Abstract
Structural alterations of DNA in the chromatin of target cells are primary events in the multistep process of malignant transformation and tumorigenesis by most chemical carcinogens (Lawley 1976; Pegg 1977; Weinstein 1977; Grover 1979; Singer 1979; Pullman et al. 1980; Rajewsky 1980a). In general, covalent binding occurs between nucleophilic centers (electron-rich nitrogen and oxygen atoms) in cellular DNA and highly reactive, electrophilic derivatives (ultimate carcinogens) generated from the respective parent compounds (precarcinogens), either by enzyme-catalyzed “metabolic activation” or via nonenzymatic decomposition (Miller and Miller 1976, 1979). As a consequence of their reaction with DNA, most chemical carcinogens are also mutagenic (McCann et al. 1975; Nagao et al. 1978; Hollstein et al. 1979). The strong correlation of carcinogenicity and mutagenicity does not, however, constitute proof for an obligatory requirement of mutation (nor even of modification of DNA structure in general) for malignant tranformation. Cellular macromolecules other than DNA also contain multiple nucleophilic sites which can, and indeed do, react with carcinogen-generated electrophiles. In spite of this proviso, the central importance of DNA structure and conformation for the expression of genetic information provides a strong argument for a critical role of DNA alterations as a prerequisite for the initiation of carcinogenesis by chemical agents.
Experimental studies in the author’s laboratory were supported by the Deutsche Forschungsgemeinschaft (SFB 102) and by the Fritz Thyssen Stiftung (1980/2/41)
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Abbott PJ, Saffhill R (1977) DNA synthesis with methylated poly (dA-dT) templates: possible role of O4-methylthymine as a pro-mutagenic base. Nucleic Acids Res 4:761–769
Abbott PJ, Saffhill R (1979) DNA synthesis with methylated poly (dC-dG) templates. Evidence for a competitive nature of miscoding by O6-methylguanine. Biochim Biophys Acta 562:51–61
Adamkiewicz J, Eberhardt W, Langenberg U, Müller R, Rajewsky MF (1981) Monoclonal antibodies for the specific detection and quantification of DNA components structurally modified by alkylating carcinogens. Proc. Sect. Exp. Cancer Res. German Cancer Soc. J Cancer Res Clin Oncol 99: A21
Baird WM (1979) The use of radioactive carcinogens to detect DNA modifications. In: Grover PL (ed) Chemical carcinogens and DNA. CRC Press, Boca Raton, pp 59–83
Barrett JC, Ts’o POP (1978) Evidence for the progressive nature of neoplastic transformation in vitro. Proc Natl Acad Sci USA 75:3761–3765
Berenblum I (1975) Sequential aspects of chemical carcinogenesis: Skin. In: Becker FF (ed) Cancer: A comprehensive treatise, vol 1. Plenum Press, New York, pp 323–344
Boehm TL, Drahovsky D (1981) Hypomethylation of DNA in Raji cells after treatment with N-methyl-N-nitrosourea. Carcinogenesis 2:39–42
Bogden JM, Eastman A, Bresnick E (1981) A system in mouse liver for the repair of O6-methylguanine lesions in methylated DNA. Nucleic Acids Res 9: 3089–3102
Cairns J (1981) The origin of human cancers. Nature 289:353–357
Chang MJW, Hart RW, Koestner A (1980) Retention of promutagenic O6-ethylguanine in the DNA of various rat tissues following transplacental inoculation with ethylnitrosourea. Cancer Lett 9:199–205
Crick F (1979) Split genes and RNA splicing. Science 204:264–271
Denlinger RH, Koestner A, Wechsler W (1974) Induction of neurogenic tumors in C3HeB/FeJ mice by nitrosourea derivatives: Observations by light microscopy, tissue culture, and electron microscopy. Int J Cancer 13: 559–571
Druckrey H, Landschütz C, Ivankovic S (1970a) Transplacentare Erzeugung maligner Tumoren des Nervensystems. II. Äthyl-nitrosoharnstoff an 10 genetisch definierten Rattenstämmen. Z Krebsforsch 73:371–386
Druckrey H, Schagen B, Ivankovic S (1970b) Erzeugung neurogener Malignome durch einmalige Gabe von Äthyl-nitrosoharnstoff (ÄNH) an neugeborene und junge BDIX-Rat-ten. Z Krebsforsch 74: 141–161
Ehrlich M, Wang RY-H (1981) 5-Methylcytosine in eukaryotic DNA. Science 212:1350–1357
Foote RS, Mitra S, Pal BC (1980) Demethylation of O6-methylguanine in a synthetic DNA polymer by an inducible activity in Escherichia coli. Biochem Biophys Res Commun 97:654–659
Fox RR, Diwan BA, Meier H (1975) Transplacental induction of primary renal tumors in rabbits treated with 1-ethyl-l-nitrosourea. J Natl Cancer Inst 54: 1439–1448
Fuchs RPP, Lefévre JF, Pouyet J, Daune MP (1976) Comparative orientation of the fluorene residue in native DNA modified by N-acetoxy-N-2-acetylaminofluorene and two 7-halogeno derivatives. Biochemistry 15: 3347–4451
Fuchs RPP, Schwartz N, Daune MP (1981) Hot spots of frameshift mutations induced by the ultimate carcinogen N-acetoxy-N-2-acetylaminofluorene. Nature 294:657–659
Garel A, Axel R (1976) Selective digestion of transcriptionally active ovalbumin genes from oviduct nuclei. Proc Natl Acad Sci USA 73:3966–3970
Goth R, Rajewsky MF (1972) Ethylation of nucleic acids by ethylnitrosourea-l-14C in the fetal and adult rat. Cancer Res 32: 1501–1505
Goth R, Rajewsky MF (1974a) Persistence of O6-ethylguanine in rat brain DNA: Correlation with nervous system specific carcinogenesis by ethylnitrosourea. Proc Natl Acad Sci USA 71: 639–653
Goth R, Rajewsky MF (1974b) Molecular and cellular mechanisms associated with pulse-carcinogenesis in the rat nervous system by ethylnitrosourea: Ethylation of nucleic acids and elimination rates of ethylated bases from the DNA of different tissues. Z Krebsforsch 82:37–64
Graf T, Beug H (1978) Avian leukemia viruses: interaction with their target cells in vivo and in vitro. Biochim Biophys Acta 516:269–299
Grover PL (ed) (1979) Chemical carcinogens and DNA. CRC Press, Boca Raton
Grunberger D, Weinstein IB (1979) Conformational changes in nucleic acids modified by chemical carcinogens. In: Grover PL (ed) Chemical carcinogens and DNA. CRC Press, Boca Raton, pp 59–93
Hanawalt PC, Cooper PK, Ganesan AK, Smith CA (1979) DNA repair in bacteria and mammalian cells. Annu Rev Biochem 48:783–836
Hecker E, Fusenig NE, Kunz W, Marks F, Thielmann HW (eds) Cocarcinogenesis and biological effects of tumor promoters. Raven Press, New York
Hollstein M, McCann J, Angelosanto FA (1979) Short-term tests for carcinogens and mutagens. Mutat Res 65:133–226
IARC (1978) IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans, vol 17, some N-nitroso compounds. International Agency for Research on Cancer, Lyon
Ingold CK (1953) Structure and mechanism in organic chemistry, Chapter 7. Cornell University Press, Ithaca, New York
Ivankovic S, Druckrey H (1968) Transplacentare Erzeugung maligner Tumoren des Nerven-systems. I. Äthylnitrosoharnstoff (ÄNH) an BDIX-Ratten. Z Krebsforsch 71: 320–360
Jaenisch W (1980) Retroviruses and embryogenesis: Microinjection of Moloney leukemia virus into midgestation mouse embryos. Cell 19: 181–188
Jeggo P, Defais M, Samson L, Schendel P (1977) An adaptive response of E. coli to low levels of alkylating agents: Comparison with previously characterised DNA repair pathways. Mol Gen Genet 157:1–9
Johansson-Brittebo EJ, Tjälve H (1979) Studies on the tissue-disposition and fate of N-(14C)ethyl-N-nitrosourea in mice. Toxicology 13: 275–285
Johnson FM, Lewis SE (1981) Electrophoretically detected germinal mutations induced in the mouse by ethylnitrosourea. Proc Natl Acad Sci USA 78:3138–3141
Jones EL, Searle CE, Smith TW (1976) Medulloblastomas and other neural tumours in mice treated neonatally with N-ethyl-N-nitrosourea. Acta Neuropathol 36:57–70
Kakunaga T, Lo K-Y, Leavitt J, Ikenaga M (1980) Relationship between transformation and mutation in mammalian cells. In: Pullman B, Ts’o POP, Gelboin H (eds) Carcinogenesis: Fundamental mechanisms and environmental effects. Reidel, Dordrecht Boston London, pp 527–541
Karran P, Lindahl T, Griffin B (1979) Adaptive response to alkylating agents involves alteration in situ of O6-methylguanine residues in DNA. Nature 280:76–77
Kleihues P, Margison GP (1976) Exhaustion and recovery of repair excision of O6-methyl-guanine from rat liver DNA. Nature 259: 153–155
Kleihues P, Bücheler J, Riede UN (1978) Selective induction of melanomas in gerbils (meriones unguiculatus) following postnatal administration of N-ethyl-N-nitrosourea. J Natl Cancer Inst 61:859–863
Laerum OD, Rajewsky MF (1975) Neoplastic transformation of fetal rat brain cells in culture following exposure to ethylnitrosourea in vivo. J Natl Cancer Inst 55: 1177–1187
Laerum OD, Haugen Å, Rajewsky MF (1979) Neoplastic transformation of foetal rat brain cells in culture after exposure to ethylnitrosourea in vivo. In: Franks LM, Wigley CB (eds) Neoplastic transformation in differentiated epithelial cell systems in vitro. Academic Press, London, New York,’ pp 190–201
Lajtha L (1979) Stem cell concepts. Differentiation 14:23–34
Lane M-A, Sainten A, Cooper GM (1981) Activity of related transforming genes in mouse and human mammary carcinomas. Proc Natl Acad Sci USA 78:5185–5189
Lapeyre JN, Becker FF (1979) 5-Methylcytosine content of nuclear DNA during chemical hepatocarcinogenesis, and in carcinomas which result. Biochem Biophys Res Commun 87:698–705
Lavi S (1981) Carcinogen-mediated amplification of viral DNA sequences in simian virus 40-transformed Chinese hamster embryo cells. Proc Natl Acad Sci USA 78:6144–6148
Lawley PD (1976) Carcinogenesis by alkylating agents. In: Searle CE (ed) Chemical carcinogens. ACS Monograph No. 173. American Chemical Society, Washington, D.C., pp 83–244
Lehmann AR, Karran P (1981) DNA repair. Int Rev Cytol 72: 101–146
Lewis JG, Swenberg JA (1980) Differential repair of O6-methylguanine in DNA in rat hepatocytes and non-parenchymal cells. Nature 288: 185–187
Lindahl T (1979) DNA glycosylases, endonucleases for apurinic/apyrimidinic sites, and base excision repair. Progr Nucleic Acid Res Mol Biol 22: 135–192
Lindahl T (1982) DNA repair enzymes. Annu Rv Biochem 51: 59–85
Loveless A (1969) Possible relevance of O6-alkylation of deoxyguanosine to the mutagenicity and carcinogenicity of nitrosamines and nitrosamides. Nature 223: 206–207
Margison GP, O’Connor PJ (1979) Nucleic acid modification by N-nitroso compounds. In: Grover PL (ed) Chemical carcinogens and DNA, vol 1. CRC Press, Boca Raton, pp 111–159
Margison GP, Margison JM, Montesano R (1976) Methylated purines in the deoxyribonucleic acid of various Syrian-golden-hamster tissues after administration of a hepatocarcinogenic dose of dimethylnitrosamine. Biochem J 157: 627–634
McCann J, Choi E, Yamasaki E, Ames BN (1975) Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc Natl Acad Sci USA 72:5135–5139
Mehta JR, Ludlum DB, Renard A, Verly WG (1981) Repair of O6-ethylguanine in DNA by a chromatin fraction from rat liver: Transfer of the ethyl group to an acceptor protein. Proc Natl Acad Sci USA 78:6766–6770
Miller EC, Miller JA (1976) The metabolism of chemical carcinogens to reactive electrophiles and their possible mechanisms of action in carcinogenesis. In: Searle CE (ed) Chemical carcinogens. ACS Monograph 173. American Chemical Society, Washington, D.C., pp 737–762
Miller JA, Miller EC (1979) Perspectives on the metabolism of chemical carcinogens. In: Emmelot P, Kriek E (eds) Environmental carcinogenesis. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 25–50
Montesano R (1981) Alkylation of DNA and tissue specificity in nitrosamine carcinogenesis. J Supramolec Struct Cell Biochem 17:259–273
Müller R, Rajewsky MF (1978) Sensitive radioimmunoassay for detection of O6-ethyldeoxy-guanosine in DNA exposed to the carcinogen ethylnitrosourea in vivo or in vitro. Z Naturforsch 33c: 897–901
Müller R, Rajewsky MF (1980) Immunological quantification by high affinity antibodies of O6-ethyldeoxyguanosine in DNA exposed to N-ethyl-N-nitrosourea. Cancer Res 40:887–896
Müller R, Rajewsky MF (1981) Antibodies specific for DNA components structurally modified by chemical carcinogens. J Cancer Res Clin Oncol 102:99–113
Müller R, Adamkiewicz J, Rajewsky MF (1982) Immunological detection and quantification of carcinogen-modified DNA components. In: Bartsch H, Armstrong B (eds) Host factors in human carcinogenesis. IARC Scientific Publications No. 39. International Agency for Research on Cancer, Lyon, pp 443–459
Nagao M, Sugimura T, Matsushima T (1978) Environmental mutagens and carcinogens. Annu Rev Genet 12:117–159
Nehls P, Rajewsky MF (1981) Ethylation of fetal rat brain chromosomal DNA by ethylnitrosourea. Proc. Sect. Exp. Cancer Res. German Cancer Soc. J Cancer Res Clin Oncol 99:A38
Nordheim A, Pardue ML, Lafer EM, Möller A, Stollar BD, Rich A (1981) Antibodies to left-handed Z-DNA bind to interband regions of Drosophilia polytene chromosomes. Nature 294:417–423
O’Connor P, Saffhill R, Margison GP (1979) N-nitroso compounds: Biochemical mechanisms of action. In: Emmelot P, Kriek E (eds) Environmental carcinogenesis. Elsevier/North Holland Biomedical Press, Amsterdam, pp 73–96
Olsson M, Lindahl T (1980) Repair of alkylated DNA in E. coli: Methyl group transfer from O6-methylguanine to a protein cysteine residue. J Biol Chem 255: 10569–10572
Pegg AE (1977) Formation and metabolism of alkylated nucleosides: Possible role in carcinogenesis by nitroso compounds and alkylating agents. Adv Cancer Res 25:195–269
Pegg AE, Balog B (1979) Formation and subsequent excision of O6-ethylguanine from DNA of rat liver following administration of diethylnitrosamine. Cancer Res 39:5003–5009
Pegg AE, Hui G (1978) Formation and subsequent removal of O6-methylguanine from DNA in rat liver and kidney after small doses of dimethylnitrosamine. Biochem J 173: 739–748
Pegg AE, Perry W, Bennett RA (1981) Effect of partial hepatectomy on removal of O6-methylguanine from alkylated DNA by rat liver extracts. Biochem J 197: 195–201
Pegg AE, Roberfroid M, von Bahr C, Foote RS, Mitra S, Bresil H, Likhachev A, Montesano R (1982) Removal O6-methylguanine from DNA by human liver fractions. Proc Natl Acad Sci USA 79:5162–5165
Pfohl-Leszkowicz A, Salas C, Fuchs RPP, Dirheimer G (1981) Mechanism of inhibition of enzymatic deoxyribonucleic acid methylation by 2-(acetylamino)fluorene bound to deoxyribonucleic acid. Biochemistry 20:3020–3024
Pullman B, Ts’o POP, Gelboin H (eds) (1980) Carcinogenesis: Fundamental mechanisms and environmental effects. Reidel, Dordrecht Boston London
Rabes HM, Kerler R, Wilhelm R, Rode G, Riess H (1979) Alkylation of DNA and RNA by [14C] dimethylnitrosamine in hydroxyureasynchronized regenerating rat liver. Cancer Res 39:4228–4236
Radman M, Villani G, Boiteux S, Defais M, Caillet-Fauquet P (1977) On the mechanism and genetic control of mutagenesis induced by carcinogenic mutagens. In: Hiatt HH, Watson JD, Winston JA (eds) Origins of human cancer. Book B: Mechanisms of carcinogenesis. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., pp 903–922
Rajewsky MF (1972) Proliferative parameters of mammalian cell systems and their role in tumour growth and carcinogenesis. Z Krebsforsch 78: 12–30
Rajewsky MF (1974) Proliferative properties of malignant cell systems. In: Altmann H et al. (eds) Geschwülste / Tumors I. Springer, Berlin Heidelberg New York (Handbuch der allgemeinen Pathologie, vol VI/5, pp 289–325)
Rajewsky MF (1980a) Specificity of DNA damage in chemical carcinogenesis. In: Montesano R, Bartsch H, Tomatis L (eds) Molecular and cellular aspects of carcinogen screening tests. IARC Scientific Publications No. 27. International Agency for Research on Cancer, Lyon, pp 41–54
Rajewsky MF (1980b) Possible determinants for the differential susceptibility of mammalian cells and tissues to chemical carcinogens. Arch Toxicol [Suppl] 3: 229–236
Rajewsky MF, Augenlicht LH, Biessmann H, Goth R, Hülser DF, Laerum OD, Lomakina LYa (1977) Nervous system-specific carcinogenesis by ethylnitrosourea in the rat: Molecular and cellular mechanisms. In: Hiatt HH, Watson JD, Winsten JA (eds) Origins of human cancer. Book B: Mechanisms of carcinogenesis. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y., pp 709–726
Rajewsky MF, Müller R, Adamkiewicz J, Drosdziok W (1980) Immunological detection and quantification of DNA components structurally modified by alkylating carcinogens (ethylnitrosourea). In: Pullman B, Ts’o POP, Gelboin H (eds) Carcinogenesis: Fundamental mechanisms and environmental effects. Reidel, Dordrecht Boston London, pp 207–218
Renz M, Nehls P, Hozier J (1977) Involvement of histone H1 in the organization of the chromosome fiber. Proc Natl Acad Sci USA 74: 1879–1883
Rudland PS, Ormerod EJ, Paterson FC (1980) Stem cells in rat mammary development and cancer: a review. JR Soc Med 73: 437–442
Russel WL, Kelly EM, Hunsicker PR, Bangham JW, Maddux SC, Phipps EL (1979) Specific-locus test shows ethylnitrosourea to be the most potent mutagen in the mouse. Proc Natl Acad Sci USA 76: 5818–5819
Saffhill R, Boyle JM (1981) Detection of carcinogen-DNA adducts by radio-immunoassay. Abstr. Proc. 22nd Ann. Gen. Meeting Brit. Assoc. Cancer Res. Br J Cancer 44:275
Sage E, Leng M (1980) Conformation of poly (dG-dC) • poly (dG-dC) modified by the carcinogens N-acetoxy-N-acetyl-2-aminofluorene and N-hydroxy-N-2-aminofluorene. Proc Natl Acad Sci USA 77:4597–4601
Samson L, Cairns J (1977) A new pathway for DNA repair in Escherichia coli. Nature 267:281–283
Santella RM, Grunberger D, Weinstein IB, Rich A (1981) Induction of the Z conformation in poly (dG-dC) • poly (dG-dC) by binding of N-2-acetylaminofluorene to guanine residues. Proc Natl Acad Sci USA 78: 1451–1455
Saunders GF (ed) (1978) Cell differentiation and neoplasia. Raven, New York
Seeberg E, Kleppe K (eds) (1981) Chromosome damage and repair. Plenum, New York
Singer B (1979) N-nitroso alkylating agents: Formation and persistence of alkyl derivatives in mammalian nucleic acids as contributing factors in carcinogenesis. J Natl Cancer Inst 62:1329–1339
Singer B, Kroger M (1979) Participation of modified nucleosides in translation and transcription. Prog Nucleic Acid Res Mol Biol 23: 151–194
Singer B, Bodell WJ, Cleaver JE, Thomas EH, Rajewsky MF, Thon W (1978) Oxygens in DNA are main targets for ethylnitrosourea in normal and Xeroderma pigmentosum fibroblasts and fetal rat brain cells. Nature 276: 85–88
Slaga TJ, Sivak A, Boutwell RK (eds) (1978) Carcinogenesis., A comprehensive survey, vol 2. Mechanisms of tumor promotion and cocarcinogenesis. Raven, New York
Stavrou D, Hänichen T, Wriedt-Lübbe I (1975) Onkogene Wirkung von Äthylnitrosoharnstoff beim Kaninchen während der pränatalen Periode. Z Krebsforsch 84: 207–215
Stavrou D, Dahme E, Schroder B (1977) Transplacentare neuroonkogene Wirkung von Äthylnitrosoharnstoff beim Kaninchen während der frühen Graviditätsphase. Z Krebsforsch 89:331–339
Stumpf R, Margison GP, Montesano R, Pegg AE (1979) Formation and loss of alkylated purines from DNA of hamster liver after administration of dimethylnitrosamine. Cancer Res 39:50–54
Stutman O (1979) Transplacental carcinogenesis in athymic nude mice. Pathol Res Pract 165:170
Sun L, Singer B (1975) The specificity of different classes of ethylating agents toward various sites of HeLa cell DNA in vitro and in vivo. Biochemistry 14: 1795–1802
Tomatis L, Cefis F (1967) The effects of multiple and single administration of dimethylnitrosamine to hamsters. Tumori 53: 447–452
Vogel E, Natarajan AT (1979a) The relation between reaction kinetics and mutagenic action of mono-functional alkylating agents in higher eukaryotic system. I. Recessive lethal mutations and translocations in Drosophilia. Mutat Res 62:51–100
Vogel E, Natarajan AG (1979b) The relation between reaction kinetics and mutagenic action of mono-functional alkylating agents in higher eukaryotic systems. II. Total and partial sex-chromosome loss in Drosophilia. Mutat Res 62: 101–123
Wang AH, Quigley GJ, Kolpak FJ, Cranford JL, Van Boom JA, Van der Macel G, Rich A (1979) Molecular structure of a left-handed double helical DNA fragment at atomic resolution. Nature 282:680–686
Weinberg RA (1981) Use of transfection to analyze genetic information and malignant transformation. Biochim Biophys Acta 651:25–35
Weinstein IB (1977) Types of interaction between carcinogens and nucleic acids. In: Méchanismes d’alteration et de réparation du DNA, relations avec la mutagenèse et la cancerogenèse chimique. Colloques Internationaux du CNRS No. 256. Centre National de la Recherche Scientifique, Paris, pp 2–40
Weintraub H, Groudine M (1976) Chromosomal subunits in active genes have an altered conformation. Science 193:848–856
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1983 Springer-Verlag Berlin • Heidelberg
About this chapter
Cite this chapter
Rajewsky, M.F. (1983). Structural Modifications and Repair of DNA in Neuro-Oncogenesis by N-Ethyl-N-nitrosourea. In: Nass, G. (eds) Modified Nucleosides and Cancer. Recent Results in Cancer Research/Fortschritte der Krebsforschung/Progrès dans les recherches sur Ie cancer, vol 84. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-81947-6_4
Download citation
DOI: https://doi.org/10.1007/978-3-642-81947-6_4
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-81949-0
Online ISBN: 978-3-642-81947-6
eBook Packages: Springer Book Archive