Skip to main content
SpringerLink
Log in

Structure-activity relations in carcinogenesis by N-nitroso compounds

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

For a large number of N-nitroso compounds a comparison of their carcinogenic effects in rats and Syrian golden hamsters has been made. Nitrosamines, which require metabolic activation, and nitrosoalkylamides, which do not, produce quite different tumor responses. There are also large differences in the types of tumor induced in rats and in hamsters. In all the studies doses of the various compounds, equimolar to the extent that was possible, are administered orally. Continuous doses (in drinking water or food) often produce a response different from that after administration of the same compound in pulsed doses (by gavage), even though the same total dose is delivered. Continuous doses of nitrosamines are usually more effective than pulsed doses, but with the nitrosoalkylureas, the reverse is more generally the case. Rat and hamster liver is a common target of many nitrosamines, but rarely of nitrosamides. The most common site of tumor induction in rats by N-nitroso compounds is the esophagus, but the hamster esophagus never responds. The pancreas duct of the hamster is a common target of nitrosamines containing a β-oxygenated propyl group, but pancreas duct tumors are never seen in rats. Nitrosomethyl-n-alkylamines (with an even numbered carbon chain) induce bladder tumors in rats and hamsters. Many nitrosoalkylureas induce tumors of the nervous system in rats, as well as a great variety of other tumors. In hamsters, nitrosoalkylureas give rise only to tumors of the forestomach and spleen, but no tumors of the nervous system. The similar carcinogenic actions of certain groups of N-nitroso compounds can be related to their generation, directly or by metabolism, of similar simple moieties having certain organs as their target.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barnes JM, Magee PN: Some toxic properties of dimethylnitrosamine. Brit J Ind Med 11: 167–174, 1954

    Google Scholar 

  2. Magee PN, Barnes JM: The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine. Brit J Cancer 10: 114–122, 1956

    Google Scholar 

  3. Druckrey H, Preussmann R, Schmähl D, Ivankovic S: Organotrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z Krebsforsch 69: 103–201. 1967

    Google Scholar 

  4. Lijinsky W, Loo J, Ross A: Mechanism of alkylation of nucleic acids by nitrosodimethylamine. Nature 218: 1174–1175, 1968

    Google Scholar 

  5. Ross AE, Keefer L, Lijinsky W: Alkylation of nucleic acids of rat liver and lung by deuterated N-nitrosodiethylamine in vivo. J Natl Cancer Inst 47: 789–795, 1971

    Google Scholar 

  6. Lijinsky W, Garcia H, Keefer L, Loo J: Carcinogenesis and alkylation of rat liver nucleic acids by nitrosomethylurea and nitrosoethylurea administered by intraportal injection. Cancer Res 32: 893–897, 1972

    Google Scholar 

  7. Goodall CM, Lijinsky W, Tomatis L, Wenyon CEM: Toxicity and oncogenicity of nitrosomethylaniline and nitrosomethyleyclohexylamine. Toxicol Appl harmacol 17: 426–432, 1970

    Google Scholar 

  8. Lijinsky W, Keefer L, Loo J, Ross AE: Studies of alkylation of nucleic acids in rats by cyclic nitrosamines. Cancer Res 33: 1634–1641, 1973

    Google Scholar 

  9. Cardy RH, Lijinsky W, Hildebrandt P: Neoplastic and nonncoplastic urinary bladder lsions induced in Fischer 344 rats and B6C3F1 hybrid mice by N-nitrosodiphenylmine. Ecotoxicology & Environ Safety 3: 29–35. 1979

    Google Scholar 

  10. Lijinsky W, Reuber MD: Transnitrosation by nitrosamines in vivo. N-Nitroso Compounds: Occurrence and Biological Effects. IARC Scientific Publication No. 41, 625–631, 1982

  11. Lijinsky W: Significance of N-nitroso compounds as environmental carcinogens. J Environ Sci Health C4(1) 1–45, 1986

    Google Scholar 

  12. Lijinsky W, Reuber MD, Manning WB: Potent carcinogenicity of nitrosodiethanolamine in rats. Nature 288: 309–310, 1980

    Google Scholar 

  13. Lijinsky W, Reuber MD: Dose response study with N-nitrosodiethanolamine. Fd Chem Toxicol 22: 23–26, 1984

    Google Scholar 

  14. Lijinsky W, Kovatch RM: Induction of liver tumors in rats by nitrosodiethanolamine at low doses. Carcinogenesis 6: 1679–1681, 1985

    Google Scholar 

  15. Lijinsky W, Reuber MD, Singer GM: Induction of tumors of the esophagus in rats by nitrosmethylalkylamines. J Can Res Clin Oncol 106: 171–175, 1983

    Google Scholar 

  16. Magee PN, Barnes JM: Carcinogene nitroso compounds. Adv Cancer Res 10: 163–246, 1967

    Google Scholar 

  17. Bogovski P, Bogovski S: Animal species in which N-nitroso compounds induce cancer. Int J Cancer 27: 471–474, 1981

    Google Scholar 

  18. Krüger FW, Pour P, Althoff J: Induction of pancreas tumous by diispropanolnitrosamine. Naturwissenschaften 61: 328, 1974

    Google Scholar 

  19. Lijinsky W: Species differences in nitrosamine carcinogenesis. J Cancer Res Clin Oncol 108: 46–55, 1984

    Google Scholar 

  20. Preussmann R, Stewart BW: N-Nitroso Carcinogens. In: Searle CE (ed) Chemical Carcinogens. American Chemical Society Monograph 182. Washington, 1984, pp 643–828

  21. Keefer LK. Fodor CH: Facile hydrogen isotope exchange as evidence for an α-nitrosamaine carbanion. J Am Chem Soc 92: 5747–5748, 1970

    Google Scholar 

  22. Singer GM, Lijinsky W: Relative extents of hydrogendeuterium exchange of nitrosamines: Relevance to biological isotope effect studies. Cancer Lett 8: 29–34, 1979.

    Google Scholar 

  23. Keefer L, Lijinsky W, Garcia H: Deuterium isotope effect on the carcinogenicity of dimethylnitrosamine in rat liver. J Natl Canc Inst 51 299–302, 1973

    Google Scholar 

  24. Lijinsky W, Reuber M: Carcinogenicity in rats of nitrosomethylethylamies labeled with deuterium in several positions. Cancer Res 40: 19–21, 1980

    Google Scholar 

  25. Lijinsky W, Reuber MD, Riggs CW: Dose-response studies in rats with nitrosodiethylamine. Cancer Res 41: 4997–5003, 1981

    Google Scholar 

  26. Lijinsky W, Saavedra JE. Reuber MD, Singer SS: Esophageal carcinogenesis in Fischer 344 rats by nitrosomethylethylamines substituted in the ethyl group. J Natl Cancer Inst 68: 681–684, 1982

    Google Scholar 

  27. Koepke SR, Creasia DR, Knutsen GI, Michejda CJ: Carciogenicity of methyl-2-hydroxyethyl-, methyl-2-tosyloxyethyl and methyl-3-hydroxypropyl- nitrosamines in Fischer 344 rats. Cancer Res submitted.

  28. Lijinsky W. Reuber MD: Comparative carcinogenicity of some aliphatic nitrosamines in Fischer rats. Cancer Letters 14: 297–302. 1981

    Google Scholar 

  29. Lijinsky W, Reuber MD, Saavedra JE, Blackwell B-N: Effect of deuterium on the carcinogenicity of nitrosomethyl-n-butylamine. Carcinogenesis 1: 157–160. 1980

    Google Scholar 

  30. Kleihues P. Von Hofe E, Schmerold I, Keefer LK, Lijinsky W: Organ specificity, metabolism and reaction with DNA of aliphatic methylalkylnitrosamins. In:N-Nitroso Compounds, Relevance to Human Cancer. IARC Scientific Publication, No. 84, 49–54, 1987

  31. Lijinsky W, Reuber MD, Davies TS, Saavedra JE, Riggs CW: Dose-esponse studies in carcinogeesis by nitrosomethyl-2-phenylethylamine in rats and the effect of deuterium. Fd Cosmet Toxicol 20: 393–399. 1982

    Google Scholar 

  32. Lijinsky W, Deuterium isotope effects in carcinogenesis by N-nitroso compounds and related carcinogens. J Can-cerRes Clin Oncol. 112: 229–239, 1986

    Google Scholar 

  33. Lijinsky W, Reuber MD: Carcinogenicity of deuteriumlabeled N-nitroso-N-methyleyclohexylamine in rats. J Natl Cancer Inst 64: 1535–1536, 1980

    Google Scholar 

  34. Lijinsky W, Kovatch RM: The effect of age on susceptibility of rats to carcinogenesis by two nitrosamines. GANN 77: 1222–1226, 1986

    Google Scholar 

  35. Lijinsky W. Saavedra JE, Knutsen GM, Kovatch R: Comparison of the carcinogenic effectiveness of nitrosobis(2-hydroxypropyl)amine, nitrosobis(2-oxopropyl)amine, nitrosohydroxypropyloxopropylamine and nitroso-2,6-dimethylmorpholine in Syrian hamsters. J Natl Cancer Ins 72: 685–688, 1984

    Google Scholar 

  36. Andrews AW, Lijinsky W: Mutagenicity of N-nitroso compounds in the Salmonclla Assay. In: Rao TK, et al. (ed) Genotoxicology of N-Nitroso Compounds. Plenum Publishing Corp, New York, 1984, pp 13–43

    Google Scholar 

  37. Lijinsky W: Interaction with nucleic acids of carcinogenic and mutagenic N-nitroso compounds. Progress in Nucleic Acid Research 17: 247–269, 1976

    Google Scholar 

  38. Lijinsky W, Taylor HW, Keefer LK: Reduction of rat liver carcinogenicity of nitrosomorpholine by alpha deuerium substitution. J Natl Cancer Inst 57: 1311–1313, 1976

    Google Scholar 

  39. Charnley G, Archer MC: Deuterium isotope effect in the activation of nitrosomorpholine into a bacterial mutagen. Mutat Res 46: 265–268, 1977

    Google Scholar 

  40. Lijinsky W, Taylor HW: Carcinogenicity of nitrosoazetidine and tetradeuteronitrosoazetidine in Sprague-Dawley rats. Z Krebsforsh 89: 215–219, 1977

    Google Scholar 

  41. Lijinsky W, Reuber MD, Davies TS, Riggs CW: Doseresponse studies with nitrosoheptamethyleneimine and its alpha deuterium labeled derivative in F344 rats. J Natl Cancer Inst 69: 1127–1133, 1982

    Google Scholar 

  42. Lijinsky W, Saavedra JE, Reuber MD, Blackwell BN: The effect of deuterium labeling on the carcinogenicity of nitroso-2,6-dimethylmorpholine in rats. Cancer Letters 10: 325–31, 1980

    Google Scholar 

  43. Rao MS, Scarpelli DG, Lijinsky W: Carcinogenesis in Syrian hamsters by N-nitroso-2,6-dimethylmorpholine, its cis and trans isomers, and the effect of deuterium labeling. Carcinogenesis 2: 731–735, 1981

    Google Scholar 

  44. Gingell R, Wallcave L, Nagel D, Kupper R, Pour P: Common metabolites of N-nitroso-2,6-dimethylmorpholine and N-Nitrosobis-(2-oxopropyl)amine in the Syrian hamster. Cancer Lett 2: 47–52, 1976

    Google Scholar 

  45. Underwood B, Lijinsky W: Comparative metabolism of 2,6-dimethylnitrosomorpholine in rats, hamstes and guinea pigs. Cancer Res 42: 54–58, 1982

    Google Scholar 

  46. Lijinsky W: Metabolism and cellular interactions of some aliphatic nitrogenous carcinogens. Cancer Lett 26: 33–42, 1985

    Google Scholar 

  47. Hard GC, Butler WH: Cellular analysis of renal neoplasia: Light microscope study of the development of interstitial lesions induced in the rat kidney by a single carcinogenic dose of dimethylnitrosamine. Cancer Res 30: 2806–2815, 1970

    Google Scholar 

  48. Lijinsky W, Kovatch RM: Carcinogenesis by nitrosodialkylamines and azoxyalkanes given by gavage to rats and hamsters. Cancer Res 47: 3968–3972, 1987

    Google Scholar 

  49. Lijinsky W, Reuber MD: Carcinogenesis in F344 rats by nitrosodimethylamine and other nitrosomethylalkylamines at low doses. Cancer Lett 22: 83–88, 1984

    Google Scholar 

  50. Lee KY, Lijinsky W, Magee PN: Methylation of ribonucleic acids of liver and other organs in different species treated with C14 and H3-dimethylnitrosamine in vivo. J Natl Cancer Inst 32: 65–75, 1964

    Google Scholar 

  51. Tomatis L, Cefis F: The effects of muliple and single administration of dimethylnitrosamine to hamsters. Tumori 53: 447–452, 1967

    Google Scholar 

  52. Lijinsky W Saavedra JE, Reuber MD: Induction of carcinogenesis in Fischer rats by methylalkylnitrosamines. Cancer Res 41: 1288–1292, 1981

    Google Scholar 

  53. Lijinsky W, Reuber MD: Carcinogenesis in Fischer rats by nitrosodipropylamine, nitosodibutylamine and nitrosobis(2-oxopropyl)amine given by gavage. Cancer Lett 19: 207–213, 1983

    Google Scholar 

  54. Lijinsky W, Reuber MD, Davies TC, Riggs CW: Doseresponse studies with nitroso-1,2,3,6-tetrahydropyridine and dinitrosohomopiperazine. Ecotoxicol Envir Safety 6: 513–527, 1982

    Google Scholar 

  55. Lijinsky W, Reuber MD: Carcinogenicity of hydroxylated alkylnitrosoureas and of nitrosooxazolidones by mouse skin painting and by gavage in rats. Cancer Res 43: 214–221, 1983

    Google Scholar 

  56. Singer GM, Lijinsky W, Buettner L, McClusky GA: Relationship of rat urinary metabolites of N-nitrosomethyl-N-alkylamine to bladder carcinogenesis. Cancer Res 41: 4942–4946, 1981

    Google Scholar 

  57. Lijinsky W, Reuber MD, Saavedra JE, Singer GM: Carcinogenesis in F344 rats by nitrosomethyl-n-propylamine derivatives. J Natl Cancer Inst 70: 959–963, 1983

    Google Scholar 

  58. Hashimoto Y, Suzuki K, Okada M: Induction of urinary bladder tumors by intravesicular instillation of butyl(4-hydroxybutyl)nitrosoamine and its principal urinary metabolite, butyl(3-carboxypropyl)nitrosoamine in rats. GANN 65: 69–73, 1974

    Google Scholar 

  59. Ketkar MB, Althoff J, Lijinsky W: The carcinogenic effect of nitrosomethyldodecylamine in European hamsters. Cancer Lett 13: 165–168, 1981

    Google Scholar 

  60. Lijinsky W, Losikoff AM, Sansone EP: N-Nitrosodiethanolamine and N-nitrosomorpholine readily penetrate rat skin. J Natl Cancer Inst 66: 125–127, 1981

    Google Scholar 

  61. Lijinsky W: Comparison of the carcinogenic effectiveness in mouse skin of methyl-and ethyl-nitrosourea, nitroourethane and nitrosonitroguanidine and the effect of deuterium labeling. Carcinogenesis 3: 1289–1291, 1982

    Google Scholar 

  62. Berenblum I, Shubik P: The role of croton oil application associated with a single painting of a carcinogen, in tumour induction in the mouse's skin. Brit J Cancer 1: 379–383, 1947

    Google Scholar 

  63. Waynforth HB, Magee PN: The effect of various doses and schedules of administration of N-methyl-N-nitrosourea, with and without croton oil promotion, on skin papilloma production in Balb/c mice. GANN Monogr Cancer Res 17: 439–448, 1975

    Google Scholar 

  64. Winn DM: Tobacco chewing and snuff dipping: An association with human cancer. In: O'Neill IK, Von Borstel RC, Miller CT, Long S, Bartsch H (eds) N-Nitroso Compounds: Occurrence, Biological Effects and Relevance to Human Cancer. IARC Scientifi Publications No. 57, Lyon. 1984, pp 401–409

  65. Hoffmann D, Brunnemann KD, Adams JD, Hecht SS: Formation and analysis of N-nitrosamines in tobacco products and their endogenous formation in consumers. In: O'Neill IK, Von Borstel RC, Miller CT Long S, Bartsch H (eds) N-Nitroso Compounds: Occurrence, Biological Effects and Relevance to Human Cancer. IARC Scientific Publications No. 57, Lyon, 1984, pp 743–762

  66. Goodall CM, Lijinsky W: Strain and sex differences in N-nitrosohexamethylencimine carcinogenesis in NZB, NZC, NZO and NZY mice. J Natl Cancer Inst 73: 1215–1218, 1984

    Google Scholar 

  67. Lijinsky W, Singer GM, Kovatch RM: Similar carcinogenic effect in rats of 1-ethyl-1-nitroso-3-hydroxyethylurea and 1-hydroxyethyl-1-nitroso-3-ethylurea. Carcinogenesis 6: 641–643, 1985

    Google Scholar 

  68. Goth R, Rajewsky MF: Persistence of O6-ethylguanine in rat brain DNA. Correlation with nervous system-specific carcinogenesis by ethylnitrosourea. Proc Natl Acad Sci USA 71: 639–643, 1974

    Google Scholar 

  69. Lickachev AJ, Ivanov MN, Bresil H. Planche-Martel G, Montesano R, Margison GP: Carcinogenicity of single doses of N-nitroso-N-methylurea and N-nitroso-N-ethylurea in Syrian golden hamsters and the persistence of alkylated purines in the DNA of various tissues. Cancer Res 43: 829–833, 1983

    Google Scholar 

  70. Magee PN, Farber E: Toxic liver injury and carcinogenesis. Methylation of rat-liver nucleic acids by dimethylnitrosamine in vivo. Biochem J 83: 114–124, 1962

    Google Scholar 

  71. VonHofe E, Kleihues P, Keefer LK: Extent of DNA 2-hydroxyethylation by N-nitrosomethylethylamine and N-nitrosodiethylamine in vivo. Carcinogenesis 7: 1335–1337, 1986

    Google Scholar 

  72. Okada M: Comparative metabolism of N-nitrosamines in relation to their organ and species specificity. In: O'Neill IK. Von Borstel RC. Miller CT, Long J. Barsch E (eds) N-Nitroso Compouns: Occurrence, Biological Effects and Relevance to Hman Cancer. IARC Scientific Publications No. 57, Lyon, 1984, pp 401–409

  73. Krüger FW: Metabolism of nitrosamines in vivo. I. Evidence for α-oxydation of aliphatic di-n-alkylnitrosamines: The stimultaneous formation of 7-methylguanine besides 7-propyl- or 7-butylguanine after application of di-n-propyl-or di-n-butylnitrosamine. Z Krebsforsch 76: 145–154. 1971

    Google Scholar 

  74. Kroeger-Koepke MB, Koepke SR, Mclusky GA, Magee PN, Michejda CJ: α-Hydroxylation pathway in the in vitro metabolism of carcinogenic nitrosamines: N-Nitrosodimethylamine and N-nitroso-N-methylaniline. Proc Natl Acad Sci USA 78: 6489–6493, 1981

    Google Scholar 

  75. Preussmann R, Ivankovic S, Lanschütz C, Gimmy J, Flohr E, Griesbach U: Carcinogenic activity of 13 aryldialkyl triazenes in BD-rats. Z Krebsforsch 81: 285–310, 1974

    Google Scholar 

  76. Magee PN, Lee KY: Cellular injury and carcinogenesis. Alkylation of ribunucleic acid of rat liver by diethylnitrosamine and n-butylmethylnitrosamine in vivo. Biochem J 91: 35–42, 1964

    Google Scholar 

  77. Lijinsky W, Taylor HW: Carcinogenicity of methylated derivatives of nitrosodiethylamine and related compounds in Sprague-Dawley rats. J Natl Cancer Inst 62: 407–410, 1979

    Google Scholar 

  78. Mehta R, Labuq GE, Archer MC: Tissue and species specificity of the microsomal metabolism of N-nitro-omethylbenzylamine. In: O'Neill IK, Von Borstel RC, Miller CT, Long J. Bartsch H (eds) N-Nitroso Compounds: Occurrence. Bioogical Effects and Relevance to Human Cancer. IARC Scientific Publications No. 57, Lyon. 1984, pp 473–478

  79. Lijinsky W, Taylor HW, Mangino M, Singer GM: Carcinogenesis of nitosomethylundecylamine in Fiscer rats. Cancer Lett 5: 209–213, 1978

    Google Scholar 

  80. Okada M, Suzuki E, Mochizuki M: Possible impotant role of urinary N-methyl-N-(3-carboxypropyl)nitrosamine in the induction of bladder tumors in rats by N-methyl-N-dodecylnitrosamine. GANN 67: 771–772, 1976

    Google Scholar 

  81. Althoff J, Lijinsky W: Urinary bladder neoplasms in Syrian hamsters after administration of N-nitroso-N-methyl-N-dodecylamine. Z Krebsforsch 90: 227–231, 1977

    Google Scholar 

  82. Lijinsky W, Kovatch RM: Carcinogenesis by oxygenated nitrosomethylpropylamines in Syrian hamsters. J Cancer Res Clin Oncol 109: 1–4, 1985

    Google Scholar 

  83. Cardy RH, Lijinsky W: Comparison of the carcinogenic effects of five nitrosamines in guinea pigs. Cancer Res 40: 1879–1884, 1980

    Google Scholar 

  84. White IMH, Smith AG, Farmer PB: Formation of N-alkylated protoporphyrin IX in the livers of mice after diethylnitrosamine treatment. Biochem J 212: 599–608, 1983

    Google Scholar 

  85. Farrelly JG, Thomas BJ, Lijinsky W: Metabolism and cellular interactions of N-nitrosodiethanolamine. N-Nitroso Copounds: Relevance to Human Cancer. In: N-Nitroso Compounds, Relevance to Human Cancer, IARC Scientific Publications No. 84, 1987, pp 87–90

  86. Lijinsky W, Taylor HW: Relative carcinogenic effectiveness of derivatives of diethylnitrosamine in rats. Cancer Res 38: 2391–2394, 1978

    Google Scholar 

  87. Airoldi L, Bonfanti M, Fanelli R, Benfenati E, Gariboldi P: Identification of a nitrosamine aldehyde and a nitrosamino acid resulting from β-oxidation of N-nitrosodiethanolamine. Chem-Biol Interact 51: 103–113, 1984

    Google Scholar 

  88. Pour P, Gingell R, Langenbach R, Nagel D, Grandjean C, Lawson T, Salmasi S: Carcinogenicity of N-(nitrosomethyl-2-oxopropyl)amine in Syrian hamsters. Cancer Res 40: 3585–3590, 1980

    Google Scholar 

  89. Pour P, Althoff J, Krüger FW, Mohr U: A potent pancreatic carcinogen in Syrian hamsters: N-nitrosobis-(2-oxopropyl)amine. J Natl Cancer Inst 58: 1449–1453, 1977

    Google Scholar 

  90. Lijinsky W, Saavedra JE, Reuber MD: Carcinogenesis in F334 rats by nitrosobis-(2-oxopropyl)amine and related compounds administered in drinking water. J Cancer Res Clin Oncol 107: 178–182, 1984

    Google Scholar 

  91. Pour P, Wallcave L, Gingell R, Lawson T, Grandjean C: Carcinogenic effect of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, a postulated proximate pancreatic carcinogen in Syrian hamsters. Cancer Res 39: 3828–3833, 1979

    Google Scholar 

  92. Lijinsky W, Singer GM, Saavedra JE, Reuber MD: Carcinogenesis in rats by asymmetric nitrosamines containing the allyl group. Cancer Lett 22: 281–288, 1984

    Google Scholar 

  93. Lijinsky W, Winter C: Skin tumors by painting nitrosoalkylureas on mouse skin. Cancer Res & Clinical Oncology 102: 13–20, 1981

    Google Scholar 

  94. Lijinsky W, Saavedra JE, Reuber MD: Carcinogenesis in rats by some hydroxylated acyclic nitrosamines. Carcinogenesis 5: 167–170, 1984

    Google Scholar 

  95. Lijinsky W, Knutsen GM, Kovatch RM: Comparative carcinogenesis by hydroxylated nitrosopropylamines in Syrian hamsters. J Natl Cancer Inst 74: 923–926, 1985

    Google Scholar 

  96. Hilfrich J, Schmeltz J, Hoffmann D: Effects of N-nitrosodiethanolamine and 1,1-diethanolhydrazine in Syrian golden hamsters. Cancer Lett 4: 55–60, 1977

    Google Scholar 

  97. Lijinsky W, Knutsen GM, Kovatch RM: Carcinogenic effects of nitrosoalkylureas and nitrosoalkylcarbamates in Syrian hamsters. Cancer Res 45: 542–545, 1985

    Google Scholar 

  98. Mochizuki M, Anjo T, Okada M: Isolation and characterization of N-alkyl-N-(hydroxymethyl)nitrosamines from N-alkyl-N-(hydroperoxymethyl)nitrosamines by deoxygenation. Tetrahedron Lett 21: 3693–3696, 1980

    Google Scholar 

  99. Lijinsky W, Greenblatt M, Kommineni C: Feeding studies of nitrilotriacetic acid and derivatives in rats. J Natl Cancer Inst 50: 1061–1063, 1973

    Google Scholar 

  100. Lijinsky W, Taylor HW: Comparative carcinogenicity of some derivatives of nitrosodi-n-propylamine in rats. Ecotoxicology and Environ Safety 2: 421–426, 1978

    Google Scholar 

  101. Preussmann R, Habs M, Pool B, Stummeyer D, Lijinsky W, Reuber MD: Fluoro-substituted N-nitrosamines. 1. Inactivity of N-nitroso-bis-(2,2,2-trifluoroethyl)amine in carcinogenicity and mutagenicity tests. Carcinogenesis 2: 753–756, 1981

    Google Scholar 

  102. Lijinsky W, Kovatch RM, Knutsen GL: Carcinogenesis by nitrosomorpholines, nitrosooxazolidines and nitrosoazetidine given by gavage to Syrian golden hamsters. Carcinogenesis 5: 875–878, 1984

    Google Scholar 

  103. Dontenwill W: Experimental studies on the organotropic effect of nitrosamines in the respiratory tract. Food Cosmet Toxicol 6: 571, 1968

    Google Scholar 

  104. Lijinsky W, Taylor HW: Carcinogenicity of methylated nitrosopiperidines. Intern J Cancer 16: 318–322, 1975

    Google Scholar 

  105. Lijinsky W, Reuber MD: Carcinogenic effect of nitrosopyrrolidine, nitrosopiperidine and nitrosohexamethyleneimine in Fischer rats. Cancer Lett 12: 99–103, 1981

    Google Scholar 

  106. Althoff J, Wilson R, Cardesa A, Pour P: Comparative studies of neoplastic response to a single dose of nitroso compounds. 3. The effect of N-nitrosopiperidine and N-nitrosomorpholine in Syrian golden hamsters. Z Krebsforsch 81: 251–259, 1974

    Google Scholar 

  107. Stewart BW, Swann PF, Holsman JW, Magee PN: Cellular injury and carcinogenesis. Evidence for the alkylation of rat liver nucleic acids in vivo by N-nitrosomorpholine. Z Krebsforsch 82: 1–12, 1974

    Google Scholar 

  108. Lijinsky W, Reuber MD: Comparative carcinogenesis by nitrosomorpholines, nitrosooxazolidines and nitrosotetrahydrooxazine in rats. Carcinogenesis 3: 911–915, 1982

    Google Scholar 

  109. Garcia H, Keefer L, Lijinsky W, Wenyon CEM: Carcinogenicity of nitrosothiomorpholine and 1-nitrosopiperazine in rats. Z krebsforsch 74: 179–184, 1970

    Google Scholar 

  110. Goodall CM, Lijinsky W, Tomatis L: Tumorigenicity of N-nitrosohexamethyleneimine. Cancer Res 28: 1217–1222, 1968

    Google Scholar 

  111. Lijinsky W, Tomatis L, Wenyon CEM: Lung tumors in rats treated with N-nitrosoheptamethyleneimine and N-nitrosooctamethyleneimine. Proc Soc Exper Biol and Med 130: 945–949, 1969

    Google Scholar 

  112. Schreiber H, Nettesheim P, Lijinsky W, Richter CB, Walburg HE: Induction of lung cancer in germ free, specific pathogen free and infected rats by N-nitrosoheptamethyleneimine: Enhancement by respiratory infection. J Natl Cancer Inst 49: 1107–1114, 1972

    Google Scholar 

  113. Althoff J, Pour P, Cardesa A, Mohr U: Comparative studies of neoplastic response to a single dose of nitroso compounds. 1. The effect of N-nitrosohexamethyleneimine in Syrian golden hamsters and Swiss mice. Z Krebsforsch 78: 78–81, 1972

    Google Scholar 

  114. Lijinsky W, Ferrero A, Montesano R, Wenyon CEM: Tumorigenicity of cyclic nitrosamines in Syrian golden hamsters. Z Krebsforsch 74: 185–189, 1970

    Google Scholar 

  115. Lijinsky W, Taylor HW: Carcinogenicity tests in rats of two nitrosamines of high molecular weight, nitrosododecamethyleneimine and nitrosodi-n-octylamine. Ecotoxicoloy and Environ Safety 2: 407–411, 1978

    Google Scholar 

  116. Goodall CM, Lijinsky W: Carcinogenicity of nitrosododecamethyleneimine in NZR/Gd inbred rats. Carcinogenesis 5: 537–540, 1984

    Google Scholar 

  117. Goodall CM, Lijinsky W, Keefer L, D'Ath EF: Oncogenic activity of N-nitrosododecamethyleneimine in liver, glandular stomach and other tissue of NZO/B1 mice. Internat J Cancer 11: 369–376, 1973

    Google Scholar 

  118. Lijinsky W, Taylor HW: The effect of substituents on the carcinogenicity of N-nitrosopyrrolidine in Sprague-Dawley rats. Cancer Res 36: 1988–1990, 1976

    Google Scholar 

  119. Lijinsky W, Reuber MD, Singer SS, Singer GM: Carcinogenesis by isomers of 3,5-dimethylnitrosopiperidine. J Natl Cancer Inst 68: 989–991, 1982

    Google Scholar 

  120. Lyle RE, Saavedra JE, Lyle GG, Fribush MM, Marshall JL, Lijinsky W, Singer GM: Conformational stereospecificity in electrophilic reactions with cyclic anions. Tet Lett 4431–4434, 1976

  121. Lijinsky W, Singer GM, Reuber MD: The effect of 4-substitution on the carcinogenicity of nitrosopiperidine. Carcinogenesis 2: 1045–1048, 1981

    Google Scholar 

  122. Singer GM, Taylor HW: Carcinogenicity of N′-nitrosonornicotine in Sprague-Dawley rats. J Natl Cancer Inst 57: 1275–1276, 1976

    Google Scholar 

  123. Hoffmann D, Raineri R, Hecht SS, Maronpot R, Wynder EL: A study of tobacco carcinogenesis. XIV. Effects of N′-nitrosonornicotine and N′-nitrosoanabasine in rats. J Natl Cancer Inst 55: 977–979, 1975

    Google Scholar 

  124. Lijinsky W, Reuber MD, Reznik-Schüller HM: Contrasting carcinogenic effects of nitroso-2,6-dimethylmorpholine given by gavage to F344 rats and Syrian golden hamsters. Cancer Lett 16: 281–286, 1982

    Google Scholar 

  125. Mohr U, Reznik G, Emminger E, Lijinsky W: Induction of pancreatic duct carcinomas in the Syrian golden hamster with 2,6-dimethylnitrosomorpholine. J Natl Cancer Inst 58: 429–432, 1977

    Google Scholar 

  126. Lijinsky W, Reuber MD: Comparison of carcinogenesis by two isomers of nitroso-2,6-dimethylmorpholine. Carcinogenesis 1: 501–503, 1980

    Google Scholar 

  127. Lijinsky W, Reuber MD: Comparative carcinogenicity of two isomers of dimethylnitrosomorpholine in guinea pigs. Cancer Lett 14: 7–11, 1981

    Google Scholar 

  128. Underwood B, Lijinsky W: Comparative metabolism of the cis and trans isomers of N-nitroso-2,6-dimethylmorpholine in rats, hamsters and guinea pigs. Chem-Biol Interactions 50: 175–188, 1984

    Google Scholar 

  129. Lijinsky W, Taylor HW: Carcinogenicity tests of N-nitroso derivatives of two drugs. phenmetrazine and methylphenidate. Cancer Lett 1: 359–363, 1976

    Google Scholar 

  130. Garcia H, Lijinsky W: Tumorigenicity of five cyclic nitrosamines in MRC rats. Z Krebsforsch 77: 257–261, 1972

    Google Scholar 

  131. Kupper R, Reuber MD, Blackwell BN, Lijinsky W, Koepke SR, Michejda CJ: Carcinogenicity of the isomeric 355–1 and 355–2 in rats and the in vivo isomerization of the 355–3 to the 355–4. Carcinogenesis 1: 753–757, 1980

    Google Scholar 

  132. Lijinsky W, Taylor HW: Carcinogenicity of two unsaturated derivatives of nitrosopiperidine in Sprague-Dawley rats. J Natl Cancer Inst 57: 1315–1317, 1976

    Google Scholar 

  133. Garcia H, Lijinsky W: Studies of the tumorigenic effect in feeding of nitrosamino acids and of low concentrations of amines and nitrite to rats. Z Krebsforsch 79: 141–144, 1973

    Google Scholar 

  134. Chu C, Magee PN: Metabolic fate of nitrosoproline in the rat. Cancer Res 41: 3653–3657, 1981

    Google Scholar 

  135. Lijinsky W, Taylor HW: Carcinogenesis tests of nitroso-N-methylpiperazine, 2,3.5,6-tetramethyldinitrosopiperazine, nitrosoisonipecotic acid and nitrosomethoxy-methylamine in rats. Z Krebsforsch 89: 31–36, 1977

    Google Scholar 

  136. Hecker LJ, Saavedra JE: In vitro formation and properties of β- and λ-hydroxy-N-nitrosohexamethyleneimine. Carcinogenesis 1: 1017–1025, 1980

    Google Scholar 

  137. Lijinsky W, Epstein SS: Nitrosamines as environmental carcinogens. Nature 225: 21–23, 1970

    Google Scholar 

  138. Eisenbrand G, Habs M, Schmähl D, Preussmann R: Carcinogenicity of N-nitroso-3-hydroxypyrrolidine and doseresponse study with N-nitrosopiperidine in rats. In: Walker EA, Griciute L, Castegnaro M, Börzsönyi M (eds) N-Nitroso Compounds: Analysis, Formation and Occurrence. IARC Scientific Publications No 31, Lyon, 1980, pp 657–663

  139. Lijinsky W, Taylor HW: Tumorigenesis by oxygenated nitrosopiperidines. J Natl Cancer Inst 55: 705–708, 1975

    Google Scholar 

  140. Singer GM, Reuber MD, Lijinsky W: The effect of 3-methyl substitution on carcinogenesis by nitroso-4-piperidone. Carcinogenesis 5: 1351–1353, 1984

    Google Scholar 

  141. Lijinsky W, Saavedra JE, Reuber MD, Blackwell B-N: Carcinogenicity of 3-chloro-, 4-chloro- and 3,4-dichloronitrosopiperidine in Fischer rats. Cancer Res 40: 3325–3327, 1980

    Google Scholar 

  142. Lijinsky W, Taylor HW: Carcinogenicity of 4-chloronitrosopiperidine in Sprague-Dawley rat. Z Krebsforsch 92: 217–220, 1978

    Google Scholar 

  143. Lijinsky W, Taylor HW: Carcinogenicity of N-nitroso-3,4-dichloro-and N-nitroso-3,4-dibromopiperidine in rats. Cancer Res 35: 3209–3211, 1975

    Google Scholar 

  144. Hansen TJ, Angeles RM, Keefer LK, Day CS, Gaffield W: N-nitrosothialdine. Synthesis, X-ray crystallography, and N-N rotational barrier. Tetrahedron 37: 4143–4149 1981

    Google Scholar 

  145. Love LA, Lijinsky W, Keefer LK, Garcia H: Chronic oral administration of 1-nitrosopiperazine at high doses to MRC rats. Z Krebsforsch 89: 69–73, 1977

    Google Scholar 

  146. Lijinsky W, Taylor HW: Increased carcinogenicity of 2,6-dimethylnitrosomorpholine compared with nitrosomorpholine in rats. Cancer Res 35: 2123–2125. 1975

    Google Scholar 

  147. Singer SS, Singer GM, Saavedra JE. Reuber MD, Lijinsky W: Carcinogenesis by derivatives of 1-nitroso-3,5-dimethyl-piperazine in rats. Cancer Res 41: 1034–1038, 1981

    Google Scholar 

  148. Lijinsky W, Knutsen GM, Reuber MD: Carcinogenicity of methylated nitrosopiperazines in rats and hamsters. Carcinogenesis 4: 1165–1167, 1983

    Google Scholar 

  149. Lijinsky W, Taylor HW: Carcinogenicity of methylated dinitrosopiperazines in rats. Cancer Res 35: 1270–1273, 1975

    Google Scholar 

  150. Reznik G, Mohr U, Lijinsky W: Carcinogenic effect of N-nitroso-2.6-dimethylmorpholine in Syrian golden hamsters. J Natl Cancer Inst 60: 371–378, 1978

    Google Scholar 

  151. Lijinsky W, Elespuru RK, Andrews AW: Structure-activity relations in mutagenesis and phage induction among nitrosoalkylureas. Mutation Res, 178: 157–165, 1987

    Google Scholar 

  152. Lijinsky W, Taylor HW: Induction of neurogenic tumors by nitrosotrialkylurcas in rats. Z Krebsforsch 93: 315–321, 1975

    Google Scholar 

  153. Sugimura T, Fujimura S: Tumour production in glandular stomach of rat by N-methyl-N'-nitro-N-nitrosoguanidine. Nature (London) 216: 943–944, 1967

    Google Scholar 

  154. Matsukura M, Kawachi T, Sugimura T, Nakadate M, Hirota T: Induction of intestinal metaplasia and carcinoma in the glandular stomach of rats by N-alkyl-N'-nitro-N-nitrosoguanidnes. GANN 70: 181–185, 1979

    Google Scholar 

  155. Lijinsky W, Reuber MD: Comparison of nitrosocimetidine with nitrosomethylnitroguanidine in chronic feeding tests in rats. Cancer Res 44: 447–449. 1984

    Google Scholar 

  156. Habs M, Eisenbrand G, Habs H, Schmähl D: No evidence of carcinogenicity of N-nitrosocimetidine in rats. Hepatogastroenterology 29: 265–266, 1982

    Google Scholar 

  157. Lijinsky W: Carcinogenesis studies with nitrosocimetidine. Banbury Report 12: Nitrosamines and Human Cancer, Cold Spring Harbor Laboratory. 1982, pp 397–401

  158. Lijinsky W, Elespuru RK: Mutagenicity and carcinogenicity of N-nitroso derivatives of carbamate insecticides. In: Walker FA, Bogovski P, Griciute L (eds) Environmental N-Nitroso Compounds, Analysis and Formation. IARC Scientific Publicaions No 14, 1976, pp 425–428

  159. Blevins RD, Lijinsky W, Regan JD: Nitrosated methylcarbamate insecticides: Effect on the DNA of human cells. Mutation Res 44: 1–7, 1977

    Google Scholar 

  160. Lijinsky W, Taylor HW: Carcinogenesis in Sprague-Dawley rats of N-nitroso-N-alkylcarbamate esters. Cancer Lett 1: 275–279, 1976

    Google Scholar 

  161. Lijinsky W, Schmähl D: Carcinogenicity of N-nitroso derivatives of N-methylcarbamate insecticides in rats. Ecotoxicology and Environ Safety 2: 413–419, 1978

    Google Scholar 

  162. Lijinsky W: Mutagenesis, carcinogenesis and alkylating properties of nitrosamines and related compounds. In: Ramel C, Lambert B, Magnusson J (eds) Genetic Toxicology of Environmental Chemicals, Part B: Genetic Effects and Applied Mutagenesis. Alan R Liss, Inc, New York, 1986, pp 141–148

    Google Scholar 

  163. Kleihues P, Hodgson RM, Veit C, Schweinsberg F, Wiessler M: DNA modification and repair in vivo: Towards a biochemical basis of organspecific carcinogenesis by methylating gents. In: Langenbach R, Nesnow S, Rice JM (eds) Organ and Species Specificity in Chemical Carcinogenesis. Plenum Publishing Corp, New York, 1983, pp 509–528

    Google Scholar 

  164. Lijinsky W: Structure-activity relations in carcinogenesis by N-nitroso compounds. In: Rao TK, et al. (eds) Genotoxicology of N-Nitroso Compounds. Plenum Publishing Corp, New York, 1984, pp 189–231

    Google Scholar 

  165. Lijinsky W, Andrews AW: The mutagenicity of nitrosamides in Salmonella typhimurium. Mutation Res 68: 1–8, 1979

    Google Scholar 

  166. Ivancovic: Perinatale carcinogenese. In: Schmähl D (ed) Maligne Tumoren. Editio Cantor, Aulendorf, Germany, 1981, pp 272–288

    Google Scholar 

  167. Ivancovic S: Teratogenic and carcinogenic effects of some chemicals during prenatal life in rats, Syrian golden hamsters and minipigs. National Cancer Institute Monograph No 51, 103–115, 1979

  168. Ivancovic S, Klimpel F, Wiessler M, Preussmann R: Carcinogenicity in BD-IX rats of 7 homologues of N-nitroso-N-n-alkylureas in different stages of postnatal development. Arch Geschwulstforsch 51: 187–203, 1981

    Google Scholar 

  169. Yokoro K, Takizawa S, Kawamura Y, Nakano M, Kawase A: Multicarcinogenicity of N-nitrosobutylurea in mice and rats as demonstrated by host conditioning. GANN 64: 193–196, 1973

    Google Scholar 

  170. Lijinsky W, Kovatch RM, Singer SS: Carcinogenesis in F344 rats by nitrosohydroxyalkylchloroethylureas. J Cancer Res Clin Oncol 112: 221–228, 1986

    Google Scholar 

  171. Lijinsky W, Reuber MD, Blackwell B-N: Carcinogenicity of nitrosotrialkylureas in Fischer rats. J Natl Cancer Inst 65: 451–453, 1980

    Google Scholar 

  172. Ketkar MD, Mohr U, Lijinsky W: The carcinogenic effect of 1,1-diethyl-3-methyl-3-nitrosourea in Syrian golden hamsters. Cancer Lett 23: 177–182, 1984

    Google Scholar 

  173. Ketkar MB, Althoff J, Lijinsky W: The carcinogenic effect of 1,1-diethyl-3-methylnitrosourea in European hamsters. Exp Path 20: 153–155, 1981

    Google Scholar 

  174. Lijinsky W, Taylor HW: Carcinogenicity of chlorinated nitrosotrialkylureas in rats. J Cancer Res Clin Oncol 94: 131–137, 1979

    Google Scholar 

  175. Kroeger-Koepke MB, Reuber MD, Iype PT, Lijinsky W, Michejda CJ. The effect of substituents in the aromatic ring on carcinogenicity of N-nitrosomethylaniline in F344 rats. Carcinogenesis 4: 157–160, 1983

    Google Scholar 

  176. Lijinsky W, Taylor HW: The change in carcinogenic effectiveness of some cyclic nitrosamines at different doses. Z Krebsforsch 92: 221–225, 1978

    Google Scholar 

  177. Pour P, Gingell R, Langenbach R, Nagel D, Grandjcan C, Lawson T, Salmasi S: Carcinogenicity of N-(nitrosomethyl-2-oxopropyl)amine in Syrian hamsters. Cancer Res 40: 3585–3590, 1980

    Google Scholar 

  178. Okada M, Suzuki E, Aoki J, Iiyoshi M, Hashimoto H: Metabolism and carcinogenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine and related compounds, with special reference to induction of urinary bladder tumors. GANN Monogr Cancer Res 17: 161–176, 1975

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. BRI-Basic Research Program, Chemical Carcinogenesis Program, NCI-Frederick Cancer Research Facility, 21701, Frederick, MD, USA

    William Lijinsky

Authors
  1. William Lijinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Note. In this article all reference citations are enclosed in brackets, while the N-nitroso compounds referred to in Table 1 are enclosed in parentheses and italicized.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lijinsky, W. Structure-activity relations in carcinogenesis by N-nitroso compounds. Cancer Metast Rev 6, 301–356 (1987). https://doi.org/10.1007/BF00144269

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00144269

Key words

Search

Navigation