Organ Specificity and Interspecies Differences in Carcinogenesis by Metabolism-Independent Alkylating Agents

  • Jerry M. Rice
  • Alan Perantoni
Part of the Basic Life Sciences book series


The metabolism-independent or “direct-acting” alkylating agents comprise a structurally diverse group of chemically reactive organic compounds that include some of the most potent known mutagens and carcinogens. Their conversion to reactive intermediates requires no enzyme-mediated catalysis, and in this respect these compounds differ from the great majority of organic chemical carcinogens. Many of the direct-acting alkylating agents have been used in chemical syntheses for decades, and their chemistry is accordingly well known. The carcinogenicity of a number of these compounds has been studied extensively in both rodent and non-rodent species, and the results of such studies provide a remarkable illustration of qualitative interspecies differences in susceptibility to carcinogenesis that cannot be ascribed to differences in metabolism of xenobiotic compounds.


Peripheral Nervous System Alkylating Agent Syrian Hamster Interspecies Difference Patas Monkey 
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  1. 1.
    Clayson, D.B. 1962. Chemical Carcinogenesis. Little, Brown, and Co.: Boston. p. 181.Google Scholar
  2. 2.
    Van Duuren, B.L., ed. 1969. Biological Effects of Alkylating Agents. Ann. N.Y. Acad. Sci., 163, Article 2. pp. 589–1029.Google Scholar
  3. 3.
    Lawley, P.D. 1976. Carcinogenesis by alkylating agents. In: Chemical Carcinogens, ACS Monograph 173. C.E. Searle, ed. American Chemical Society: Washington, DC. pp. 83–244.Google Scholar
  4. 4.
    Wheeler, G.P., and B.J. Bowdon. 1972. Comparison of the effects of cysteine upon the decomposition of nitrosoureas and of 1-methyl-3-nitro-l-nitrosoguanidine. Biochem. Pharmacol. 21: 265–267.PubMedCrossRefGoogle Scholar
  5. 5.
    Schoental, R. 1961. Interaction of the carcinogenic N-methylnitrosourethane with sulfhydryl groups. Nature 192: 670.PubMedCrossRefGoogle Scholar
  6. 6.
    Garrett, E.R., G. Shigeru, and J.F. Stubbins. 1965. Kinetics of solvolyses of various N-alkyl-N-nitrosoureas in neutral and alkaline solutions. J. Pharm. Sci. 54: 119–123.PubMedCrossRefGoogle Scholar
  7. 7.
    Lijinsky, W., M.D. Reuber, and B.N. Blackwell. 1980. Carcinogenicity of nitrosotrialkylureas in Fischer 344 rats. J. Natl. Cancer Inst. 65: 451–453.PubMedGoogle Scholar
  8. 8.
    Lijinsky, W., J. Loo, and A.E. Ross. 1968. Mechanism of alkylation of nucleic acids by nitrosodimethylamine. Nature 218: 1174–1175.PubMedCrossRefGoogle Scholar
  9. 9.
    Lijinsky, W., H. Garcia, L. Keefer, J. Loo, and A.E. Ross. 1972. Carcinogenesis and alkylation of rat liver nucleic acids by nitrosomethylurea and nitrosoethylurea administered by intraportal injection. Cancer Res. 32: 893–897.PubMedGoogle Scholar
  10. 10.
    Zeller, W.J., and S. Ivankovic. 1972. Steigerung der toxischen Wirkung von Alkylnitrosoharnstoffen durch Schwermetalle. Naturwissenschaften 59: 82.PubMedCrossRefGoogle Scholar
  11. 11.
    Ivankovic, S., W.J. Zeller, and D. Schmähl. 1972. Steigerung der carcinogenen Wirkung von Athylnitrosoharnstoff durch Schwermetalle. Naturwissenschaften 59: 369.PubMedCrossRefGoogle Scholar
  12. 12.
    Singer, B. 1975. The chemical effects of nucleic acid alkylation and their relation to mutagenesis and carcinogenesis. In: Progress in Nucleic Acid Research and Molecular Biology, Volume 15. W.E. Cohn, ed. Academic Press: New York. pp. 219–284, 330–332.Google Scholar
  13. 13.
    Lawley, P.D., D.J. Orr, and M. Jarman. 1975. Isolation and identification of products from alkylation of nucleic acids: ethyl- and isopropylpurines. Biochem. J. 145: 73–84.PubMedGoogle Scholar
  14. 14.
    Bannon, P., and W. Verly. 1972. Alkylation of phosphates and stability of phosphate triesters in DNA. Eur. J. Biochem. 31: 103–111.PubMedCrossRefGoogle Scholar
  15. 15.
    Sun, L., and B. Singer. 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.Google Scholar
  16. 16.
    Singer, B., W.J. Bodell, J.E. Cleaver, G.H. Thomas, M.F. Rajewsky, and W. Thon. 1978. Oxygens in DNA are main targets for ethylnitrosourea in normal and xeroderma pigmentosum fibroblasts and fetal rat brain cells. Nature 276: 85–88.PubMedCrossRefGoogle Scholar
  17. 17.
    Van Duuren, B.L., C. Katz, M. Goldschmidt, K. Frenkel, and A. Sivak. 1972. Carcinogenicity of halo-ethers, II. Structure-activity relationships of analogs of bis(chloromethyl)ether. J. Natl. Cancer Inst. 48: 1431–1439.PubMedGoogle Scholar
  18. 18.
    Leong, B.K.J., H.N. MacFarland, and W.H. Reese, Jr. 1971. Induction of lung adenomas by chronic inhalation of bis(chloromethyl)ether. Arch. Environ. Hlth. 22: 663–666.Google Scholar
  19. 19.
    Laskin, S., M. Kuschner, R.T. Drew, V.P. Cappiello, and N. Nelson. 1971. Tumors of the respiratory tract induced by inhalation of bis(chloromethyl)ether. Arch. Environ. Hlth. 23: 135–136.Google Scholar
  20. 20.
    Gargus, J.L., W.H. Reese, Jr., and H.A. Rutter. 1969. Induction of lung adenomas in newborn mice by bis(chloromethyl)ether. Toxicol. Appl. Pharmacol. 15: 92–96.Google Scholar
  21. 21.
    Van Duuren, B.L., A. Sivak, B.M. Goldschmidt, C. Katz, and S. Melchionne. 1969. Carcinogenicity of halo-ethers. J. Natl. Cancer Inst. 43: 481–486.PubMedGoogle Scholar
  22. 22.
    Graffi, A., F. Hoffmann, and M. Schutt. 1967. N-Methyl-N-nitrosourea as a strong topical carcinogen when painted on skin of rodents. Nature (London) 214: 611.CrossRefGoogle Scholar
  23. 23.
    Narisawa, T., C.-Q. Wong, R.R. Maronpot, and J.H. Weisburger. 1976. Large bowel carcinogenesis in mice and rats by several intrarectal doses of methylnitrosourea and negative effect of nitrite plus methylurea. Cancer Res. 36: 505–510.PubMedGoogle Scholar
  24. 24.
    Narisawa, T., C.-Q. Wong, and J.H. Weisburger. 1975. Induction of carcinoma of the large intestine in guinea pigs by intrarectal instillation of N-methyl-N-nitrosourea. J. Natl. Cancer Inst. 54: 785–787.PubMedGoogle Scholar
  25. 25.
    Hicks, R.M., and J.St.J. Wakefield. 1972. Rapid induction of bladder cancer in rats with N-methyl-N-nitrosourea, I. Histology. Chem.-Biol. Interact. 5: 139–152.CrossRefGoogle Scholar
  26. 26.
    Adamson, R.H., F.J. Krolikowski, P. Correa, S.M. Sieber, and D.W. Dalgard. 1977. Carcinogenicity of 1-methyl-l-nitrosourea in non-human primates. J. Natl. Cancer Inst. 59: 415–422.Google Scholar
  27. 27.
    Stavrou, D., E. Dahme, and J. Kalich. 1976. Gastroonkogene Wirkung von Methylnitrosoharnstoff beim Miniaturschwein. Res. Exp. Med. 169: 33–343.CrossRefGoogle Scholar
  28. 28.
    Thomas, C., J.L. Sierra, and G. Kersting. 1968. Neurogene Tumoren bei Ratten nach intraperitonealer Applikation von N-Nitroso-N-methylharnstoff. Naturwissenschaften 55: 183.PubMedCrossRefGoogle Scholar
  29. 29.
    Reznik, G., U. Mohr, and N. Kmock. 1976. Carcinogenic effect of different nitroso-compounds in Chinese hamsters: N-dibutylnitrosamine and N-nitrosomethylurea. Cancer Lett. 1: 183–188.PubMedCrossRefGoogle Scholar
  30. 30.
    Mohr, U., H. Haas, and J. Hilfrich. 1974. The carcinogenic effects of dimethylnitrosamine and nitrosomethylurea in European hamsters (Cricetus cricetus L.). Brit. J. Cancer 29: 359–364.PubMedCrossRefGoogle Scholar
  31. 31.
    Schreiber, D., and W. JHnisch. 1967. Geschwulste bei Ratten nach wiederholter Applikation von N-Methyl-N-nitrosoharnstoff durch die Magensonde. Exp. Path. 1: 331–338.Google Scholar
  32. 32.
    Joshi, V.V., and J.V. Frei. 1970. Effects of dose and schedule of methylnitrosourea on incidence of malignant lymphoma in adult female mice. J. Natl. Cancer Inst. 45: 335–339.PubMedGoogle Scholar
  33. 33.
    Denlinger, R.H., A. Koestner, and J.A. Swenberg. 1973. An experimental model for selective production of neoplasms of the peripheral nervous system. Acta Neuropath. ( Berlin ) 23: 219–228.PubMedCrossRefGoogle Scholar
  34. 34.
    Swenberg, J.A., A. Koestner, and W. Wechsler. 1972. The induction of tumors of the nervous system with intravenous methylnitrosourea. Lab. Invest. 26: 74–85.PubMedGoogle Scholar
  35. 35.
    Gullino, P.M., H.M. Pettigrew, and F.H. Grantham. 1975. N-Nitrosomethylurea as mammary gland carcinogen in rats. J. Natl. Cancer Inst. 54: 401–444.PubMedGoogle Scholar
  36. 36.
    Bots, G.T.A.M., and R.G.T. Willighagen. 1975. Tumors in the mammary gland induced in Lewis rats by intravenous methylnitrosourea. Brit. J. Cancer 31: 372–374.PubMedCrossRefGoogle Scholar
  37. 37.
    Leaver, D.D., P.F. Swann, and P.N. Magee. 1969. The induction of tumours in the rat by a single oral dose of N-nitrosomethylurea. Brit. J. Cancer 23: 177–187.PubMedCrossRefGoogle Scholar
  38. 38.
    Terracini, B., and M.C. Testa. 1970. Carcinogenicity of a single administration of N-nitrosomethylurea: a comparison between newborn and 5-week-old mice and rats. Brit. J. Cancer 24: 588–598.PubMedCrossRefGoogle Scholar
  39. 39.
    Murthy, A.S.K., G.F. Vawter, and A. Bhaktaviziam. 1973. Newplasms in Wistar rats after an N-methyl-N-nitrosourea injection. Arch. Pathol. 96: 53–57.PubMedGoogle Scholar
  40. 40.
    Druckrey, H., D. Steinhoff, R. Preussmann, and S. Ivankovic. 1964. Erzeugung von Krebs durch eine einmalige Dosis von Methylnitrosoharnstoff und verschiedenen Dialkylnitrosaminen an Ratten. Z. Krebsforch. 66: 1–10.CrossRefGoogle Scholar
  41. 41.
    Druckrey, H., R. Preussmann, S. Ivankovic, and D. Schmahl. 1967. Organtrope carcinogene Wirkungen bei 65 verschiedenen N-Nitroso-Verbindungen an BD-Ratten. Z. Krebsforsch. 69: 103–201.PubMedCrossRefGoogle Scholar
  42. 42.
    Kleihues, P., and K. Patzschke. 1971. Verteilung von N-[14C] Methyl-N-nitrosoharnstoff in der Ratte nach systemischer Applikation. Z. Krebsforsch. 75: 193–200.PubMedCrossRefGoogle Scholar
  43. 43.
    Swann, P.F. 1968. The rate of breakdown of methyl methane sulphonate, dimethyl sulphate and N-methyl-N-nitrosourea in the rat. Biochem. J. 110: 49–52.PubMedGoogle Scholar
  44. 44.
    International Agency for Research on Cancer. 1978. Some Nitroso Compounds. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Volume 17. Lyons, France. pp. 191–215, 227–255.Google Scholar
  45. 45.
    Craddock, V.M., and J.V. Frei. 1974. Induction of liver cell adenomata in the rat by a single treatment with N-methyl-N-nitrosourea given at various times after partial hepatectomy. Brit. J. Cancer 30: 503–511.PubMedCrossRefGoogle Scholar
  46. 46.
    Vesselinovitch, S.D., K.V.N. Rao, N. Mihailovich, J.M. Rice, and L.S. Lombard. 1974. Development of broad spectrum of tumors by ethylnitrosourea in mice and the modifying role of age, sex, and strain. Cancer Res. 34: 2530–2538.PubMedGoogle Scholar
  47. 47.
    Druckrey, H., B. Schagen, and S. Ivankovic. 1970. Erzeugung neurogener Malignome durch einmalige Gabe von Athyl-nitrosoharnstoff (ÄNH) an neugeborene und junge BD IX-Ratten. Z. Krebsforsch. 74: 141–161.PubMedCrossRefGoogle Scholar
  48. 48.
    Kleihues, P., J. Bucheler, and U.N. Riede. 1978. Selective induction of melanomas in gerbils (Meriones unguiculatus) following postnatal administration of N-ethyl-N-nitrosourea. J. Natl. Cancer Inst. 61: 859–863.PubMedGoogle Scholar
  49. 49.
    Hadjiolov, D. 1972. Thymic lymphoma and myeloid leukemia in the rat induced with ethylnitrosourea. Z. Krebsforsch. 77: 98–100.CrossRefGoogle Scholar
  50. 50.
    Zeller, W.J., and D. Schmähl. 1979. Leukemias induced by ethylnitrosourea in Wistar rats: Incidence and chemotherapy. Leuk. Res. 3: 239–248.PubMedCrossRefGoogle Scholar
  51. 51.
    Denlinger, R.H., A. Koestner, and W. Wechsler. 1974. Induction of neurogenic tumors in C3HeB/F3J mice by nitrosourea derivatives: Observations by light microscopy, tissue culture, and electron microscopy. Int. J. Cancer 13: 559–571.Google Scholar
  52. 52.
    Eckert, V.H., and E. Seidler. 1971. Zur tumorerzeugendem Wirkung von Methylnitrosoharnstoff an der Maus. Arch. Geschwulstforsch. 38: 7–9.PubMedGoogle Scholar
  53. 53.
    Druckrey, H., S. Ivankovic, and R. Preussmann. 1965. Selektive Erzeugung maligner Tumoren in Gehirn und Rückenmark von Ratten durch N-Methyl-N-Nitrosoharnstoff. Z. Krebsforsch. 66: 389–408.PubMedCrossRefGoogle Scholar
  54. 54.
    Swenberg, J.A., A. Koestner, W. Wechsler, M.N. Branden, and H. Abe. 1975. Differential oncogenic effects of methylnitrosourea. J. Natl. Cancer Inst. 54: 89–96.PubMedGoogle Scholar
  55. 55.
    Herrold, K.M. 1969. Adenocarcinomas of the intestine induced in Syrian hamsters by N-methyl-N-nitrosourea. Path. Vet. 6: 403–412.Google Scholar
  56. 56.
    Rao, M.S., and J.K. Reddy. 1977. Pathology of tumors developed in guinea pigs given intraperitoneal injections of N-methyl-N-nitrosourea. Neoplasma 24: 57–61.PubMedGoogle Scholar
  57. 57.
    Rice, J.M., W.T. London, A.E. Palmer, D.L. Sly, and G.M. Williams. 1977. Direct and transplacental carcinogenesis by ethylnitrosourea in the patas monkey (Erythrocebus patas). Proc. Am. Assoc. Cancer Res. 18: 53.Google Scholar
  58. 58.
    Ketkar, M., G. Reznik, H. Haas, J. Hilfrich, and U. Mohr. 1977. Tumors of the heart and stomach induced in European hamsters by intravenous administration of N-methyl-N-nitrosourea. J. Natl. Cancer Inst. N58: 1695–1699.PubMedGoogle Scholar
  59. 59.
    Haas, H., J. Hilfrich, N. Kmoch, and U. Mohr. 1975. Specific carcinogenic effect of N-methyl-N-nitrosourea on the midventral sebaceous gland of the gerbil (Meriones unguiculatus). J. Natl. Cancer Inst. 55: 637–640.PubMedGoogle Scholar
  60. 60.
    Schreiber, V.D., and W. Janisch. 1973. Tumoren des Gefass systems bei Kaninchen nach Applikation von Methylnitrosoharnstoff (MNH). Zbl. allg. Path. 117: 99–105.PubMedGoogle Scholar
  61. 61.
    Schreiber, D., A. Lageman, and M. Geyer. 1972. Erzeugung von Dünndarmkarzinomen bei Kaninchen mit Methylnitrosoharnstoff. Zbl. allg. Path. 115: 40–47.PubMedGoogle Scholar
  62. 62.
    Stavrou, D., K.G. Haglid, and W. Weidenbach. 1975. Experimentelle Induktion neurogener Tumoren beim Hund durch chronische parenterale Applikation von Methylnitrosoharnstoff. In: Proc. VII International Congress of Neuropathology, Budapest, 1974. Excerpta Medica: Amsterdam. pp. 425–431.Google Scholar
  63. 63.
    Denlinger, R.J., A. Koestner, and J.A. Swenberg. 1978. Neoplasms in purebred boxer dogs following long-term administration of N-methyl-N-nitrosourea. Cancer Res. 38: 1711–1717.PubMedGoogle Scholar
  64. 64.
    Ivankovic, S., and H. Druckrey. 1968. Transplacentare Erzeugung maligner Tumoren des Nervensystems. I. Athylnitrosoharnstoff (ÄNH) an BD IX-Ratten. Z. Krebsforsch. 71: 320–360.PubMedCrossRefGoogle Scholar
  65. 65.
    Vesselinovitch, S.D., M. Koka, K.V.N. Rao, N. Mihailovich, and J.M. Rice. 1977. Prenatal multicarcinogenesis by ethylnitrosourea in mice. Cancer Res. 37: 1822–1828.PubMedGoogle Scholar
  66. 66.
    Diwan, B.A., and H. Meier. 1974. Strain- and age-dependent transplacental carcinogenesis by 1-ethyl-l-nitrosourea in inbred strains of mice. Cancer Res. 34: 764–770.PubMedGoogle Scholar
  67. 67.
    Druckrey, H., C. Landschütz, and S. Ivankovic. 1970. Transplacentare Erzeugung maligner Tumoren des Nervensystems. II. Äthylnitrosoharnstoff an 10 genetisch definierten Rattenstämmen. Z. Krebsforsch. 73: 371–386.PubMedCrossRefGoogle Scholar
  68. 68.
    Rice, J.M. 1973. Biological behaviour of transplacentally induced tumours in mice. In: Transplacental Carcinogenesis. L. Tomatis and U. Mohr, eds. IARC Scientific Publications No. 4. International Agency for Research on Cancer: Lyons, France. pp. 71–83.Google Scholar
  69. 69.
    Kleihues, P., P.N. Magee, J. Austoker, D. Cox, and A.P. Mathias. 1973. Reaction of N-methyl-N-nitrosourea with DNA of neuronal and glial cells in vivo. FEBS Lett. 32: 105–108.PubMedCrossRefGoogle Scholar
  70. 70.
    Kleihues, P., and G.P. Margison. 1974. Carcinogenicity of N-methyl-N-nitrosourea: Possible role of excision repair of 06-methylguanine from DNA. J. Natl. Cancer Inst. 53: 1839–1841.PubMedGoogle Scholar
  71. 71.
    Pegg, A.E., and J.W. Nicoll. 1976. Nitrosamine carcinogenesis: The importance of the persistence in DNA of alkylated bases in the organotropism of tumour induction. In: Screening Tests in Chemical Carcinogenesis. R. Montesano, H. Bartsch, and L. Tomatis, eds. IARC Scientific Publications No. 12. International Agency for Research on Cancer: Lyons, France. pp. 571–592.Google Scholar
  72. 72.
    Bücheler, J., and P. Kleihues. 1977. Excision of 06-methylguanine from DNA of various mouse tissues following a single injection of N-methyl-N-nitrosourea. Chem.-Biol. Interact. 16: 325–333.CrossRefGoogle Scholar
  73. 73.
    Slaga, T.J., A. Sivak, and R.K. Boutwell, eds. 1978. Mechanisms of Tumor Promotion and Cocarcinogenesis. In: Carcinogenesis, a Comprehensive Survey, Volume 2. Raven Press: New York. 588 pp.Google Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Jerry M. Rice
    • 1
  • Alan Perantoni
    • 1
  1. 1.Laboratory of Comparative CarcinogenesisNational Cancer InstituteFrederickUSA

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