Some Critical Consideration Concerning Sequential Analysis of Carcinogenesis with Chemicals

  • Emmanuel Farber
Part of the NATO Advanced Study Institutes Series book series (NSSA, volume 52)


Cancer development with chemicals can begin with a brief exposure (a few hours or days) to an activated form of a carcinogen and the chemical need not be present as such ever again, as far as can be determined. This is valid not only in the skin, which was the first tissue in which this was demonstrated clearly but also in liver, colon, mammary gland, urinary bladder, kidney, brain and other organs or tissues2,3,6,7. The brief exposure to the chemical induces neither a cancer cell nor a neoplastic cell but rather some cell that can be differentially stimulated to produce a focal proliferation. By neoplastic is meant a cell that can proliferate without the need for an added or known stimulus for growth, i.e., a cell that has acquired some degree of autonomy.


Polycyclic Aromatic Hydrocarbon Chemical Carcinogen Xeroderma Pigmentosum Chemical Carcinogenesis Polycyclic Hydrocarbon 
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.
    Foulds L: Neoplastic Development. 1969, 1975. New York: Academic Press, Vols. 1 and 2Google Scholar
  2. 2.
    Pitot HC: Biological and Enzymatic Events in Chemical Carcinogenesis. Ann Rev Med. 30: 25–39, 1979PubMedCrossRefGoogle Scholar
  3. 3.
    Farber E, Cameron R: The Sequential Analysis of Cancer Development. Adv Cancer Res. 31: 125–226, 1980.PubMedCrossRefGoogle Scholar
  4. 4.
    Miller EC: Some Current Perspectives on Chemical Carcino- genesis in Humans and Experimental Animals: Presidential Address. Cancer Res 38: 1479–1496, 1978.PubMedGoogle Scholar
  5. 5.
    Rajalakshmi S, Rao PM, Sarma DSR: Chemical Carcinogenesis: Interactions of Carcinogens with Nucleic Acids. In: Becker FF, ed. Cancer: A Comprehensive Treatise. 2nd ed. New York: Plenum Press in press.Google Scholar
  6. 6.
    Berenblum I: Sequential Aspects of Chemical Carcinogenesis. In: Becker FF. ed. Cancer: A Comprehensive Treatise. New York: Plenum Press 1: 323–244, 1975.Google Scholar
  7. 7.
    Scribner JD, Suss R: Tumour Initiation and Promotion. Int Rev Exp Pathol 18: 137–198, 1978PubMedGoogle Scholar
  8. 8.
    Gelboin HV, Ts’o POP, eds: Polycyclic Hydrocarbons and Cancer. Vols 1 and 2. New York: Academic Press 1978.Google Scholar
  9. 9.
    Lu AYH, West SB: Multiplicity of Mammalian Microsomal Cytochromes P-450. Pharmacol Rev 31: 277–295, 1979.PubMedGoogle Scholar
  10. 10.
    Bresnick E: Nuclear Metabolism of Polycyclic Hydrocarbons and Interaction of Polycyclic Hydrocarbons with Nuclear Components. Adv Enzyme Regulation 16: 345–361, 1978.Google Scholar
  11. 11.
    Wattenberg LW: Inhibitors of Chemical Carcinogenesis. Adv Cancer Res 26: 197–226, 1978.PubMedCrossRefGoogle Scholar
  12. 12.
    Weisberger JH, Williams GM: Metabolism of Chemical Carcinogens. In: Becker FF, ed. Cancer: A Comprehensive Treatise. New York: Plenum Publ Corp 1: 185–234, 1975.Google Scholar
  13. 13.
    Levin W, Lu AYH, Ryan D, et al: Properties of Liver Microsomal Monoxygenase System and Epoxide Hydrase: Factors Influencing the Metabolism and Mutagenicity of Benzo(a)pyrene. In: Hiatt HH, Watson JD, Winsten JA, eds. Origins of Human Cancer. New York: Cold Spring Harbor Laboratory 659–682, 1977.Google Scholar
  14. 14.
    Bentley P, Oesch F: Enzymes Involved in Activation and Inactivation of Carcinogens and Mutagens. In: Remmer H, Bolt HM, Bannasch P, Popper H, eds. Primary Liver Tumours. Lancast, MTP Press 239–252, 1978.Google Scholar
  15. 15.
    Schulte-Hermann R: Reactions of the Liver to Injury: Adaptation. In: Farber E, Fisher MM, eds. Toxic Liver Injury. New York: Marcel Dekker 285–444, 1979.Google Scholar
  16. 16.
    Farber E: Toxicological Significance of Liver Hypertrophy Produced by Inducers of Drug-metabolizing Enzymes. In: Environmental Chemicals, Enzyme Function and Human Disease. CIBA Foundation Symposium 76. Amsterdam: Excerpta Medica 261–274, 1980.Google Scholar
  17. 17.
    Environmental Chemicals, Enzyme Function and Human Disease. CIBA Foundation Symposium 76. Amsterdam: Excerpta Medica 1980.Google Scholar
  18. 18.
    McLean AEM, Magee PN: Increased Renal Carcinogenesis by Dimethylnitrosamine in Protein Deficient Rats. Br J Exp Pathol 51: 587–590, 1970.PubMedGoogle Scholar
  19. 19.
    Magee PN, Farber E: Toxic Liver Injury and Carcinogenesis. Methylation of Liver Nucleic Acids by Demylnitrosamine In Vivo. Biochem J 83: 114–124, 1962.PubMedGoogle Scholar
  20. 20.
    Singer B: N-nitrosoalkylating Agents: Formation and Persistence of Alkyl Derivatives in Mammalian Nucleic Acid as Contributing Factors in Carcinogenesis. J Natl Cancer Inst 62: 1329–1339, 1979.PubMedGoogle Scholar
  21. 21.
    Lawley PD: Approaches to Chemical Dosimetry in Mutagenesis and Carcinogenesis: the Relevance of Reactions of Chemical Mutagens and Carcinogens with DNA. In: Grover PL, ed. Chemical Carcinogens and DNA. Boca Raton, Florida: CRC Press 1: 1–36, 1978.Google Scholar
  22. 22.
    Marquardt H: DNA–The Critical Cellular Target in Chemical Carcinogenesis? In: Grover PL, ed. Chemical Carcinogens and DNA. Boca Raton, Florida: CRC Press, 2: 159–179, 1978.Google Scholar
  23. 23.
    Cairns J: The Origin of Human Cancers. Nature 289: 353–357, 1981.PubMedCrossRefGoogle Scholar
  24. 24.
    Takebe H: Genetic Complementation Tests for Japanese Xeroderma Pigmentosum Patients and Their Skin Cancers and DNA Repair Characteristics. In: Magee PN, Takayama S, Sugimura T, Matsushima T, eds. Fundamentals in Cancer Prevention. 7th Int Symp of Princess Takamatsu Cancer Res Fund, Tokyo: Univer Tokyo Press 383–395, 1975.Google Scholar
  25. 25.
    Maher VM, McCormick JJ: DNA Repair and Carcinogenesis. In: Grover PL, ed. Chemical Carcinogens and DNA. Boca Raton, Florida, CRC Press 2: 133–158, 1978.Google Scholar
  26. 26.
    German J, ed: Chromosomes and Cancer. New York: Wiley and Sons, 1974.Google Scholar
  27. 27.
    Goth R, Rajewsky MF: Persistence of 06-ethylguanine in Rat Brain DNA: Correlation with Nervous System Specific Carcinogenesis by Ehtylnitrosourea. Proc Natl Acad Sci. USA 71: 639–643, 1974.PubMedCrossRefGoogle Scholar
  28. 28.
    Magee PN, Swann PF, Mohr U, Resnik G, Green U: Possible Repair of Carcinogenesis by Nitroso Compounds. In: Magee PN, Takayama S, Sugimura T, Matsushima T, eds. Fundamentals in Cancer Prevention. Tokyo: University of Tokyo Press 281–289, 1976.Google Scholar
  29. 29.
    Lewis JG, Swenberg JA: Differential Repair of 06-methylguanine in DNA of Rat Hepatocytes and Non-parenchymal Cells. Nature 288: 185–188, 1980.PubMedCrossRefGoogle Scholar
  30. 30.
    Buechler J, Kleihues P: Excision of 06-methylguanine from DNA of Various Mouse Tissues Following a Single Injection of N-methyl-N-nitrosourea. Chem Biol Interact 16: 325–333, 1977.CrossRefGoogle Scholar
  31. 31.
    Ying TS: Studies on Acute Cell Injury, Cell Replication and DNA Repair during Initiation of Liver Carcinogenesis. Ph.D. Thesis, University of Toronto 1980.Google Scholar
  32. 32.
    Olsson M, Lindahl T: Repair of Alkylated DNA in Escherichia Coli. Methyl Group Transfer from 06-methylguanine to a Protein Cysteine Residue. J. Biol Chem 255: 10569–10571, 1980.PubMedGoogle Scholar
  33. 33.
    Conney AH, Levin W: Carcinogen Metabolism in Experimental Animals and Man. In: Montesano R, Tomatis L, Davis W, eds. Chemical Carcinogenesis Essays. Lyon: Int Agency for Res on Cancer Publ 10 3–22, 1974.Google Scholar
  34. 34.
    Montesano R, Magee PN: Comparative Metabolism In Vitro of Nitrosamines in Various Animal Species including Man. In: Montesano R, Tomatis L, Davis W, eds. Chemical Carcinogenesis Essays. Lyon: Int Agency for Res on Cancer Publ 10 39–56, 1974.Google Scholar
  35. 35.
    Shinohara K, Cerutti P: Formation of Benzo(a)pyrene–DNA adducts in Peripheral Human Lung Tissue. Cancer Lett 3: 303–310, 1977.CrossRefGoogle Scholar
  36. 36.
    Prough RA, Patrizi VW, Okta RT, Masters BSS, Jakobsson SW: Characteristics of Benzo(a)pyrene Metabolism by Kidney, Liver and Lung Microsomal Fractions from Rodents and Humans. Cancer Res 39: 1199–1206, 1979.Google Scholar
  37. 37.
    Autrup H, Schwartz RD, Essigman JM, Smith L, Trump BF, Harris CC: Metabolism of Aflatoxin B1, Benzo(a)pyrene and 1,2-dimethylhydrazine by Cultured Rat and Human Colon. Teratogenesis, Carcinogenesis and Mutagenesis 1: 3–13, 1980.CrossRefGoogle Scholar
  38. 38.
    Autrup H, Jeffery AM, Harris CC: Metabolism of Benzo(a)pyrene in Cultured Human Bronchus, Trachea, Colon and Esophagus. In: Bj$rseth A, Dennis AJ, eds. Polynuclear Aromatic Hydrocarbons. New York: Raven Press 4: 89–105, 1980.Google Scholar
  39. 39.
    Mass MJ, Rodgers NT, Kaufman DG: Benzo(a)pyrene Metabolism in Organ Cultures of Human Endometrium. Chem Biol Int 33: 195–205, 1981.CrossRefGoogle Scholar
  40. 40.
    Hsu IC, Poirier MC, Yuspa SH, Yolken RH, Harris CC: Ultrasensitive-enzymatic Radioimmunoassay (USERIA) Detects Femtomoles of Acetylaminofluroene-DNA adducts. Carcinogenesis 1: 455–458, 1981.CrossRefGoogle Scholar
  41. 41.
    Poirier MC, Dubin MA, Yuspa SH: Formation and Removal of Specific Acetylaminofluorene-DNA adducts in Mouse and Human Cells Measured by Radioimmunoassay. Cancer Res 39: 1377–1381, 1979.PubMedGoogle Scholar
  42. 42.
    Hsu IC, Poirier MC, Yuspa SH, Grunberger D, et al: Measurement of Benzo(a)pyrene-DNA adducts by Enzyme Immunoassays and Radioimmunoassay. Cancer Res 41: 1091–1095, 1981.PubMedGoogle Scholar
  43. 43.
    Cairns J: Mutation, Selection and the Natural History of Cancer. Nature 255: 197–200, 1975.PubMedCrossRefGoogle Scholar
  44. 44.
    Nowell PC: The Clonal Evolution of Tumour Cell Populations. Science 194: 23–28, 1976.PubMedCrossRefGoogle Scholar
  45. 45.
    Burnet FM: Cancer: Somatic-genetic Considerations. Adv Cancer Res 28: 1–29, 1978.PubMedCrossRefGoogle Scholar
  46. 46.
    Cayama E, Tsuda H, Sarma DSR, Farber E: Initiation of Chemical Carcinogenesis Requires Cell Proliferation. Nature 275: 60–62, 1978.PubMedCrossRefGoogle Scholar
  47. 47.
    Tsuda H, Lee G, Farber E. Induction of Resistant Hepatocytes as a New Principle for a Possible Short-term In Vivo Test for Carcinogens. Cancer Res 40: 1157–1164, 1980.PubMedGoogle Scholar
  48. 48.
    Emmelot P, Scherer E: The First Relevant Cell Stage in Rat Liver Carcinogenesis. A Quantitative approach. Biochem Biophys Acta 605: 247–304, 1980.PubMedGoogle Scholar
  49. 49.
    Craddock, VM: Cell Proliferation and Experimental Liver Cancer. In: Cameron HM, Linsell DA, Warwick GP, eds. Liver Cell Cancer. Amsterdam: Elservier-North Holland Blomed Press 153–201, 1976.Google Scholar
  50. 50.
    Borek C.Sachs L: In Vitro Cell Transformation by X-irradiation. Nature 210: 276–278, 1966.CrossRefGoogle Scholar
  51. 51.
    Tooze J: The Molecular Biology of Tumour Viruses. New York: Cold Spring Harbour Laboratory, 1973.Google Scholar
  52. 52.
    Kakunaga T: Requirement for Cell Replication in the Fixation and Expression of the Transformed State in Mouse Cells treated with 4-nitro-quinolin-l-oxide. Int J Cancer 14: 736–42, 1974.PubMedCrossRefGoogle Scholar
  53. 53.
    Ying TS, Sarma DSR, Farber E: Role of Acture Hepatic Necrosis in the Induction of Early Steps in Liver Carcinogenesis by Diethylnitrosamine. Cancer Res 41: 2096–2101, 1981.PubMedGoogle Scholar
  54. 54.
    Columbano A, Rajalakshmi S, Sarma DSR: Requirement of Cell Proliferation for the Initiation of Liver Carcinogenesis as Assayed by Three Different Procedures. Cancer Res 41: 2079–2083, 1981.PubMedGoogle Scholar
  55. 55.
    Stutman 0: Immunodepression and Malignancy. Adv Cancer Res 22: 261–422, 1975.CrossRefGoogle Scholar
  56. 56.
    Thomas L: Discussion. In: Lawrence HS, ed. Cellular and Humoral Aspects of Hypersensitivity. New York: Harper and Row 529: 532, 1959.Google Scholar
  57. 57.
    Rice JM. ed. Perinatal Carcinogenesis. Natl Cancer Inst Monograph 51, 1979.Google Scholar
  58. 58.
    Neubert D, Merker H-J, Nau H, Langman J, eds. Role of Pharmacokinetics in Pernatal and Perinatal Toxicology. Stuttgart: G. Thieme Publ, 1978.Google Scholar
  59. 59.
    Pelkonen 0: Environmental Influences on Human Foetal and Placental Xenobiotic Metabolism. Eur J Clin Pharmacol 18: 17–24, 1980.CrossRefGoogle Scholar
  60. 60.
    Berenblum I: Speculative Review: Probable Nature of Promoting Action and its Significance in Understanding of Mechanism of Carcinogenesis. Cancer Res 14: 471–477, 1954.PubMedGoogle Scholar
  61. 61.
    Lipkin M, Deschner E: Early Proliferative Chances in Intestinal Cells. Cancer Res 36: 2665–2668, 1976.PubMedGoogle Scholar
  62. 62.
    Pitot HC, Sirica AE: The Stages of Initiation and Promotion in Hepatocarcinogenesis. Biochem Biophys Acta 605: 191–215, 1980.PubMedGoogle Scholar
  63. 63.
    Farber E: The Sequential Analysis of Liver Cancer Induction.Biochem Biophys Acta 605: 149–166, 1980.Google Scholar
  64. 64.
    Ohde G, Schuppler J, Schulte-Hermann R, Keiger H: Proliferation of Rat Liver Cells in Perneoplastic Nodules after Stimulation of Liver Growth by Xenobiotic Inducers. Arch Toxicol Suppl 2 451–455, 1979.PubMedCrossRefGoogle Scholar
  65. 65.
    Farber E: Sequential Events in Chemical Carcinogenesis. In: Becker FF, ed. Cancer: A Comprehensive Treatise. 2nd Edition. New York: Plenum Press Corp, in press, 1981.Google Scholar
  66. 66.
    Boutwell RK: Some Biological Aspects of Skin Carcinogenesis. Prog Exp Tumour Res 4: 207–250, 1964.Google Scholar
  67. 67.
    Boutwell RK: The Function and Mechanism of Promoters of Carcinogenesis. CRC Crit Rev Toxicol 2: 419–443, 1974.PubMedCrossRefGoogle Scholar
  68. 68.
    Peraino C, Fry RJM, Grube DD: Drug-induced Enhancement of Hepatic Tumourigenesis. In: Slaga TJ, Sivak A, Boutwell RK, eds. Carcinogenesis: Mechanisms of Tumour Promotion and Cocarcinogenesis. Raven Press, New York 2: 421–432, 1978.Google Scholar
  69. 69.
    Pitot HC, Barsness L, Kitagawa T: Stages in the Process of Hepatocarcinogenesis in Rat Liver. In: Slaga TJ, Sivak A, Boutwell RK, eds. Carcinogenesis: Mechanisms of Tumour Promotion and Carcinogenesis, Raven Press, New York 2: 433–442, 1978.Google Scholar
  70. 70.
    Scherer E, Emmelot P: Kinetics of Induction and Growth of Enzyme-deficient Islands Involved in Hepatocarcinogenesis. Cancer Res 36: 2544–25, 1976.PubMedGoogle Scholar
  71. 71.
    Solt DB, Farber E: A New Principle for the Analysis of Chemical Carcinogenesis. Nature 263: 701–703, 1976.CrossRefGoogle Scholar
  72. 72.
    Solt DB, Medline A. Farber E: Rapid Emergence of Carcinogen-induced Hyperplastic Lesions in a New Model for the Sequential Analysis of Liver Carcinogenesis. Am J Pathol 88: 595–618, 1977.PubMedGoogle Scholar
  73. 73.
    Heidelberger C: Mammalian Cell Transformation and Mammalian Cell Mutagenesis In Vitro. J Environmental Pathol Toxicol 3: 69–87, 1980.Google Scholar
  74. 74.
    Reddy JK, Azarnoff DL, Hignite CE: Hypolipidaemic Hepatic Peroxisome Proliferators Form a Novel Class of Chemical Carcinogens. Nature 283: 397–398, 1980.PubMedCrossRefGoogle Scholar
  75. 75.
    Rinkus SJ, Legator MS: Chemical Characterization of 465 Known or Suspected Carcinogens and Their Correlation with Mutagenic Activity in the Salmonella Typhimurium System. Cancer Res 39: 3289–3318, 1979.PubMedGoogle Scholar
  76. 76.
    Lijinsky W, Reuber MD, Blackwell BN: Liver Tumours Induced in Rats by Oral Administration of the Antihistaminic Methapyrilene Hydrochloride. Science: 209: 817–819, 1980.PubMedCrossRefGoogle Scholar
  77. 77.
    Scherer E, Hoffmann M: Probable Clonal Genesis of Cellular Islands Induced in Rat Liver by Diethylnitrosamine. Eur J Cancer 7: 369–371, 1971.PubMedCrossRefGoogle Scholar
  78. 78.
    Iannaconne PM, Gardner RL, Harris H: The Cellular Origin of Chemi-ally Induced Tumour. J Cell Sci 29: 249–269, 1978.Google Scholar
  79. 79.
    Kennedy AR, Fox M, Murphy G, Little JB: Relationship Between X-ray Exposure and Malignant Transformation in C3H10T1/2 cells. Proc Natl Acad Sci USA 77: 7262–7266, 1980.PubMedCrossRefGoogle Scholar
  80. 80.
    Mondal S, Heidelberger C: In Vitro Malignant Transformation by Methylcholanthrene of the Progeny of Single Cells Derived from C3H Mouse Prostate. Proc Natl Acad Sci 65: 219–225, 1970.PubMedCrossRefGoogle Scholar
  81. 81.
    German J: Carriers in Chromosome-breakage Syndromes. Proc 6th Int Congress Radiation Res: 496–505, 1979.Google Scholar
  82. 82.
    Prehn RT: Tumor progression and homeostasis. Adv Cancer Res 23: 203–236, 1976.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1982

Authors and Affiliations

  • Emmanuel Farber
    • 1
  1. 1.Department of Pathology and BiochemistryUniversity of TorontoTorontoUSA

Personalised recommendations