinogenesis - A biochemical selection mechanism. J. Toxicol. Environ. Hlth. 2: 1245–1258.Google Scholar
  27. 25.
    Huberman, E., and L. Sachs. 1974. Cell-mediated mutagenesis with chemical carcinogens. Int. J. Cancer 13: 326–333.Google Scholar
  28. 26.
    Huberman, E., and L. Sachs. 1976. Mutability of different genetic loci in mammalian cells by metabolically activated carcinogenic polycyclic hydrocarbons. Proc. Natl. Acad. Sci. USA 731: 188–192.Google Scholar
  29. 27.
    Jones, C.A., and E. Huberman. 1980. A sensitive hepatocyte- mediated assay for the metabolism of nitrosamines to mutagens for mammalian cells. Cancer Res. 40: 406–411.PubMedGoogle Scholar
  30. 28.
    Langenbach, R., H.J. Freed, and E. Huberman. 1978. Liver cell-mediated mutagenesis of mammalian cells with liver carcinogens. Proc. Natl. Acad. Sci. USA 75: 2864–2867.Google Scholar
  31. 29.
    Chu, E.H.Y., and H.V. Mailing. 1968. Mammalian cell genetics. II. Chemical induction of specific locus mutations in Chinese hamster cells in vitro. Proc. Natl. Acad. Sci. USA 61: 1306–1312.Google Scholar
  32. 30.
    Arlett, C.F., C. Turnbull, S.A. Harcourt, A.R. Lehman, and C.M. Colletta. 1975. A comparison of the 8-azaguanine and ouabain-resistance systems for the selection of induced mutant Chinese hamster cells. Mutat. Res. 33: 261–278.Google Scholar
  33. 31.
    Baker, R.M., D.M. Brunette, R. Mankovitz, L.H. Thompson, G.F. Whitmore, L. Siminovitch, and J.E. Till. 1974. Ouabain-resistant mutants of mouse and hamster cells in culture. Cell 1: 9–21.CrossRefGoogle Scholar
  34. 32.
    Van Zeeland, A.A., and J.Y.I.M. Simons. 1975. Linear dose-response relationships after prolonged expression times in V79 Chinese hamster cells. Mutat. Res. 35: 129–138.Google Scholar
  35. 33.
    Langenbach, R., H.J. Freed, D. Raveh, and E. Huberman. 1978. Cell specificity in metabolic activation of aflatoxin B1 and benzo[a]pyrene to mutagens for mammalian cells. Nature 276: 277–280.PubMedCrossRefGoogle Scholar
  36. 34.
    Jones, C.A., P.J. Marlino, W. Lijinsky, and E. Huberman. (in press). The relationship between the carcinogenicity and mutagenicity of nitrosamines in a hepatocyte-mediated mutagenicity assay. Carcinogenesis.Google Scholar
  37. 35.
    IARC Monograph Series 3. 1973. pp. 91–136.Google Scholar
  38. 36.
    Jones, C.A., R. Santella, E. Huberman, J.K. Selkirk, and D. Grunberger. MS in preparation.Google Scholar
  39. 37.
    Huberman, E., L. Sachs, S.K. Yang, and H.V. Gelboin. 1976. Identification of the mutagenic metabolites ofGoogle Scholar
  40. benzo[a]pyrene in mammalian cells. Proc. Natl. Acad. Sci. USA 73: 606–611.Google Scholar
  41. 38.
    Slaga, T.J., S.M. Fischer, K. Nelson, and E.L. Gleason. 1980. Studies on the mechanism of skin tumor promotion. Evidence for several stages in promotion. Proc. Natl. Acad. Sci. USA 77: 3659–3663.Google Scholar
  42. 39.
    Weinstein, I.B., M. Wigler, P.B. Fisher, E. Sisskin, and C. Pietropaolo. Cell culture studies on biological effects of tumor promoters. In: Mechanisms of Tumor Promotion and Cocarcinogenesis. T.J. Slaga, A. Sivak, and R.K. Boutwell, eds. Raven Press: New York. pp. 313–333.Google Scholar
  43. 40.
    Hecker, E. 1978. Structure-activity relationships in diterpine esters irritant and cocarcinogenic to mouse skin. In: Mechanisms of Tumor Promotion and Cocarcinogenesis. T.J. Slaga, A. Sivak, and R.K. Boutwell, eds. Raven Press: New York. pp. 14–48.Google Scholar
  44. 41.
    Cohen, R., M. Pacifici, N. Rubenstein, J. Biehl, and H. Holtzer. 1977. Effect of a tumor promoter on myogenesis. Nature (London) 266–538–540.Google Scholar
  45. 42.
    Diamond, L., T.G. O’brien, and G. Rovera. 1977. Inhibition of adipose conversion of 313 fibroblasts by tumor promoters. Nature (London) 269: 247–248.CrossRefGoogle Scholar
  46. 43.
    Ishii, D., E. Fibach, H. Yamasaki, and I.B. Weinstein. 1978. Tumor promoters inhibit morphological differentiation in cultured mouse neuroblastoma cells. Science 200: 556–559.PubMedCrossRefGoogle Scholar
  47. 44.
    Lowe, M.E., M. Pacifico, and M. Holtzer. 1978. Effects of phorbol-l2-myristate-l3-acetate on the phenotypic program of cultured chondroblasts and fibroblasts. Cancer Res. 38: 2350–2356.PubMedGoogle Scholar
  48. 45.
    Rovera, G., T.A. O’Brien, and L. Diamond. 1977. Tumor promoters inhibit spontaneous differentiation of Friend erythroleukemia cells in culturs. Proc. Natl. Acad. Sci. USA 74: 2894–2898.Google Scholar
  49. 46.
    Yamasaki, H., E. Fibach, U. Nudel, I.B. Weinstein, R.A. Rifkind, and P.A. Marks. 1977. Tumor promoters inhibit spontaneous and induced differentiation of murine erythroleukemia cells in culture. Proc. Natl. Acad. Sci. USA 74: 3451–3456.Google Scholar
  50. 47.
    Miao, R.M., A.H. Fieldsteel, and D.W. Fodge. 1978. Opposing effects of tumor promoters on erythroid differentiation. Nature 274: 271–272.PubMedCrossRefGoogle Scholar
  51. 48.
    Lotem, J., and L. Sachs. 1979. Regulation of normal differentiation in mouse and human myeloid leukemia cells by phorbol esters and the mechanism of tumor promotion. Proc. Natl. Acad. Sci. USA 76: 5162.Google Scholar
  52. 49.
    Huberman, E., C. Heckman, and R. Langenbach. 1979. Stimulation of differentiated functions in human melanoma cells by tumor promoting agents and dimethylsulfoxide. Cancer Res. 39: 2618–2624.PubMedGoogle Scholar
  53. 50.
    Huberman, E., and M. Callaham. 1979. Induction of terminal differentiation in human promyelocytic leukemia cells by tumor promoting agents. Proc. Natl. Acad. Sci. USA 76: 1293–1297.Google Scholar
  54. 51.
    Rovera, G., T.G. O’Brien, and L. Diamond. 1979. Induction of differentiation in human promyelocytic leukemia cells by tumor promoters. Science 204: 868–870.PubMedCrossRefGoogle Scholar
  55. 52.
    Rovera, G., D. Santoli, and W.C. Damsk. 1979. Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester. Proc. Natl. Acad. Sci. USA 76: 2779–2783.Google Scholar
  56. 53.
    Emanuelsson, H., and 0. Heby. 1978. Inhibition of putrescine synthesis blocks development of the polychete Ophryotrocha labronica at gastrulation. Proc. Natl. Acad. Sci. USA 75: 1039–1042.Google Scholar
  57. 54.
    Fozard, J.R., M-L. Part, N.J. Prakash, J. Grove, P.J. Schechter, A. Sjoerdsma, and J. Koch-Weser. 1980. L-Ornithine decarboxylase: An essential role in early mammalian embryogenesis. Science 208: 505–508.Google Scholar
  58. 55.
    Gazitt, Y., and C. Friend. 1980. Polyamine biosynthesis enzymes in the induction and inhibition of differentiation in Friend erythroleukemia cells. Cancer Res. 40: 1727–1732.PubMedGoogle Scholar
  59. 56.
    Takigawa, M., H. Ishida, T. Teruko, and F. Suzuki. 1980. Polyamine and differentiation: Induction of ornithine decarboxylase by parathyroid hormone is a good marker of differentiated chondrocytes. Proc. Natl. Acad. Sci. USA 77: 1481–1485.Google Scholar
  60. 57.
    Janne, J., H. Poso, and A. Raina. 1978. Polyamines in rapid growth and cancer. Biochim. Biophys. Acta 473: 241–293.Google Scholar
  61. 58.
    Tabor, C.W., and H. Tabor. 1976. 1,4-Diaminobutane (putrescine), spermidine, and spermine. Ann. Rev. Biochem. 45: 285–306.Google Scholar
  62. 59.
    Weeks, C.E., and T.J. Slaga. 1979. Inhibition of phorbol ester polyamine accumulation in mouse epidermis by anti-inflammatory steroid. Biochem. Biophys. Res. Comm. 91: 1488–1496.Google Scholar
  63. 60.
    Yuspa, S.H., U. Lichti, T. Ben, E. Patterson, H. Hennings, T. Slaga, N. Colburn, and W. Kelsey. 1976. Phorbol esters stimulate DNA synthesis and ornithine decarboxylase activity in mouse epidermal cell cultures. Nature 262: 402–404.PubMedCrossRefGoogle Scholar
  64. 61.
    Huberman, E., C.E. Weeks, A. Herrmann, M. Callaham, and T.J. Slaga. 1981. Alterations in polyamine levels induced by phorbol diesters and other agents that promote differentiation in human promyelocytic leukemia cells. Proc. Natl. Acad. Sci. USA 78: 1062–1066.Google Scholar
  65. 62.
    Abdel-Monem, M.M., N.E. Newton, and C.E. Weeks. 1974. Inhibitors of polyamine biosynthesis. I.Google Scholar
  66. a-Methylornithine, an inhibitor of ornithine decarboxylase. J. Med. Chem. 17: 447–451.Google Scholar
  67. 63.
    Mamont, P., M-C. Duchesne, J. Grove, and P. Bey. 1978. Anti-proliferative properties of DL- a-difluoromethyl ornithine in cultured cells. A consequence of the irreversibleGoogle Scholar
  68. inhibition of ornithine decarboxylase. Biochem. Biophys. Res. Comm. 81: 59–66.Google Scholar
  69. 64.
    Newton, N.E., and M.M. Abdel-Monem. Inhibitors of polyamine biosynthesis. 4. Effects of a-methyl(+)-ornithine and methylglyoxal bis(guanylhydrazone) on growth and polyamine content of L1210 leukemic cells of mice. J. Med. Chem. 20: 249–253.Google Scholar
  70. 65.
    Folk, J.E., M.H. Park, S.I. Chung, J. Schrode, E.P. Lester, and H.L. Cooper. 1980. Polyamines as physiological substrates for transglutaminases. J. Biol. Chem. 255: 3695–3700.Google Scholar
  71. 66.
    Driedger, P.E., and P.M. Blumberg. 1980. Specific binding of phorbol ester tumor promoters. Proc. Natl. Acad. Sci. USA 77: 576–581.Google Scholar
  72. 67.
    Solanki, V., T.J. Slaga, M. Callaham, and E. Huberman. 1981. The down regulation of specific binding of [20–3H]phorbol 12,13-dibutyrate and phorbol ester-induced differentiation of human promyelocytic leukemia cells. Proc. Natl. Acad. Sci. USA 78: 1722–1725.Google Scholar
  73. 68.
    Fox, C.F., and M. Das. 1979. Internalization and processing of the EGF receptor in the induction of DNA synthesis in cultued fibroblasts: The endocytic activation hypothesis. J. Supramol. Struct. 10: 199–214.Google Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Carol Jones
    • 1
  • Eliezer Huberman
    • 1
  1. 1.Biology DivisionOak Ridge National LaboratoryOak RidgeUSA

Personalised recommendations