Summary
It is just about 50 years since the publication of the report on the toxicity and carcinogenicity of the potent carcinogenN-acetyl-2-aminofluorene (AAF). In 1940 very few reports on the carcinogenic activity of chemical compounds in experimental animals were available. The discovery of pure chemicals as carcinogens, such as AAF, azo dyes and benzo[a]pyrene, provided cancer researchers with a number of tools whereby the progressive changes involved in the induction of cancer could be studied in experimental systems. Contrary to the results with other carcinogens then known, AAF induced numerous types of tumors, but not at the site of application. This finding stimulated a great deal of interest in its use as an experimental carcinogen to study its metabolic fate and mechanism of action. During the following years an ever increasing number of reports appeared on the carcinogenicity of AAF in various species, on its metabolic fate, on the interaction of reactive metabolites with nucleic acids and proteins, and on its mutagenic activity. Particularly studies on the metabolism of AAF and the interaction with nucleic acids have contributed appreciably to our understanding of the mechanism of action of aromatic amines and also of other chemical carcinogens. It can be expected that AAF and its derivatives will continue to be used for specific applications in experimental cancer research. One of the most recent achievements is the preparation of site-specific AAF- and aminofluorene-modified DNA sequences for mutagenesis studies.
Abbreviations
- AAF:
-
N-acetyl-2-aminofluorenem
References
Armier J, Mezzina M, Leng M, Fuchs RPP, Sarasin A (1988)N-acetoxy-N-2-acetylaminofluorene-induced damage on SV40 DNA: inhibition of DNA replication and visualization of DNA lesions. Carcinogenesis 9:789–795
Baan RA, Lansbergen MJ, De Bruin PAF, Willems MI, Lohman PHM (1985) The organ-specific induction of DNA adducts in 2-acetylaminofluorene-treated rats, studied by means of a sensitive immunochemical method. Mutat Res 150:23–32
Ball SS, Quaranata V, Shadravan F, Walford RL (1987) An ELISA for detection of DNA-bound carcinogen using a monoclonal antibody toN-acetoxy-2-acetylaminofluorene-modified DNA. J Immunol Methods 98:195–200
Beland FA, Kadlubar FF (1990) Metabolic activation and DNA adducts of aromatic amines. In: Cooper CS, Grover PL (eds) Chemical carcinogenesis and mutagenesis. I. Springer, Berlin Heidelberg New York, pp 267–325
Beland FA, Dooley KL, Jackson CD (1982) Persistence of DNA adducts in rat liver and kidney after multiple doses of the carcinogenN-hydroxy-2-acetylaminofluorene. Cancer Res 42:1348–1354
Beland FA, Heflich RH, Howard PC, Fu PP (1985) The in vitro metabolic activation of nitro polycyclic aromatic hydrocarbons. In: Harvey RG (ed) Polycyclic hydrocarbons and carcinogenesis. ACS Symposium Series. American Chemical Society, Washington, pp 371–396
Broyde S, Hingerty BE (1983) Conformation of 2-aminofluorene-modified DNA. Biopolymers 22:2423–2441
Bryant MS, Skipper PL, Tannenbaum SR, Maclure M (1987) Hemoglobin adducts of 4-aminobiphenyl in smokers and nonsmokers. Cancer Res 47:602–608
Burnouf D, Koehl P, Fuchs RPP (1989) Single adduct mutagenesis: strong effect of the position of a single acetylaminofluorene aduct within a mutation hot spot. Proc Natl Acad Sci USA 86:4147–4151
Cartwright RA, Glashan RW, Rogers HJ, Ahmad RA, Hall DB, Higgins E, Kahn MA (1982) Role ofN-acetyltransferase phenotypes in bladder carcinogenesis: a pharmacogenetic epidemiological approach to bladder cancer. Lancet II:842–846
Clayson DB (1953) A working hypothesis for the mode of carcinogenesis of aromatic amines. Br J Cancer 7:460–471
Clayson DB, Garner RC (1976) Carcinogenic aromatic amines and related compounds. In: Searle CE (ed) Chemical carcinogens. American Chemical Society, Washington, pp 366–461
Cramer JW, Miller JA, Miller EC (1960)N-Hydroxylation: a new metabolic reaction observed in the rat with the carcinogen 2-acetylaminofluorene. J Biol Chem 235:885–888
Deelman HT (1924) Die Entstehung des experimentellen Teerkrebses und die Bedeutung der Zellenregeneration. Z Krebsforsch 21:220–226
Defrancq E, Pelloux N, Leterme A, Lhomme M-F, Lhomme J (1991) Interaction and reactivity of carcinogenicN-acetyl-N-(acyloxy)-2-aminofluorene with deoxyguanosine. An intramolecular approach. J Org Chem 56:4817–4819
Den Engelse L, Van Benthem J, Scherer E (1990) Immunocytochemical analysis of in vivo DNA modification. Mutat Res 233:265–287
Doll R (1972) Cancers related to smoking. In: Richardson RG (ed) Proceedings 2nd World Conference on Smoking and Health. Pitman, London, pp 10–23
Farber E (1973) Hyperplastic liver nodules. Meth Cancer Res 7:345–375
Farber E (1984) Cellular biochemistry of the stepwise development of cancer with chemicals. Cancer Res 44:5463–5474
Foulds L (1969) Neoplastic development, vol 1. Academic Press, New York
Foulds L (1975) Neoplastic development, vol 2. Academic Press, New York
Friedewald WF, Rous P (1944) The initiating and promotion elements in tumor promotion. J Exp Med 80:101–125
Fuchs RPP, Daune M (1974) Dynamic structure of DNA modified with the carcinogenN-acetoxy-N-2-acetylaminofluorene. Biochemistry 13:4435–4440
Fuchs RPP, Bichara M, Koffel-Schwartz N (1988) Molecular mechanisms involved in mutagenesis induced byN-2-aminofluorene derivatives. In: King CM, Romano LJ, Schuetzle D (eds) Carcinogenic and mutagenic responses to aromatic amines and nitroarenes. Elsevier, Amsterdam, pp 373–384
Giese RW, Vouros P (1990) Analysis of NO2-PAH DNA adducts by mass spectrometry. In: Howard PC, Hecht SS, Beland FA (eds) Nitroarenes, occurrence, metabolism and biological impact. Plenum, New York, pp 211–217
Guigues M, Leng (1979) Reactivity of the antibodies to DNA modified by the carcinogenN-acetoxy-N-acetyl-2-aminofluorene. Nucleic Acids Res 6:733–744
Gupta PK, Johnson DL, Reid TM, Lee M-S, Romano LJ, King CM (1989) Mutagenesis by single site-specific arylamine-DNA adducts. J Biol Chem 264:20120–21030
Hein DW (1988) Acetylator genotype and arylamine-induced carcinogenesis. Biochem Biophys Acta 948:37–66
Heringlake R, Kiese M, Renner G, Wenz W (1960)N-Oxydation von 2-Naphthylamin in vivo und Wirkungen von Oxydationsprodukten des 2-Naphthylamins. Naunyn-Schmiedebergs Arch Pharmakol Exp Pathol 239:370–382
Hong S-J, Piette LH (1976) Electron spin resonance spin-label studies of intercalation of ethidium bromide and aromatic amine carcinogens in DNA. Cancer Res 36:1159–1171
Hueper WC, Wiley FH, Wolfe HD, Ranta KE, Leming MF, Blood FR (1938) Experimental production of bladder tumors in dogs of β-naphthylamine. J Ind Hyg Toxicol 20:46–84
Huitfeldt HS, Spangler EF, Baron J, Poirier MC (1987) Microfluorimetric determination of DNA adducts in immunofluorescent-stained liver tissue from rats fed 2-acetylaminofluorene. Cancer Res 47:2098–2102
International Agency for Research on Cancer (1986) Tobacco smoking. IARC Monogr Eval Carcino Risk Hum 38
Jeffrey et al. (1980) In: Pullman B, Ts'o POP, Gelboin H (eds) Carcinogenesis: fundamental mechanisms and environmental effects. Reidel, Dordrecht, pp 565–578
Johnson DL, Reid TM, Lee M-S, King CM, Romano LJ (1986) Preparation and characterization of a viral DNA molecule containing a site-specific 2-aminofluorene adduct: a new probe for mutagenesis by carcinogens. Biochemistry 25:449–456
Kadlubar FF, Beland FA (1985) Chemical properties of ultimate carcinogenic metabolites of arylamines and arylamides. In: Harvey RG (ed) Polycyclic hydrocarbons and carcinogenesis. American Chemical Society, Washington, pp 341–370
King CM, Reid TM, Tamura N, Gupta PK (1990) Mutagenic and biochemical consequences of the reaction of arylamines with DNA. In: Howard PC, Hecht SS, Beland FA (eds) Nitroarenes, occurrence, metabolism and biological impact. Plenum, New York, pp 95–103
Kriek E (1965) On the interaction ofN-2-fluorenylhydroxylamine with nucleic acids. Biochem Biophys Res Commun 20:793–799
Kriek E, Miller JA, Juhl U, Miller EC (1967) 8-(N-2-Fluorenylacetamido)-guanosine, an arylamidation reaction product of guanosine and the carcinogenN-acetoxy-N-2-fluorenylacetamide in neutral solution. Biochemistry 6:177–182
Landegent JE, Jansen in de Wal N, Van Ommen G-JB, Baas F, Vijlder JJM de, Van Duyn P, Van der Ploegh M (1985) Chromosomal localization of a unique gene by nonautoradiographic in situ hybridization. Nature 317:175–177
Lasko DD, Basu AK, Kadlubar FF, Evans FE, Lay Jr JO, Essigmann JM (1987) A probe for the mutagenic activity of the carcinogen 4-aminobiphenyl: synthesis and characterization of an M13mp 10 genome containing the major carcinogen-DNA adduct at a unique site. Biochemistry 26:3072–3081
Leng M, Sage E, Fuchs RPP, Daune MP (1978) Antibodies to DNA modified by the carcinogenN-acetoxy-N-2-acetylaminofluorene. FEBS Lett 92:207–210
Leng M, Ptak M, Rio P (1980) Conformations of acetylaminofluorene and aminofluorene modified guanosine and guanosine derivatives. Biochem Biophys Res Commun 96:1095–1102
Levine AF, Fink LM, Weinstein IB, Grunberger D (1974) Effect ofN-2-acetylaminofluorene modification on the conformation of nucleic acids. Cancer Res 34:319–327
Lutgerink JT, Retèl J, Westra JG, Welling MC, Loman H, Kriek E (1985) By-pass of the major aminofluorene-DNA adduct during in vivo replication of single- and double-stranded ϕX174 DNA treated withN-hydroxy-2-aminofluorene. Carcinogenesis 6:1501–1506
Marroquin F, Farber E (1962) The apparent binding of radioactive 2-acetylaminofluorene to rat liver ribonucleic acid in vivo. Biochem Biophys Acta 55:403–405
Menkveld GJ, Van der Laken CJ, Hermsen G, Kriek E, Scherer E, Den Engelse L (1985) Immunohistochemical localization ofO 6-ethyldeoxyguanosine and deoxyguanosin-8-yl-(acetyl)aminofluorene in liver sections of rats treated with diethylnitrosamine, ethylnitrosourea orN-acetylaminofluorene. Carcinogenesis 6:263–270
Michaels ML, Reid TM, King CM, Romano LJ (1991) Accurate in vitro translesion synthesis byEscherichia coli DNA polymerase I (large fragment) on a site-specific, aminofluorene-modified template. Carcinogenesis 12:1641–1646
Miller JA, Miller EG (1953) The carcinogenic amino-azo dyes. Adv Cancer Res 1:339–396
Miller EC, Miller JA (1981) Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer 47:2327–2345
Miller EC, Miller JA, Hartmann HA (1961)N-hydroxy-2-acetylaminofluorene: a metabolite of 2-acetylaminofluorene with increased carcinogenic activity in the rat. Cancer Res 21:815–824
Miller EC, Miller JA, Enomoto M (1964) The comparative carcinogenicities of 2-acetylaminofluorene and itsN-hydroxy metabolite in mice, rats and guinea pigs. Cancer Res 24:2018–2032
Mommsen S, Aagaard J (1983) Tobacco as a risk factor in bladder carcinogenesis. Carcinogenesis 4:335–338
Mulder GJ, Wierckx FCJ, Wedzinga R, Meerman JHN (1990) Generation of reactive intermediates from 2-nitrofluorene that bind covalently to DNA, RNA and protein in vitro and in vivo in the rat. In: Howard PC, Hecht SS, Beland FA (eds) Nitroarenes, occurrence, metabolism and biological impact. Plenum, New York, pp 219–230
Möller L, Rafter J, Törnquist S, Eriksson L, Beije B, Toftgård R, Midvedt T, Corrie M, Gustafsson J-Å (1990) In vivo metabolism and genotoxic effects of the air pollutant and marker for nitro-PAHs, 2-nitrofluorene. In: Howard PC, Hecht SS, Beland FA (eds) Nitroarenes, occurrence, metabolism and biological impact. Plenum, New York, pp 39–59
Norman D, Abuaf P, Hingerty BE, Live D, Grunberger D, Broyde S, Patel DJ (1989) NMR and computational characterization of theN-(deoxyguanosin-8-yl)-aminofluorene adduct [(AF)G] opposite adenosine in DNA: (AF)G[syn].A[anti] pair formation and its pH dependence. Biochemistry 28:7462–7476
Peraino C, Fry RJM, Staffeldt E (1971) Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res 31:1506–1512
Pfeifer AMA, Kasid U, Tsokos MG, Kessler DK, Weichselbaum RR, Thorgeirsson SS, Dritschilo A, Mark GE (1989) Implication of the c-raf-1 proto-oncogene in neoplastic transformation in vivo and in vitro. Cancer Cells 7:177–181
Phillips DH (1990) Modern methods of DNA adduct determination. In: Cooper CS, Grover PL (eds) Chemical carcinogenesis and mutagenesis. I. Springer, Berlin Heidelberg New York, pp 503–546
Pitot HC, Sirica AE (1980) The stages of initiation and promotion in hepatocarcinogenesis. Biochim Biophys Acta 605:191–215
Poirier MC (1981) Antibodies to carcinogen-DNA adducts. J Natl Cancer Inst 67:515–519
Poirer MC, Yuspa SH, Weinstein IB, Blobstein S (1977) Detection of carcinogen-DNA adducts by radioimmunoassay. Nature 270: 186–188
Poirer MC, Hunt JM, True BA, Laishes BA, Young JF, Beland FA (1984) DNA adduct formation, removal and persistence in rat liver during one month of feeding 2-acetylaminofluorene. Carcinogenesis 5:1591–1596
Rehn L (1895) Blasengeschwülste bei Fuchsin-Arbeitern. Arch Klin Chir 50:588–600
Scherer E (1984) Neoplastic progression in experimental hepatocarcinogenesis. Biochim Biophys Acta 738:219–236
Singer B, Essigmann JM (1991) Site-specific mutagenesis: retrospective and prospective. Carcinogenesis 12:949–955
Spodheim-Maurizot M, Saint-Ruf R, Leng M (1979) Conformational changes induced in DNA by in vitro reaction withN-hydroxy-N-2-aminofluorene. Nucleic Acids Res 6:1683–1694
Solt DB, Farber E (1976) New principle for the analysis of chemical carcinogenesis. Nature 263:701–703
Talaska G, Al-Juburi AZSS, Kadlubar FF (1991) Smoking related carcinogen-DNA adducts in biopsy samples of human urinary bladder: identification ofN-(deoxyguanosine-8-yl)-4-aminobiphenyl as a major adduct. Proc Natl Acad Sci USA 88:5350–5354
Tchen P, Fuchs RPP, Sage E, Leng M (1984) Chemically modified nucleic acids as immunodetectable probes in hybridization experiments. Proc Natl Acad Sci USA 81:3466–3470
Van der Laken CJ, Hagenaars AM, Hermsen G, Kriek E, Kuipers AJ, Nagel J, Scherer E, Welling M (1982) Measurement ofO 6-ethyldeoxyguanosine andN-(deoxyguanosin-8-yl)-N-acetyl-2-aminofluorene in DNA by high-sensitive enzyme immunoassays. Carcinogenesis 3:569–572
Van Houte LPA, Bokma JT, Lutgerink JT, Westra JG, Retèl J, Van Grondelle R, Blok J (1987) An optical study of the conformation of the aminofluorene-DNA complex. Carcinogenesis 8:759–766
Vineis P, Caporaso N, Tannenbaum SR, Skipper PL, Glogowski J, Bartsch H, Coda M, Talaska G, Kadlubar FF (1990) Acetylation phenotype, carcinogen-hemoglobin adducts, and cigarette smoking. Cancer Res 50:3002–3004
Vousden KH, Bos JL, Marshall CJ, Phillips DH (1986) Mutations activating human c-Ha-ras-1 proto-oncogne (HRAS1) induced by chemical carcinogens and depurination. Proc Natl Acad Sci USA 83:1222–1226
Watson JD, Crick FHC (1953) Molecular structure of nucleic acids. A structure for deoxyribose nucleic acid. Nature 171:737–738
Weisburger EK, Weisburger JH (1958) Chemistry, carcinogenicity and metabolism of 2-fluorenamine and related compounds. Adv Cancer Res 5:331–431
Weston A, Caporaso NE, Hoover RN, Tannenbaum SR, Skipper PL, Resau JH, Trump BF, Harris CC (1991) Measurement of 4-aminobiphenyl-hemoglobin adducts in lung cancer cases and controls. Proc Am Assoc Cancer Res 32:1329
Westra JG, Visser A, Tulp A (1982) Binding and repair of 2-acetylaminofluorene adducts in distinct liver cell populations. Environ Health Perspect 49:87–91
Wilson RH, DeEds F, Cox AJ (1941) The toxicity and carcinogenicity of 2-acetaminofluorene. Cancer Res 1:595–608
Wiseman RW, Stowers SJ, Miller EC, Anderson MW, Miller JA (1986) Activating mutations of the c-Ha-ras-protooncogene in chemically induced hepatomas of the male B6C3F mouse. Proc Natl Acad Sci USA 83:5825–5829
Zielinska B, Arey J, Atkinson R (1990) The atmospheric formation of nitroarenes and their occurrence in ambient air. In: Howard PC, Hecht SS, Beland FA (eds) Nitroarenes, occurrence, metabolism and biological impact. Plenum, New York, pp 73–84
Author information
Authors and Affiliations
Additional information
The “Journal of Cancer Research and Clinical Oncology” publishes in loose succession “Editorials” and “Guest editorials” on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author The Editors
Rights and permissions
About this article
Cite this article
Kriek, E. Fifty years of research onN-acetyl-2-aminofluorene, one of the most versatile compounds in experimental cancer research. J Cancer Res Clin Oncol 118, 481–489 (1992). https://doi.org/10.1007/BF01225261
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01225261