Chemically and Metabolically Induced DNA Adducts: Relationship to Chemical Carcinogenesis

  • Charles Heidelberger


It is clearly impossible within the assigned scope to give a complete literature review and overview of this enormous field. Therefore, it is inevitable that this chapter will reflect my own biases, interests, and research. In the literature citations, emphasis will be placed on reviews, but important original papers will be covered.


Polycyclic Aromatic Hydrocarbon Mouse Skin Chemical Carcinogen 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. Abell, C.W., and Heidelberger, C., 1962, The interaction of carcino genic hydrocarbons with tissues. VIII. Binding of tritium labeled hydrocarbons to the soluble proteins of mouse skin,Cancer Res. 22: 931–946.Google Scholar
  2. Ames, B.N., Durston, W.E., Yamasaki, E., and Lee, F.D., 1973, Car cinogens are mutagens: A simple test system combining liver homogenates for activation and bacteria for detection, Proc. Nat. Acad. Sci. USA 70: 2281–2285.Google Scholar
  3. Ames, B.N., Sims, P., and Grover, P.L., 1972, Epoxides of carcino genic polycyclic hydrocarbons are frameshift mutagens,Science 176: 47–49.PubMedCrossRefGoogle Scholar
  4. Andoh, T., Ide, T., Saito, M., and Kawazoe, Y., 1975, Breakage of a DNA-protein complex induced by 4-nitroquinoline 1-oxide, 4-nitropyridine 1-oxide, and their derivatives in cultured mouse fibroblasts, Cancer Res. 35: 521–527.PubMedGoogle Scholar
  5. Baird, W.M., and Brookes, P., 1973, Isolation of the hydrocarbon deoxyribonucleoside products from the DNA of mouse embryo cells treated in culture with 7-methylbenz[a]anthracene, Cancer Res. 33: 2378–2385.PubMedGoogle Scholar
  6. Baird, W.M., Dipple, A., Grover, P.L., Sims, P., and Brookes, P., 1973, Studies on the formation of hydrocarbon deoxyribonucleo side products by the binding of derivatives of 7-methylbenz [a]anthracene to DNA in aqueous solution and in mouse embryo cells in culture, Cancer Res. 33: 2386–2392.PubMedGoogle Scholar
  7. Baird, W.M., Harvey, R.G., and Brookes, P., 1975, Comparison of the cellular DNA-bound product of benzo[a]pyrene with the products formed by the reaction of benzo[a]pyrene-4,5-oxide with DNA, Cancer Res. 35: 54–57.PubMedGoogle Scholar
  8. Bartsch, H., Malaveille, C., and Montesano, R., 1975, In vitro meta bolism and microsome-mediated mutagenicity of dialkylnitros amines in rat, hamster, and mouse tissues, Cancer Res. 35: 644 651.Google Scholar
  9. Bertram, J.S., and Heidelberger, C., 1974, Cell cycle dependency of oncogenic transformation induced by N-methyl-N’-nitro-N nitrosoguanidine in culture, Cancer Res. 34: 526–537.PubMedGoogle Scholar
  10. Berwald, Y., and Sachs, L., 1965, In vitro transformation of normal cells into tumor cells by carcinogenic hydrocarbons, J. Nat. Cancer Inst. 35: 641–661.Google Scholar
  11. Blackburn, G.M., Flavell, A.J., and Thompson, M.H., 1974, Oxidative and photochemical linkage of diethylstilbestrol to DNA in vitro, Cancer Res. 34: 2015–2019.PubMedGoogle Scholar
  12. Bowden, G.T., Shapas, B.G., and Boutwell, R.K., 1974a, The binding of 7,12-dimethylbenz[a]anthracene to replicating and non-replicating DNA in mouse skin, Chem.-Biol. Interactions 8: 379–394.Google Scholar
  13. Bowden, G.T., Slaga, T.J., Shapas, B.G., and Boutwell, R.K., 1974b, The role of aryl hydrocarbon hydroxylase in skin tumor initia tion by 7,12-dimethylbenz[a]anthracene and 1,2,5,6-dibenz anthracene using DNA binding and thymidine-3H incorporation into DNA as criteria, Cancer Res. 34: 2634–2642.PubMedGoogle Scholar
  14. Boyland, E., 1950, The biological significance of metabolism of polycyclic compounds, Symp. Biochem. Soc. 5: 40–54.Google Scholar
  15. Brookes, P., 1966, Quantitative aspects of the reaction of some carcinogens with nucleic acids and the possible significance of such reactions in the process of carcinogenesis, Cancer Res. 26: 1994–2003.PubMedGoogle Scholar
  16. Brookes, P., 1975, Covalent interaction of carcinogens with DNA, Life Sciences16: 331–344.PubMedCrossRefGoogle Scholar
  17. Brookes, P., and Duncan, M.E., 1971, Carcinogenic hydrocarbons and human cells in culture, Nature 234: 40–43.PubMedCrossRefGoogle Scholar
  18. Brookes, P., and Heidelberger, C., 1969, Isolation and degradation of DNA from cells treated with tritium-labeled 7,12-dimethyl benz[a]anthracene: studies on the nature of the binding of this carcinogen to DNA, Cancer Res. 29: 157–165.PubMedGoogle Scholar
  19. Brookes, P., and Lawley, P.D., 1964, Evidence for the binding of polynuclear aromatic hydrocarbons to the nucleic acids of mouse skin: relation between carcinogenic power of hydro carbons and their binding to deoxyribonucleic acid, Nature202: 781–784.PubMedCrossRefGoogle Scholar
  20. Casto, B.C., and DiPaolo, J.A., 1973, Virus, chemicals and cancer, Prog. Med. ViroZ. 16: 1–47.Google Scholar
  21. Cavaliere, E., and Auerbach, R., 1974, Reactions between activated benzo[a]pyrene and nucleophilic compounds, with possible implications on the mechanism of tumor initiation, J. Nat. Cancer Inst. 53: 393–397.Google Scholar
  22. Chen, T.T., and Heidelberger, C., 1969, Quantitative studies on the malignant transformation of mouse prostate cells by carcino genic hydrocarbons in vitro, Int. J. Cancer4: 166–178.Google Scholar
  23. Cleaver, J.E., 1968, Defective repair replication of DNA in Xeroderma pigmentosum, Nature 218: 652–656.PubMedCrossRefGoogle Scholar
  24. Cleaver, J.E., 1974, Repair processes for photochemical damage in mammalian cells, Adv. Radiat. Biol. 4: 1–75.Google Scholar
  25. Colburn, N.H., and Boutwell, R.K., 1968, The binding of ß-propio lactone to mouse skin DNA, RNA, and protein, Cancer Res. 28: 653–660.Google Scholar
  26. Colburn, N.H., Richardson, R.G., and Boutwell, R.K., 1965, Studies of the reaction of ß-propiolactone with deoxyguanosine and related compounds, Biochem.Pharmaco2. 14: 1113–1118.Google Scholar
  27. Coombs, M.M., Bhatt, T.S., and Vose, C.W., 1975, The relationship between metabolism, DNA binding, and carcinogenicity of 15, 16-dihydro-11-methylcyclopenta[a]phenanthrene-17-one in the presence of a microsomal enzyme inhibitor, Cancer Res. 35: 305–309.Google Scholar
  28. Corbett, T.H., Heidelberger, C., and Dove, W.F., 1970, Determination of the mutagenic activity to bacteriophage T4 of carcinogenic and noncarcinogenic compounds, MolPharmacol. 6: 667–679.Google Scholar
  29. Craddock, V.M., 1973, The pattern of methylated purines formed in DNA of intact and regenerating liver of rats treated with the carcinogen dimethylnitrosamine, Biochim. Biophys. Acta 312: 202–210.Google Scholar
  30. Daudel, P., Croisy-Delcey, M., Alonso-Verduras, C., Duquesne, M., Jacquignon, P., Markovits, P., and Vigny, P., 1974, Etude par fluorescence d’acides nucléiques extraits de cellules en cultures traitées par le méthylbenzo[a]anthracène, C.R. Acad. Sci. Paris278: 2249–2252.Google Scholar
  31. Daudel, P., Croisy-Delcey, M., Jacquignon, P., and Vigny, P., 1973, Sur la structure d’un complexe résultant de l’action d’un époxyde aromatique polycyclique sur un acid désoxyribo nucléique, C.R. Acad. Sci. Paris277: 2437–2439.Google Scholar
  32. DiPaolo, J.A., Donovan, P., and Nelson, R.L., 1969, Quantitative studies of in vitro transformation by chemical carcinogens, J. Nat. Cancer Inst. 42: 867–874.Google Scholar
  33. DiPaolo, J.A., Takano, K., and Popescu, N., 1972, Quantitation of chemically induced neoplastic transformation of BALB 3T3 cell lines, Cancer Res. 32: 2686–2695.PubMedGoogle Scholar
  34. Dipple, A., Lawley, P.D., and Brookes, P., 1968, Theory of tumour initiation by chemical carcinogens: dependence on structure of ultimate carcinogen, Europ. J. Cancer4: 493–506.Google Scholar
  35. Duncan, M.E., and Brookes, P., 1970, The relation of metabolism to macromolecular binding of the carcinogen benzo[a]pyrene by mouse embryo cells in culture, Int. J. Cancer 6: 496–505.Google Scholar
  36. Duncan, M.E., and Brookes, P., 1972, Metabolism and macromolecular binding of dibenz[a,c]anthracene and dibenz[a,h]anthracene by mouse embryo cells in culture, Int. J. Cancer 9: 349–352.Google Scholar
  37. Duncan, M., Brookes, P., and Dipple, A., 1969, Metabolism and bind ing to cellular macromolecules of a series of hydrocarbons by mouse embryo cells in culture, Int. J. Cancer 4: 813–819.Google Scholar
  38. Durston, W.E., and Ames, B.N., 1974, A simple method for the detec tion of mutagens in urine: studies with the carcinogen 2 acetylaminofluorene, Proc. Nat. Acad. Sci. USA 71: 737–741.Google Scholar
  39. Flesher, J.W., and Sydnor, K.L., 1973, Possible role of 6-hydroxy methylbenzo[a]pyrene as a proximate carcinogen of benzo[a] pyrene and 6-methylbenzo[a]pyrene, Int. J. Cancer 11: 433–437.Google Scholar
  40. Freeman, A.E., Weisburger, E.K., Weisburger, J.H., Wolford, R.G., Maryak, J.M., and Huebner, R.J., 1973, Transformation of cell cultures as an indication of the carcinogenic potential of chemicals, J. Nat. Cancer Inst. 51: 799–808.Google Scholar
  41. Fried, J., 1974, One-electron oxidation of polycyclic aromatics as a model for the metabolic activation of carcinogenic hydro carbons, in “Chemical Carcinogenesis” (P.O.P. Ts’o and J.A. DiPaolo, eds.), Part A, pp. 197–215, Marcel Dekker, New York.Google Scholar
  42. Fuchs, R., and Daune, M., 1972, Physical studies on deoxyribonucleic acid after covalent binding of a carcinogen, Biochemistry 11: 2659–2666.PubMedCrossRefGoogle Scholar
  43. Fujimura, S., Grunberger, D., Carvajal, G., and Weinstein, I.B., 1972, Modifications of ribonucleic acid by chemical carcino gens. Modification of E. coli formylmethionine transfer ribo nucleic acid with N-acetoxy-2-acetylaminofluorene, Biochemistry11: 3629–3635.CrossRefGoogle Scholar
  44. Gelboin, H.V., 1969, A microsome-dependent binding of benzo[a]pyrene to DNA, Cancer Res. 29: 1272–1276.PubMedGoogle Scholar
  45. Glazer, R.I., Glass, L.E., and Menger, F.M., 1975, Modification of hepatic ribonucleic acid polymerase activities by N-hydroxy 2-acetylaminofluorene and N-acetoxy-2-acetylaminofluorene, Mol. Pharmacol. 11: 36–43.Google Scholar
  46. Goshman, L.M., and Heidelberger, C., 1967, Binding of tritium labeled polycyclic hydrocarbons to DNA of mouse skin, Cancer Res. 27: 1678–1688.PubMedGoogle Scholar
  47. Goth, R., and Rajewsky, M.F., 1972, Ethylation of nucleic acids by ethylnitrosourea-1–14C in the fetal and adult rat, Cancer Res. 32: 1501–1505.PubMedGoogle Scholar
  48. Goth, R., and Rajewsky, M.F., 1974, Persistence of 06-ethylguanine in rat-brain DNA: correlation with nervous system-specific carcinogenesis by ethylnitrosourea, Proc. Nat. Acad. Sci. USA 71: 639–643.Google Scholar
  49. Grover, P.L., Forrester, J.A., and Sims, P., 1971a, Reactivity of the K-region epoxides of some polycyclic hydrocarbons towards the nucleic acids and protein of BHK21 cells, Biochem. Pharmacol. 20: 1297–1302.Google Scholar
  50. Grover, P.L., Hewer, A., and Sims, P., 1972, The formation of K-region epoxides as microsomal metabolites of pyrene and benzo [a]pyrene, Biochem. Pharmacol. 21: 2713–2726.Google Scholar
  51. Grover, P.L., and Sims, P., 1968, Enzyme-catalysed reactions of polycyclic hydrocarbons with deoxyribonucleic acid and protein in vitro, Biochem. J. 110: 159–160.Google Scholar
  52. Grover, P.L., and Sims, P., 1970, Interactions of the K-region epoxides of phenanthrene and dibenz[a,h]anthracene with nucleic acids and histone, Biochem. Pharmacol. 19: 2251–2259.Google Scholar
  53. Grover, P.L., Sims, P., Huberman, E., Marquardt, H., Kuroki, T., and Heidelberger, C., 1971b, In vitro transformation of rodent cells by K-region derivatives of polycyclic hydrocarbons, Proc. Nat. Acad. Sci. USA 68: 1098–1101.Google Scholar
  54. Grunberger, D., and Weinstein, I.B., 1971, Modifications of ribo nucleic acid by chemical carcinogens. III. Template activity of polynucleotides modified by N-acetoxy-2-acetylaminofluorene, J. Biol. Chem. 246: 1123–1128.Google Scholar
  55. Heidelberger, C., 1970a, Studies on the cellular and molecular mech anisms of hydrocarbon carcinogenesis, Europ. J. Cancer 6: 161 172.Google Scholar
  56. Heidelberger, C., 1970b, Chemical carcinogenesis, chemotherapy: cancer’s continuing core challenges. G.H.A. Clowes Memorial Lecture, Cancer Res. 30: 1549–1569.Google Scholar
  57. Heidelberger, C., 1972, In vitro studies on the role of epoxides in carcinogenic hydrocarbon activation, in “Topics in Chemi cal Carcinogenesis” (W. Nakahara, S. Takayama, T. Sugimura, and S. Odashima, eds.), pp. 371–386, discussion, pp. 387–388, University of Tokyo Press, Tokyo, Japan.Google Scholar
  58. Heidelberger, C., 1973a, Current trends in chemical carcinogenesis,Fed. Proc. 32: 2154–2161.Google Scholar
  59. Heidelberger, C., 1973b, Chemical oncogenesis in culture, Adv. Cancer Res. 18: 317–366.Google Scholar
  60. Heidelberger, C., 1974, Cell culture studies on the mechanisms of hydrocarbon oncogenesis, in “Chemical Carcinogenesis” (P.O.P. Ts’o and J.A. DiPaolo, eds.), Part B, pp. 457–462, Marcel Dekker, New York.Google Scholar
  61. Heidelberger, C., 1975, Chemical carcinogenesis, Annu. Rev. Biochem. 44: 79–121.Google Scholar
  62. Heidelberger, C., and Davenport, G.R., 1961, Local functional com ponents of carcinogenesis, Acta Unio Internat. Contra Cancrum 17: 55–63.Google Scholar
  63. Huberman, E., Aspiras, L., Heidelberger, C., Grover, P.L., and Sims, P., 1971a, Mutagenicity to mammalian cells of epoxides and other derivatives of polycyclic hydrocarbons, Proc. Nat. Acad. Sci. USA 68: 3195–3199.Google Scholar
  64. Huberman, E., Kuroki, T., Marquardt, H., Selkirk, J.K., Heidelber ger, C., Grover, P.L., and Sims, P., 1972, Transformation of hamster embryo cells by epoxides and other derivatives of poly-cyclic hydrocarbons, Cancer Res. 32: 1391–1396.PubMedGoogle Scholar
  65. Huberman, E., and Sachs, L., 1974, Cell-mediated mutagenesis of mammalian cells with chemical carcinogens, Int. J. Cancer 13: 326–333.Google Scholar
  66. Huberman, E., Selkirk, J.K., and Heidelberger, C., 1971b, Metabolism of polycyclic aromatic hydrocarbons in cell cultures, Cancer Res. 31: 2161–2167.PubMedGoogle Scholar
  67. Irving, C., 1973, Interaction of chemical carcinogens with DNA, Methods Cancer Res. 7: 189–244.Google Scholar
  68. Jerina, D.M., and Daly, J.W., 1974, Arene oxides: a new aspect of drug metabolism, Science 185: 573–582.PubMedCrossRefGoogle Scholar
  69. Jerina, D.M., Daly, J.W., Witkop, B., Zaltman-Nirenberg, P., and Udenfriend, S., 1970, 1,2-Naphthalene oxide as an intermediate in the microsomal hydroxylation of naphthalene, Biochemistry9: 147–155.Google Scholar
  70. Jones, P.A., Gevers, W., and Hawtrey, A.O., 1973, Evidence for the binding of the carcinogen 3-methylcholanthrene to both the purine and the pyrimidine bases of hamster fibroblast deoxyri bonucleic acid, Biochem. J. 135: 375–378.Google Scholar
  71. Kakunaga, T., 1973, A quantitative system for assay of malignant transformation by chemical carcinogens using a clone derived from BALB/3T3, Int. J. Cancer 12: 463–473.Google Scholar
  72. Kellermann, G., Luyten-Kellermann, M., and Shaw, C.R., 1973a, Genetic variation of aryl hydrocarbon hydroxylase in human lymphocytes,Am. J. Human Genet. 25: 327–331.Google Scholar
  73. Kellermann, G., Shaw, C.R., and Luyten-Kellermann, M., 1973b, Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcino ma, New England J. Med. 289: 934–937.Google Scholar
  74. Kier, L.D., Yamasaki, E., and Ames, B.N., 1974, Detection of muta-genic activity in cigarette smoke condensates, Proc. Nat. Acad. Sci. USA 71: 4159–4163.Google Scholar
  75. Kinoshita, N., and Gelboin, H.V., 1972, Aryl hydrocarbon hydroxy lase and polycyclic hydrocarbon tumorigenesis: effect of the enzyme inhibitor 7,8-benzoflavone on tumorigenesis and macromolecule binding, Proc. Nat. Acad. Sci. USA 69: 824–828.Google Scholar
  76. Krahn, D.F., and Heidelberger, C., 1975, Microsome-mediated muta-genesis in Chinese hamster cells by chemical oncogens, Proc. Am. Assoc. Cancer Res. 16: 74.Google Scholar
  77. Kriek, E., 1974, Carcinogenesis by aromatic amines, Biochim. Biophys. Acta355: 177–203.Google Scholar
  78. Krüger, F.W., 1972, New aspects in metabolism of carcinogenic nitrosamines, in “Topics in Chemical Carcinogenesis” (W.Google Scholar
  79. Nakahara, S. Takayama, T. Sugimura, and S. Odashima, eds.), pp. 213–232, University of Tokyo Press, Tokyo, Japan.Google Scholar
  80. Kubinski, H., and Szybalski, E.H., 1975, Intermolecular linking and fragmentation of DNA by ß-propiolactone, a monoalkylating carcinogen, Chem.-Biol. Interactions10: 41–55.Google Scholar
  81. Kuroki, T., and Heidelberger, C., 1971, The binding of polycyclic aromatic hydrocarbons to the DNA, RNA, and proteins of trans formable cells in culture, Cancer Res. 31: 2168–2176.Google Scholar
  82. Kuroki, T., Huberman, E., Marquardt, H., Selkirk, J.K., Heidelber ger, C., Grover, P.L., and Sims, P., 1971/1972, Binding of K region epoxides and other derivatives of benz[a]anthracene and dibenz[a,h]anthracene to DNA, RNA, and proteins of trans formable cells, Chem.-Biol. Interactions4: 389–397.Google Scholar
  83. Lawley, P.D., 1966, Effects of some chemical mutagens and carcino gens on nucleic acids, Progr. Nucleic AcidRes. Mol. Biol. 5: 89–131.Google Scholar
  84. Lawley, P.D., 1972, The action of alkylating mutagens and carcino gens on nucleic acids: N-methyl-N-nitroso compounds as methylating agents, in “Topics in Chemical Carcinogenesis” ( W. Nakahara, S. Takayama, T. Sugimura, and S. Odashima, eds.), pp. 237–256, University of Tokyo Press, Tokyo, Japan.Google Scholar
  85. Lawley, P.D., 1973, Reaction of N-methyl-N-nitrosourea (MNUA) with 32P-labelled DNA: evidence for formation of phosphotriesters, Chem.-Biol. Interactions7: 127–130.Google Scholar
  86. Lawley, P.D., and Shah, S., 1972, Methylation of RNA by the carcino gens, dimethyl sulphate, N-methyl-N-nitrosourea, or N-methyl N’-nitro-N-nitrosoguanidine: Comparisons of analyses at the base and nucleoside levels, Biochem. J. 128: 117–132.Google Scholar
  87. Lawley, P.D., and Shah, S.A., 1973, Methylation of DNA by 3H–14C methyl-labelled N-methyl-N-nitrosourea - evidence for transfer of the intact methyl group, Chem.-BioZ. Interactions7: 115–120.Google Scholar
  88. Lawley, P.D., and Thatcher, C.J., 1970, Methylation of deoxyribo nucleic acids in cultured mammalian cells by N-methyl-N’-nitro N-nitrosoguanidine, Biochem. J. 116: 693–707.Google Scholar
  89. Lesko, S.A., Hoffman, H.D., Ts’o, P.O.P., and Maher, V.M., 1971, Interaction and linkage of polycyclic hydrocarbons to nucleic acids, Progr. Mol. Subcell. BioZ. 2: 347–370.Google Scholar
  90. Levine, A.F., Fink, L.M., Weinstein, I.B., and Grunberger, D., 1974, Effect of N-2-acetylaminofluorene modification on the conformation of nucleic acids, Cancer Res. 34: 319–327.PubMedGoogle Scholar
  91. Lijinsky, W., Loo, J., and Ross, A.E., 1968, Mechanism of alkyla tion of nucleic acids by nitrosodimethylamine, Nature 218: 1174–1175.PubMedCrossRefGoogle Scholar
  92. Lin, J.-K., Miller, J.A., and Miller, E.C., 1975a, Structures of hepatic nucleic acid-bound dyes in rats given the carcinogen N-methyl-4-aminoazobenzene, Cancer Res. 35: 844–850.PubMedGoogle Scholar
  93. Lin, J.-K., Schmall, B., Sharpe, I.D., Miura, I., Miller, J.A., and Miller, E.C., 1975b, N-Substitution of carbon 8 in guanosine and deoxyguanosine by the carcinogen N-benzyloxy-N-methyl-4 aminoazobenzene in vitro, Cancer Res. 35: 832–843.PubMedGoogle Scholar
  94. Loveless, A., 1969, Possible relevance of 0–6 alkylation of deoxy guanosine to mutagenicity and carcinogenicity of nitrosamines and nitrosamides, Nature223: 206–207.PubMedCrossRefGoogle Scholar
  95. Magee, P.N., and Barnes, J.M., 1967, Carcinogenic nitroso compounds, Adv. Cancer Res. 10: 163–246.Google Scholar
  96. Maher, V.M., Miller, E.C., Miller, J.A., and Szybalski, W., 1968, Mutations and decreases in density of transforming DNA pro duced by derivatives of the carcinogens 2-acetylaminofluorene and N-methyl-4-aminoazobenzene, Mol. Pharmacol. 4: 411–426.Google Scholar
  97. Marquardt, H., and Heidelberger, C., 1972, Influence of “feeder cells” and inducers and inhibitors of microsomal mixed-func tion oxidases on hydrocarbon-induced malignant transformation of cells derived from C3H mouse prostate, Cancer Res. 32: 721 725.Google Scholar
  98. Marquardt, H., Kuroki, T., Huberman, E., Selkirk, J.K., Heidelber ger, C., Grover, P.L., and Sims, P., 1972, Malignant trans formation of cells derived from mouse prostate by epoxides and other derivatives of polycyclic hydrocarbons, Cancer Res. 32: 716–720.PubMedGoogle Scholar
  99. Marquardt, H., Sodergren, J.E., Sims, P., and Grover, P.L., 1974, Malignant transformation in vitro of mouse fibroblasts by 7,12 dimethylbenz[a]anthracene and 7-hydroxymethylbenz[a]anthracene and by their K-region derivatives, Int. J. Cancer 13: 304–310.Google Scholar
  100. Miller, E.C., 1951, Studies on the formation of protein-bound deri vatives of 3,4-benzpyrene in the epidermal fraction of mouse skin, Cancer Res. 11: 100–108.PubMedGoogle Scholar
  101. Miller, E.C., and Miller, J.A., 1947, The presence and significance of bound aminoazo dyes in the livers of rats fed p-dimethyl aminoazobenzene, Cancer Res. 7: 468–480.Google Scholar
  102. Miller, E.C., and Miller, J.A., 1966, Mechanisms of chemical car cinogens: nature of proximate carcinogens and interactions with macromolecules, Pharmacol. Rev. 18: 806–838.Google Scholar
  103. Miller, E.C., and Miller, J.A., 1971, The mutagenicity of chemical carcinogens: correlations, problems, and interpretations, in “Chemical Mutagens: Principles and Methods for their Detec tion” (A. Hollaender, ed.), Vol. 1, pp. 83–119, Plenum Press, New York.Google Scholar
  104. Miller, E.C., and Miller, J.A., 1974, Biochemical mechanisms of chemical carcinogenesis, in “The Molecular Biology of Cancer” (H. Busch, ed.), pp. 377–402, Academic Press, New York.Google Scholar
  105. Miller, J.A., 1970, Carcinogenesis by chemicals: an overview. G.H.A. Clowes Memorial Lecture, Cancer Res. 30: 559–576.Google Scholar
  106. Miller, J.A., and Miller, E.C., 1967, The metabolic activation of carcinogenic aromatic amines and amides, Progr. Exp. Tumor Res. 11: 273–301.Google Scholar
  107. Millette, B.L., and Fink, L.M., 1975, The effect of modification of T7 DNA by the carcinogen N-2-acetylaminofluorene: Termina tion of transcription in vitro, Biochemistry14: 1426–1432.Google Scholar
  108. Mirvish, S.S., 1972, Studies on N-nitrosation reactions: Kinetics of nitrosation, correlation with mouse feeding experimentsGoogle Scholar
  109. and natural occurrence of nitrosable compounds (ureides and guanidines), in “Topics in Chemical Carcinogenesis” (W. Nakahara, S. Takayama, T. Sugimura, and S. Odashima, eds.), pp. 279–294, University of Tokyo Press, Tokyo, Japan.Google Scholar
  110. Nagata, C., Inomata, M., Kodama, M., and Tagashira, Y., 1968, Elec tron spin resonance study on the interaction between chemical carcinogens and tissue components. III. Determination of the structure of the free radical produced either by stirring 3,4 benzopyrene with albumin or incubating it with liver homogenates, Gann59: 289–298.PubMedGoogle Scholar
  111. Nagata, C., Tagashira, Y., and Kodama, M., 1974, Metabolic activa tion of benzo[a]pyrene: significance of the free radical, in “Chemical Carcinogenesis” (P.O.P. Ts’o and J.A. DiPaolo, eds.), Part A, pp. 87–111, Marcel Dekker, New York.Google Scholar
  112. Nebert, D.W., and Gielen, J.W., 1972, Genetic regulation of aryl hydrocarbon hydroxylase induction in the mouse, Fed. Proc. 31: 1315–1325.Google Scholar
  113. Nelson, J.H., Grunberger, D., Cantor, C.R., and Weinstein, I.B., 1971, Modification of ribonucleic acid by chemical carcinogens.Google Scholar
  114. NCircular dichroism and proton magnetic resonance studies of oligonucleotides modified with N-2-acetylaminofluorene, J. Mol. Biol. 62: 331–346.Google Scholar
  115. Newman, M.S., and Olson, D.R., 1974, A new hypothesis concerning the reactive species in carcinogenesis by 7,12-dimethylbenz [a]anthracene. The 5-hydroxy, 7,12-dimethylbenz[a]anthracene 7,12-dimethylbenz[a]anthracene-5(6H)-one equilibrium, J. Am. Chem. Soc. 96: 6207–6208.Google Scholar
  116. Nietert, W.C., Kellicutt, L.M., and Kubinski, H., 1974, DNA-protein complexes produced by a carcinogen, ß-propiolactone, Cancer Res. 34: 859–864.PubMedGoogle Scholar
  117. NConnor, P.J., Capps, M.J., and Craig, A.W., 1973, Comparative studies of the hepatocarcinogen N-N-dimethylnitrosamine in vivo: reaction sites in rat liver DNA and the significance of their relative stabilities, Brit. J. Cancer 27: 153–166.Google Scholar
  118. Oesch, F., 1973, Mammalian epoxide hydrases: Inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds, Xenobiotica3: 305–340.Google Scholar
  119. Pegg, A.E., 1973, Alkylation of transfer RNA by N-methyl-N-nitro sourea and N-ethyl-N-nitrosourea, Chem.-BioZ. Interactions 6: 393–406.Google Scholar
  120. Peterson, A.R., Bertram, J.S., and Heidelberger, C., 1974a, DNA damage and its repair in transformable mouse fibroblasts treated with N-methyl-N’-nitro-N-nitrosoguanidine, Cancer Res. 34: 1592–1599.PubMedGoogle Scholar
  121. Peterson, A.R., Bertram, J.S., and Heidelberger, C., 1974b, Cell cycle dependency of DNA damage and repair in transformable mouse fibroblasts treated with N-methyl-N’-nitro-N-nitroso guanidine, Cancer Res. 34: 1600–1607.PubMedGoogle Scholar
  122. Pierce, G.B., 1974, Cellular heterogeneity of cancers, in “Chemical Carcinogenesis” (P.O.P. Ts’o and J.A. DiPaolo, eds.), Part B, pp. 463–472, Marcel Dekker, New York.Google Scholar
  123. Pitot, H.C., and Heidelberger, C., 1963, Metabolic regulatory circuits and carcinogenesis, Cancer Res. 23: 1694–1700.PubMedGoogle Scholar
  124. Pullman, A., and Pullman, B., 1955, Electronic structure and car cinogenic activity of aromatic molecules, Adv. Cancer Res. 3: 117–169.Google Scholar
  125. Pullman, A., and Pullman, B., 1969, A quantum chemist’s approach to the mechanism of chemical carcinogenesis, in “Physico Chemical Mechanisms of Carcinogenesis” (E. Bergmann and B. Pullman, eds.), The Jerusalem Symposia on Quantum Chemistry and Biochemistry, Vol. 1, pp. 9–24, The Israeli Academy of Sciences and Humanities, Jerusalem.Google Scholar
  126. Regan, J.D., and Setlow, R.B., 1974, Two forms of repair in the DNA of human cells damaged by chemical carcinogens and mutagens, Cancer Res. 34: 3318–3325.PubMedGoogle Scholar
  127. Reznikoff, C.A., Bertram, J.S., Brankow, D.W., and Heidelberger, C., 1973a, Quantitative and qualitative studies of chemical trans formation of cloned C3H mouse embryo cells sensitive to post-confluence inhibition of cell division, Cancer Res$133:3239 3249. CHEMICAL CARCINOGENESIS 369Google Scholar
  128. Reznikoff, C.A., Brankow, D.W., and Heidelberger, C., 1973b, Establishment and characterization of a cloned line of C3H mouse embryo cells sensitive to postconfluence inhibition of division, Cancer Res. 33: 3231–3238.PubMedGoogle Scholar
  129. Rhim, J.S., Park, D.K., Weisburger, E.K., and Weisburger, J.H., 1974, Evaluation of an in vitro assay system for carcinogens based on prior infection of rodent cells with nontransforming RNA tumor virus, J. Nat. Cancer Inst. 52: 1167–1173.Google Scholar
  130. Rogan, E.G., and Cavaliere, E., 1974, 3-Methylcholanthrene-inducible binding of aromatic hydrocarbons to DNA in purified rat liver nuclei, Biochem. Biophys. Res. Commun. 58: 1119–1126.Google Scholar
  131. Sander, J., Bürkle, G., and Schweinsberg, F., 1972, Induction of tumors by nitrite and secondary amines or amides, in “Topics in Chemical Carcinogenesis” (W. Nakahara, S. Takayama, T.Google Scholar
  132. Sugimura, and S. Odashima, eds.), pp. 297–310, University of Tokyo Press, Tokyo, Japan.Google Scholar
  133. Sarrif, A.M., Bertram, J.S., Kamarck, M., and Heidelberger, C., 1975, The isolation and characterization of polycyclic hydro carbon-binding proteins from mouse liver and skin cytosols, Cancer Res. 35: 816–824.PubMedGoogle Scholar
  134. Selkirk, J.A., Huberman, E., and Heidelberger, C., 1971, An epoxide is an intermediate in the microsomal metabolism of the chemical carcinogen, dibenz[a,h]anthracene, Biochem. Biophys. Res. Commun. 43: 1010–1016.Google Scholar
  135. Setlow, R.B., and Regan, J.D., 1972, Defective repair of N-acetoxy 2-acetylaminofluorene-induced lesions in the DNA of Xeroderma pigmentoswn cells, Biochem. Biophys. Res. Commun. 46: 1019–1024.Google Scholar
  136. Sims, P., and Grover, P.L., 1974, Epoxides in polycyclic aromatic hydrocarbon metabolism and carcinogenesis, Adv. Cancer Res. 20: 166–274.Google Scholar
  137. Sims, P., Grover, P.L., Swaisland, A., Pal, K., and Hewer, A., 1974, Metabolic activation of benzo[a]pyrene proceeds by a diol epoxide, Nature 252: 326–328.PubMedCrossRefGoogle Scholar
  138. Sloane, N.H., and Davis, T.K., 1974, Hydroxymethylation of the benzene ring. Microsomal hydroxymethylation of benzo[a] pyrene to 6-hydroxymethylbenzo[a]pyrene, Arch. Biochem. Biophys. 163: 46–52.Google Scholar
  139. Stich, H.F., and San, R.H.C., 1971, Reduced DNA repair synthesis in Xeroderma pigmentoswn cells exposed to the oncogenic 4 nitroquinoline 1-oxide and 4-hydroxyaminoquinoline 1-oxide, Mutat. Res. 13: 279–282.Google Scholar
  140. Stich, H.F., and San, R.H.C., 1973, DNA repair synthesis and sur vival of repair deficient human cells exposed to the K-region epoxide of benz[a]anthracene, Proc. Soc. Exp. Biol. Med. 142: 155–158.Google Scholar
  141. Stich, H.F., San, R.H.C., and Kawazoe, Y., 1971, DNA repair syn thesis in mammalian cells exposed to a series of oncogenic and non-oncogenic derivatives of 4-nitroquinoline 1-oxide, Nature229: 416–419.PubMedCrossRefGoogle Scholar
  142. Stich, H.F., San, R.H.C., and Kawazoe, Y., 1973, Increased sensi tivity of Xeroderma pigmentosum cells to some chemical car cinogens and mutagens, Mutat. Res. 17: 127–137.Google Scholar
  143. Stich, H.F., San, R.H.C., Miller, J.A., and Miller, E.C., 1972, Various levels of DNA repair synthesis in Xeroderma pigmentosumGoogle Scholar
  144. cells exposed to the carcinogens N-hydroxy and N-acetoxy-2 acetylaminofluorene, Nature New Biol. 238:9–10.Google Scholar
  145. Swaisland, A.J., Grover, P.L., and Sims, P., 1974a, Reactions of polycyclic hydrocarbon epoxides with RNA and polyribonucleo tides, Chem.-Biol. Interactions9: 317–326.Google Scholar
  146. Swaisland, A.J., Hewer, A., Pal, K., Keysell, G.R., Booth, J., Grover, P.L., and Sims, P., 1974b, Polycyclic hydrocarbon epoxides: the involvement of 8,9-dihydro-8,9-dihydroxybenz [a]anthracene 10,11-oxide in reactions with the DNA of benz [a]anthracene-treated hamster embryo cells, FEBS Lett. 47: 34–38.PubMedCrossRefGoogle Scholar
  147. Swenson, D.H., Miller, J.A., and Miller, E.C., 1973, 2,3-Dihydro 2,3-dihydroxy-aflatoxin B1: an acid hydrolysis product of an RNA-aflatoxin B1 adduct formed by hamster and rat liver microsomes in vitro, Biochim. Biophys. Res. Commun. 53: 1260 1267.CrossRefGoogle Scholar
  148. Tasseron, J.G., Diringer, H., Frohwirth, N., Mirvish, S.S., and Heidelberger, C., 1970, Partial purification of soluble pro tein from mouse skin to which carcinogenic hydrocarbons are specifically bound, Biochemistry 9: 1636–1644.PubMedCrossRefGoogle Scholar
  149. Teranishi, K., Hamada, K., and Watanabe, H., 1975, Quantitative relationship between carcinogenicity and mutagenicity of polyaromatic hydrocarbons in Salmonella typhimurium mutants, Mutat. Res. 31: 97–102.Google Scholar
  150. Troll, W., Belman, L., Berkowitz, E., Chmielewicz, Z.F., Ambrus, J.H., and Bardos, T.J., 1968, Differential responses of DNA and RNA polymerase to modifications of the template rat liver DNA caused by action of the carcinogen acetylaminofluorene in vivo and in vitro, Biochim. Biophys. Acta 157: 16–24.Google Scholar
  151. Ts’o, P.O.P., Caspary, W.J., Cohen, B.I., Leavitt, J.C., Lesko, S.A., Lorentzen, R.J., and Schechtman, L.M., 1974, Basic mechanisms in polycyclic hydrocarbon carcinogenesis, in “Chemical Carcino genesis” (P.O.P. Ts’o and J.A. DiPaolo, eds.), Part A, pp. 113 147, Marcel Dekker, New York.Google Scholar
  152. Weinstein, B., and Grunberger, D., 1974, Structural and functional changes in nucleic acids modified by chemical carcinogens, in “Chemical Carcinogenesis” (P.O.P. Ts’o and J.A. DiPaolo, eds.), pp. 217–235, Marcel Dekker, New York.Google Scholar
  153. Wiest, W.G., and Heidelberger, C., 1953, The interaction of carcino genic hydrocarbons with tissue constituents. I. Methods, Cancer Res. 13:246–249; II. 1,2,5,6-Dibenzanthracene-9,10 C14 in skin, Cancer Res. 13:250–254; III. 1,2,5,6-Dibenz anthracene-9,10-C14 in the submaxillary gland, Cancer Res. 13: 255–261.Google Scholar
  154. Wilk, M., and Girke, W., 1969, Radical cations of carcinogenic alternant hydrocarbons, amines and azo dyes, and their reactions with nucleobases, in “Physico-Chemical Mechanisms of Carcinogenesis” (E. Bergmann and B. Pullman, eds.), The Jerusalem Symposia on Quantum Chemistry and Biochemistry, Vol. 1, pp. 91–105, The Israeli Academy of Sciences and Humanities, Jerusalem.Google Scholar
  155. Wislocki, P.G., Miller, J.A., and Miller, E.C., 1975, The carcino genic and electrophilic activities of N-benzoyloxy derivatives of N-methyl-4-aminoazobenzene and related dyes, Cancer Res. 35: 880–885.PubMedGoogle Scholar
  156. Wunderlich, V., Tetzlaff, I., and Graffi, A., 1971/1972, Studies on nitrosodimethylamine: preferential methylation of mito chondrial DNA in rats and hamsters, Chem.-Biol. Interactions 4: 81–89.Google Scholar
  157. Yuspa, S.H., and Bates, R.R., 1970, The binding of benz[a]anthracene to replicating and nonreplicating DNA in cell culture, Proc. Soc. Exp. Biol. Med. 135: 732–734.Google Scholar
  158. Yuspa, S.H., Eaton, S., Morgan, D.L., and Bates, R.R., 1969/1970, The binding of 7,12-dimethylbenz[a]anthracene to replicating and nonreplicating DNA in cell culture, Chem.-Biol. Interac tions 1: 223–233.Google Scholar
  159. Zieve, F.J., 1973, Effects of the carcinogen N-acetoxy-2-fluorenyl acetamide on the template properties of deoxyribonucleic acid, Mol. PharmacoZ. 9: 658–669.Google Scholar

Copyright information

© Springer Science+Business Media New York 1976

Authors and Affiliations

  • Charles Heidelberger
    • 1
  1. 1.McArdle Laboratory for Cancer ResearchUniversity of WisconsinMadisonUSA

Personalised recommendations