Abstract
Several nitrosamines and an azoxyalkane have been administered intravesically to groups of 12 female F344 rats, twice a week for 20 or 30 weeks. Many of the nitrosamines were as efficacious in giving rise to the same tumors of internal organs as when similar doses were administered orally, showing that absorption from the bladder was as rapid as from other sites. The tumors produced included lung and kidney tumors by nitrosodimethylamine, colon and Zymbal gland tumors by azoxymethane, liver tumors by methylnitrosoethylamine (but not by nitrosodimethylamine), liver and esophagus tumors by nitrosodiethylamine, liver and lung tumors by methylnitrosamino‐3‐pyridylbutanone, liver tumors by nitrosomorpholine, and tumors of the esophagus by methylnitroso‐n‐butylamine, 2,6‐dimethylnitrosomorpholine and methylnitrosamino‐N,N‐dimethylethylamine. Bladder tumors were induced by intravesicular administration of only low doses of nitrosobis‐(2‐oxopropyl)amine and to a lesser extent by methylnitroso‐n‐hexylamine and nitroso‐(2‐hydroxypropyl)(2‐oxopropyl)amine, which all induced tumors systemically in addition. The bladder mucosa seemed to lack enzymes necessary to activate most nitrosamines to locally acting proximate carcinogens, but was quite transparent to the passage of carcinogenic nitrosamines present in the urine into the body to induce tumors in distant organs.
Keywords: Nitrosamine, Alkylating agent, Rat, Intravesicular, Tumor
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REFERENCES
- 1. ) Druckrey , H. , Preussmann , R. , Ivankovic , S. and Schmahl , D.Organotrope carcinogene Wirkungen bei 65 verschiedenen N‐Nitroso‐Verbindungen an BD‐Ratten. Z . Krebsforsch. , 69 , 103 – 201 ( 1967. ). [PubMed] [Google Scholar]
- 2. ) Hicks , R. M. and Wakefield , J. S.Rapid induction of bladder cancer in rats with N‐methyl‐N‐nitrosourea . Chem.-Biol. Interact. , 5 , 139 – 152 ( 1972. ). [DOI] [PubMed] [Google Scholar]
- 3. ) Lijinsky , W. , Saavedra , J. and Reuber , M. D.Induction of carcinogenesis in Fischer rats by methylalkylnitrosamines . Cancer Res. , 41 , 1288 – 1291 ( 1981. ). [PubMed] [Google Scholar]
- 4. ) Hashimoto , Y. , Suzuki , K. and Okada , M.Induction of urinary bladder tumors by intravesicular instillation of butyl(4‐hydroxybutyl)nitrosamine and its principal urinary metabolite, butyl(3‐carboxypropyl)nitrosamine in rats . Gann , 65 , 69 – 73 ( 1974. ). [PubMed] [Google Scholar]
- 5. ) Thomas , B. J. , Kovatch , R. M. and Lijinsky , W.The induction of bladder tumors in F344 rats by intravesicular administration of some nitrosamines . Jpn. J. Cancer Res. , 79 , 309 – 313 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. ) Okada , M. , Suzuki , E. and Mochizuki , M.Possible important role of urinary N‐methyl‐N‐(3‐carboxypropyl)nitro‐samine in the induction of bladder tumors in rats by N‐methyl‐N‐dodecylnitrosamine . Gann , 67 , 771 – 772 ( 1976. ). [PubMed] [Google Scholar]
- 7. ) Lijinsky , W. , Reuber , M. D. , Saavedra , J. E. and Singer , G. M.Carcinogenesis in F344 rats by mtrosomethyl‐n‐propylamine derivatives . J. Natl Cancer Inst. , 70 , 959 – 963 ( 1983. ). [PubMed] [Google Scholar]
- 8. ) Hawksworth , G. M. and Hill , M. J.The in vivo formation of N‐nitrosamines in the rat bladder and their subsequent absorption . Br. J. Cancer , 29 , 353 – 358 ( 1974. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. ) Lijinsky , W. , Reuber , M. D. and Singer , G. M.Induction of tumors of the esophagus in rats by nitrosomethyl‐alkylamines . J. Cancer Res. Clin. Oncol , 106 , 171 – 175 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Lijinsky , W. , Reuber , M. D. and Reznik‐Schüller , H. M.Contrasting carcinogenic effects of nitroso‐2,6‐dimethyl‐morpholine given by gavage to F344 rats and Syrian golden hamsters . Cancer Lett. , 16 , 281 – 286 ( 1982. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Lijinsky , W. , Saavedra , J. E. and Kovatch , R. M.Carcinogenesis and nucleic acid alkylation by some oxygenated nitrosamines in rats and hamsters . Chem.-Biol. Interact. , 66 , 37 – 47 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Lijinsky , W. , Saavedra , J. E. and Kovatch , R. M.Carcinogenesis in rats by substituted dialkylnitrosatnines given by gavage . In Vivo , 5 , 85 – 90 ( 1991. ). [PubMed] [Google Scholar]
- 13. ) Heath , D. F. and Magee , P. N.Toxic properties of dialkylnitrosamines and some related compounds . Br. J. Ind. Med. , 19 , 276 – 282 ( 1962. ). [Google Scholar]
- 14. ) Gingell , R. , Wallcave , L. , Nagel , D. , Kupper , R. and Pour , P.Common metabolites of N‐nitroso‐2,6‐dimethyl‐morpholine and N‐nitrosobis‐(2‐oxopropyl)amine in the Syrian hamster . Cancer Lett. , 2 , 47 – 52 ( 1976. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Lijinsky , W. , Saavedra , J. E. and Kovatch , R. M.Carcinogenesis by nitrosobis‐(2‐oxopropyl)‐amine labeled with deuterium and by nitroso‐2‐hydroxypropyl‐2‐oxo‐propylamine in rats and hamsters . Cancer Lett. , 42 , 37 – 41 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Tannenbaum , S. R. , Fett , D. , Young , V. R. , Land , P. D , and Bruce , W. R.Nitrite and nitrate are formed by endogenous synthesis in the human intestine . Science , 200 , 1487 – 1489 ( 1978. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Singer , G. M. , Lijinsky , W. , Buettner , L. and McClusky , G. A.Relationship of rat urinary metabolites of N‐nitro‐somethyl‐N‐alkylamine to bladder carcinogenesis . Cancer Res. , 41 , 4942 – 4946 ( 1981. ). [PubMed] [Google Scholar]
- 18. ) Liberate , D. , Saavedra , J. E. , Farnsworth , D. and Lijinsky , W.Thermospray liquid chromatography/mass spectrometry studies on mechanisms of nucleic acid alkylation by some deuterated carcinogens . Chem. Res. Toxicol , 2 , 307 – 311 ( 1989. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Belinsky , S. A. , White , C. M. , Devereaux , T. R. , Swenberg , J. A. and Anderson , M. W.Cell selective alkylation of DNA in rat lung following low dose exposure to the tobacco specific carcinogen 4‐(N‐methyl‐N‐nitrosamino)‐l‐(3‐pyridyl)‐l‐butanone . Cancer Res. , 47 , 1143 – 1148 ( 1987. ). [PubMed] [Google Scholar]
- 20. ) Underwood , B. and Lijinsky , W.Comparative metabolism of 2,6‐dimethylnitroso‐morpholine in rats, hamsters and guinea pigs . Cancer Res. , 42 , 54 – 58 ( 1982. ). [PubMed] [Google Scholar]
- 21. ) Lawson , T. A. , Gingell , R. , Nagel , D. , Hines , L. A. and Ross , A. E.Methylation of hamster DNA by the carcinogen nitrosobis‐(2‐oxopropyl)amine . Cancer Lett. , 11 , 251 – 255 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 22. ) Lijinsky , W. , Thomas , B. J. and Kovatch , R. M.Effects of feminization of male F344 rats on tumor induction and on nucleic acid alkylation by nitrosobis‐(2‐oxopropyl)‐amine . Chem.-Biol. Interact. , 66 , 111 – 119 ( 1988. ). [DOI] [PubMed] [Google Scholar]
- 23. ) Underwood , B. and Lijinsky , W.Comparative metabolism of the cis and trans isomers of N‐nitroso‐2,6‐dimethyl‐morpholine in rats, hamsters and guinea pigs . Chem. -Biol. Interact. , 50 , 175 – 188 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 24. ) Lijinsky , W.Nucleic acid alkylation by N‐nitroso compounds related to organ‐specific carcinogenesis . In“Chemical Carcinogens, Activation Mechanisms, Structural and Electronic Factors, and Reactivity ,” ed. Politzer P. and Roberts L. , pp. 242 – 263 ( 1988. ). Elsevier Science Publishers; , Amsterdam . [Google Scholar]
- 25. ) Lijinsky , W.Alkylation of DNA related to organ‐specific carcinogenesis by N‐nitroso compounds . IARC Sci. Publ , 105 , 305 – 310 ( 1991. ). [PubMed] [Google Scholar]
- 26. ) Von Hofe , E. , Schmerold , J. , Lijinsky , W. and Kleihues , P.DNA methylation in rat tissues by a series of homologous aliphatic nitrosamines ranging from N‐nitrosodimethyl‐amine to N‐nitrosomethyldodecylamine . Carcinogenesis , 8 , 1337 – 1341 ( 1987. ). [DOI] [PubMed] [Google Scholar]
- 27. ) Lijinsky , W. and Kovatch , R. M.Carcinogenesis by nitrosamines and azoxyalkanes by different routes of administration to rats . Biomed, Environ. Sci. , 2 , 154 – 159 ( 1989. ). [PubMed] [Google Scholar]