Experimental Stomach Carcinogenesis

  • Takashi Sugimura
  • Takashi Kawachi
Part of the Sloan-Kettering Institute Cancer Series book series (SKICS)


The stomach is the organ which specifically comes into contact with food. Although food differs greatly from country to country, it has been shown that food definitely contains carcinogens: naturally occurring ones (Evans and Mason, 1965), artifically added ones (Sano et al., 1977), and contaminants (Shank et al., 1972; Sugimura et al., 1977). Epidemiological studies have revealed a close correlation between diet characteristics and the frequency of stomach carcinoma (Haenszel et al., 1972; Oiso, 1975).


Gastric Cancer Intestinal Metaplasia Atrophic Gastritis Stomach Cancer Gastric Carcinogenesis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bauer, K. H., 1928, Mutationstheorie der Geschwulst-Entstehung, Übergang von K in Geschwulst-zellen durch Gen Änderung, Springer-Verlag, Berlin.CrossRefGoogle Scholar
  2. Boveri, T., 1914, Zur Frage der Entstehung maligner Tumoren, Fischer, Jena.Google Scholar
  3. Bralow, S. P., Gruenstein, M., and Meranze, D. R., 1971, Strain resistance to gastric adenocarcinoma in rats ingesting NG, Proc. Am. Assoc. Cancer Res. 12: 3.Google Scholar
  4. Craddock, V. M., 1968, The reaction of N-methyl-N’-nitro-N-nitrosoguanidine with deoxyribonucleic acid, Biochem. J. 106: 921–922.PubMedGoogle Scholar
  5. Dahm, K., and Werner, B., 1976, Susceptibility of the resected stomach to experimental carcinogenesis, Ztschr. Krebsforsch. 85: 219–229.Google Scholar
  6. Druckrey, H., Preussmann, R., Ivankovic, S., So, B. T., Schmidt, C. H., and Bucheler, J., 1966, Zur Erzeugung subcutaner Sarkome an Ratten: Carcinogene Wirkung von Hydrazodicarbonzaure-bis-(Methylnitrosamid), N-Nitroso-N-n-butyl-harnstoff, N-Methyl-N-nitrosonitroguanidin and N-Nitroso-imidazolidon, Ztschr. Krebsforsch. 68: 87–102.CrossRefGoogle Scholar
  7. Evans, I. A., and Mason, J., 1965, Carcinogenic activity of bracken, Nature (London) 208: 913–914.CrossRefGoogle Scholar
  8. Evans, I. A., and Osman, M. A., 1974, Carcinogenicity of bracken and shikimic acid, Nature (London) 250: 348–349.CrossRefGoogle Scholar
  9. Fujimura, S., Kogure, K., Sugimura, T., and Takayama, S., 1970, The effect of limited administration of N-methyl-N’-nitro-N-nitrosoguanidine on the induction of stomach cancer in rats, Cancer Res 30: 842–848.PubMedGoogle Scholar
  10. Fujita, M., Taguchi, T., Takami, M., Usugane, M., Takahashi, A., and Shiba, S., 1974, Carcinoma and related lesion in dog stomach induced by oral administration of N-methyl N’-nitro N- nitrosoguanidine, Gann 65: 207–214.PubMedGoogle Scholar
  11. Fujita, M., Taguchi, T., Takami, M., Usugane, M., and Takashi, A., 1975, Lung metastasis of canine gastric adenocarcinoma induced by N-methyl-N’-nitro-N-nitrosoguanidine, Gann 66: 107–108.PubMedGoogle Scholar
  12. Fukushima, S., Tatematsu, M., and Takahashi, M., 1974, Combined effect of various surfactants on gastric carcinogenesis in rats treated with N-methyl-N’-nitro-N-nitrosoguanidine, Gann 65: 371–376.PubMedGoogle Scholar
  13. Fukushima, S., Hananouchi, M., Shirai, T., Tatematsu, M., Hirose, M., Yoshida, S., and Takahashi, M., 1976, Effect of plastic bead on gastric carcinogenesis in rats treated with N-methyl-N’-nitro-N-nitrosoguanidine, Gann 67: 197–205.PubMedGoogle Scholar
  14. Haenszel, W., Kurihara, M., Segi, M., and Lee, R. K. C., 1972, Stomach cancer among Japanese in Hawaii, J. Natl. Cancer Inst. 49: 969–988.PubMedGoogle Scholar
  15. Haga, J. J., Russell, B. R., and Chapel, J. F., 1972, The kinetics of decomposition of N-alkyl derivatives of nitrosoguanidine, Cancer Res. 32: 2085.PubMedGoogle Scholar
  16. Hirayama, T., 1975, Epidemiology of cancer of the stomach with special reference to its recent decrease in Japan, Cancer Res. 35: 3460–3463.Google Scholar
  17. Hirayama, T. (ed.), 1977, Epidemiology of Stomach Cancer, Key Questions and Answers, WHO Collaborating Center for Evaluation of Methods of Diagnosis and Treatment of Stomach Cancer, National Cancer Center, Tokyo.Google Scholar
  18. Hirono, I., and Shibuya, C., 1972, Induction of stomach cancer by a single dose of N-methyl N’-nitro N-nitrosoguanidine through a stomach tube, in: Topics in Chemical Carcinogenesis ( W. Nakahara, S. Takayama, T. Sugimura, and S. Odashima, eds.), pp. 121–132, University of Tokyo Press, Tokyo.Google Scholar
  19. Hirose, M., Takahashi, M., Hananouchi, M., Tatematsu, M., Kinoshita, H., Fukushima, S., and Ito, N., 1976, Transplantation of chemically induced gastric cancer in Wistar rats, Gann 67: 365–369.PubMedGoogle Scholar
  20. Ichikawa, H., Yamada, T., Horikawa, H., Doi, H., Matsue, H., Tobayashi, K., Sasagawa, M., and Haga, A., 1971, X-ray diagnosis of early gastric cancer, Jpn. J. Clin. Oncol. 1: 1–17.Google Scholar
  21. Imai, T., Kubo, T., and Wantanabe, H., 1971, Chronic gastritis in Japanese with reference to high incidence of gastric carcinoma, J. Natl. Cancer Inst. 47: 179–195.PubMedGoogle Scholar
  22. Järvi, O., and Laurén, P., 1964, On the role of heterotopias of the intestinal epithelium in the pathogenesis of gastric cancer, Acta Pathol. Microbiol. Scand. 29: 26–44.CrossRefGoogle Scholar
  23. Klein, A. J., and Palmer, W. L., 1941, Experimental gastric carcinoma: a critical review with comments on the criteria of induced malignancy, J. Natl. Cancer Inst. 1: 559–584.Google Scholar
  24. Kurihara, M., Ichikawa, H., and Fujimura, S., 1971, X-ray diagnosis of cancer in the glandular stomach of rats, Gann 62: 225–229.PubMedGoogle Scholar
  25. Kurihara, M., Shirakabe, H., Murakami, T., Yasui, A., Izumi, T., Sumida, M., and Igarashi, A., 1974, A new method for producing adenocarcinomas in the stomach of dogs with N-ethyl N’-nitro N-nitrosoguanidine, Gann 65: 163–177.PubMedGoogle Scholar
  26. Kurihara, M., Izumi, T., Miyasaka, K., Shirakabe, H., Yasui, A., Kamano, T., and Kondo, S., 1975a, Diffuse metastatic carcinomatosis of dog stomach carcinoma induced with N-ethyl N’-nitro N-nitrosoguanidine,Juntendo-Igaku (Tokyo) 21: 408–414.Google Scholar
  27. Kurihara, M., Izumi, T., Miyasaka, K., Suzuki, K., Sudo, K., Kasui, A., and Kamano, T., 1975b, Transplantation of experimental dog stomach adenocarcinoma to nude mice, IRCS Med. Sci. 3: 221.Google Scholar
  28. Lawley, P. D., 1968, Methylation of DNA by N-methyl-N-nitrosourethane and N-methyl N’nitro-N-nitrosoguanidine, Nature (London) 218: 581.CrossRefGoogle Scholar
  29. Lawley, P. D., and Thatcher, C. J., 1970, Methylation of deoxyribonucleic acid in cultured mammalian cells by N-methyl-N’-nitro-N-nitrosoguanidine, Biochem. J. 116: 693–707.PubMedGoogle Scholar
  30. Loveless, A., 1969, Possible relevance of O-6 alkylation of deoxyguanosine to the mutagenicity and carcinogenicity of nitrosamines and nitrosamides, Nature (London) 223: 206–207.CrossRefGoogle Scholar
  31. Mandell, J. D., and Greenberg, J., 1960, A new chemical mutagen for bacteria, 1methyl-3-nitro- 1-nitrosoguanidine, Biochem. Biophys. Res. Commun. 3: 575–577.PubMedCrossRefGoogle Scholar
  32. Matsuda, A., 1976, Experimental chemotherapy of chemically induced gastric cancer of rats with new beomycin, Proceedings of the U.S. Japan Cooperative Cancer Research Program: Symposium on Bleomycin.Google Scholar
  33. McCalla, D. R., 1968, Reaction of N-methyl-N’-nitro-N-nitrosoguanidine and Nmethyl-N-nitroso-p-toluenesulfonamide with DNA in vitro, Biochim. Biophys. Acta 155: 114–120.PubMedCrossRefGoogle Scholar
  34. McCalla, D. R., and Reuvers, A., 1968, Reaction of N-methyl-N’-nitro-N-nitrosoguanidine with protein: Formation of nitroguanido derivatives, Can. J. Biochem. 46: 1411–1415.CrossRefGoogle Scholar
  35. McKay, A. F., 1948, A new method of preparation of diazomethane, J. Am. Chem. Soc. 70:1974-1975.PubMedCrossRefGoogle Scholar
  36. McKay, A. F., and Wright, G. F., 1947, Preparation and properties ofN-methyl N’-nitro N-nitrosoguanidine, J. Am. Chem. Soc. 69: 3028–3030.CrossRefGoogle Scholar
  37. McKay, A. F., Ott, W. L., Taylor, G. W., Buchanan, M. U., and Crooker, J. F., 1950, Diazohydrocarbons, Can. J. Res. Sect. B 28: 683–688.CrossRefGoogle Scholar
  38. Monaco, A. P., Roth, S. I., Castleman, B., and Welch, C. E., 1962, Adenomatous polyps of the stomach: A clinical and pathological study of 153 cases, Cancer 15: 456–467.PubMedCrossRefGoogle Scholar
  39. Morson, B. C., 1955, Carcinoma arising from areas of intestinal metaplasia in the gastric mucosa, Br. J. Cancer 9: 377–385.PubMedCrossRefGoogle Scholar
  40. Muñoz, N., and Asvall, J., 1971, Time trends of intestinal and diffuse types of gastric cancer in Norway, Int. J. Cancer 8: 144–157.PubMedCrossRefGoogle Scholar
  41. Muñoz, N., and Connely, R., 1971, Time trends of intestinal and diffuse types of gastric cancer in the United States, Int. J. Cancer 8: 158–164.PubMedCrossRefGoogle Scholar
  42. Murakami, T., Nakamura, S., and Suzuki, T., 1953, On the histogenesis of gastric cancer based on observations on cancer of mucosa, Gann 44: 158–162.Google Scholar
  43. Nagao, M., Yokoshima, T., Hosoi, H., and Sugimura, T., 1969, Interaction ofN-methyl-N’-nitro-N-nitrosoguanidine with ascites hepatoma cells in vitro, Biochim. Biophys. Acta 192: 191–199.PubMedCrossRefGoogle Scholar
  44. Nagao, M., Hosoi, H., and Sugimura, T., 1971. Modification of cytochrome c with N-methyl N’-ni-trosoguanidine, Biochim. Biophys. Acta 237: 369–377.PubMedCrossRefGoogle Scholar
  45. Nakamura, K., Sugano, H., Takagi, K., and Fuchigami, A., 1966, Histopathological study on early carcinoma of the stomach: Criteria for diagnosis of atypical epithelium, Gann 57: 613–620.PubMedGoogle Scholar
  46. Nakamura, K., Sugano, H., Takagi, K., and Kumakura, K., 1968, Carcinoma of the stomach in incipient phase: Its histogenesis and histological appearances, Gann 59: 251–258.PubMedGoogle Scholar
  47. Noguchi, M., Yamada, T., Ichikawa, H., Tanaka, N., Kawachi, T., and Kogure, K., 1974, Radiological study of canine stomach cancer induced by N-methyl N’-nitro N-nitrosoguanadine, Gann 65: 93–102.PubMedGoogle Scholar
  48. Oiso, T., 1975, Incidence of stomach cancer and its relation to dietary habits and nutrition in Japan between 1900 and 1975, Cancer Res. 35: 3254–3258.PubMedGoogle Scholar
  49. Oshima, A., Sakagami, F., Hanai, A., and Fujimoto, I., 1977, Evaluation of a mass screening program for gastric cancer, in: Epidemiology of Stomach Cancer: Key Questions and Answers ( T. Hirayama, ed.), WHO Collaborating Center for Evaluation of Methods of Diagnosis and Treatment of Stomach Cancer, National Cancer Center, Tokyo.Google Scholar
  50. Saito, T., and Sugimura, T., 1973, Biochemical studies on carcinogenesis in the glandular stomach of rats with N-methyl-N’-nitro-N-nitrosoguanidine, Gann 64: 373–381.PubMedGoogle Scholar
  51. Saito, T., Inokuchi, K., Takayama, S., and Sugimura, T., 1970, Sequential morphological changes in N-methyl-N’-nitro-N-nitrosoguanidine carcinogenesis in the glandular stomach of rats, J. Natl. Cancer Inst. 44: 769–783.PubMedGoogle Scholar
  52. Saito, T., Nomoto, K., Tamada, R., and Inokuchi, K., 1976, Effect ofN-methyl N’-nitro-N-nitroso- guanidine on immune response in rats in stomach carcinogenesis, Gann 67: 339–345.PubMedGoogle Scholar
  53. Saito, T., Sasaki, O., Tamada, R., Iwamatsu, M., and Inokuchi, K., 1977, Follow-up studies of carcinogenesis in the stomach of dogs, in: Pathophysiology of Carcinogenesis in Digestive Organs ( E. Farber, T. Kawachi, T. Nagayo, H. Sugano, T. Sugimura, and J. H. Weisburger, eds.), University of Tokyo Press, Tokyo.Google Scholar
  54. Sano, T., Kawachi, T., Sasajima, K., Sugimura, T., and Fukushima, S., 1976, Carcinogenic effect of croton oil on experimental stomach cancer in rats, Proc. Jpn. Cancer Assoc.,p. 30.Google Scholar
  55. Sano, T., Kawachi, T., Matsukura, N., Sasajima, K., and Sugimura, T., 1977, Carcinogenicity of a food additive, AF-2, in hamsters and mice, Ztschr. Krebsforsch. 89: 61–68.CrossRefGoogle Scholar
  56. Sasajima, K., Kawachi, T., Matsukura, N., Sano, T., and Sugimura, T., 1976, Studies on experimental intestinal metaplasia by N-propyl-N’-nitro-N-nitrosoguanidine in rats, Proc. Jpn. Cancer Assoc., p. 46.Google Scholar
  57. Sasajima, K., Kawachi, T., Sano, T., Sugimura, T., Shimosato, Y., and Shirota, A., 1977, Esophageal and gastric cancers with metastases induced in dogs by N-methyl N’-nitro Nnitrosoguanadine, J. Natl. Cancer Inst. 58: 1789–1794.PubMedGoogle Scholar
  58. Sato, T., Fukuyama, T., Urata, G., et al.,1959, Studies of the causation of gastric cancer. 1. Bleeding in the glandular stomach of mice by feeding with highly salted foods, and a comment on salted foods in Japan, Bull, Inst. Public Health 8:10–13.Google Scholar
  59. Schoenthal, R., 1966, Carcinogenic activity of N-methyl-N-nitroso-N’-nitroguanidine, Nature (London) 209: 726–727.CrossRefGoogle Scholar
  60. Schulz, U., and McCalla, D. R., 1969, Reaction of cysteine with N-methyl-N-nitroso.p-toluenesul- fonamide and N-methyl N’-nitro N-nitrosoguanidine, Can. J. Biochem. 47: 2021–2027.CrossRefGoogle Scholar
  61. Sekizuka, H., Doi, H., Sunagawa, M., Nagai, S., Kojima, S., Hiraide, H., Hoshi, K., and Murakami, T., 1975, Induction of esophageal cancer associated with gastric cancer in a dog by N-ethyl N’-nitro N-nitrosoguanidine, Gann 66: 683–688.PubMedGoogle Scholar
  62. Shank, R. C., Wogan, G. N., and Gibson, J. B., 1972, Dietary aflatoxins and human liver cancer. I. Toxigenic moulds in foods and foodstuffs of tropical South-east Asia, Food. Cosmet. Toxicol. 10: 60–65.Google Scholar
  63. Shimosato, Y., Tanaka, N., Kogure, K., Fujimura, S., Kawachi, T., and Sugimura, T., 1971, Histopathology of tumors of canine alimentary tract produced by N-methyl N’-nitro Nnitrosoguanidine, with particular reference to gastric carcinogenesis, J . Natl. Cancer Inst. 47: 1053–1070.PubMedGoogle Scholar
  64. Singer, B., Fraenkel-Conrat, H., Greenberg, J., and Michelson, A. M., 1968, Reaction of nitrosoguanidineanidine (N-methyl-N’-nitro-N-nitrosoguanidine) with tobacco mosaic virus and its RNA, Science 160: 1235–1237.PubMedCrossRefGoogle Scholar
  65. Skinner, W. A., Gram, H. F., Greene, O. M., Greenberg, J., and Baker, B. R., 1960, Potential anticancer agents. XXXI. The relationship of chemical structure to antileukaemic activity with analogues of 1-methyl-3-nitro-1-nitrosoguanidine (NSC-9369), J. Med. Pharm. Chem. 2: 299–333 (1960).PubMedCrossRefGoogle Scholar
  66. Stemmermann, G. N., and Brown, C., 1974, A survival study of intestinal and diffuse types of gastric carcinoma, Cancer 33: 1190–1195.PubMedCrossRefGoogle Scholar
  67. Stemmermann, G. N., and Hayashi, T., 1968, Intestinal metaplasia of the gastric mucosa: A gross and microscopic study of its distribution in various disease states, J . Natl. Cancer Inst. 41: 627–634.PubMedGoogle Scholar
  68. Stickland, R. G., and MacKay, I. R., 1973, A reappraisal of the nature and significance of chronic atrophic gastritis, Am. J. Digest. Dis. 18: 426–440.CrossRefGoogle Scholar
  69. Sugimura, T., and Fujimura, S., 1967, Tumour production in glandular stomach of rats by N-methyl-N’-nitro-N-nitrosoguanidine, Nature (London) 216: 943–944.CrossRefGoogle Scholar
  70. Sugimura, T., and Kawachi, T., 1973, Experimental stomach cancer, Methods Cancer Res. 7: 245–308.Google Scholar
  71. Sugimura, T., and Kawachi, T., 1976, Das experimentelle Mager Karzinom, Leber Magen Darm. 6: 80–90.PubMedGoogle Scholar
  72. Sugimura, T., Nagao, M., and Okada, Y., 1966, Carcinogenic action of N-methyl-N’-nitro-N-nitrosoguanidine, Nature (London) 210: 962–963.CrossRefGoogle Scholar
  73. Sugimura, T., Fujimura, S., Nagao, M., Yokoshima, T., and Hasegawa, S., 1968, Reaction of with protein, Biochim. Biophys. Acta 170: 427–429.PubMedCrossRefGoogle Scholar
  74. Sugimura, T., Fujimura, S., Kogure, K., Baba, T., Saito, T., Nagao, M., Hosoi, H., Shimosato, Y., and Yokoshima, T., 1969, Production of adenocarcinomas in the glandular stomach of experimental animals by N-methyl-N’-nitro-N-nitrosoguanidine, Gann Monogr. 8: 157–196.Google Scholar
  75. Sugimura, T., Fujimura, S., and Baba, T., 1970, Tumor production in the glandular stomach and alimentary tract of rat by N-methyl-N’-nitro-N-nitrosoguanidine, Cancer Res. 30: 455–465.PubMedGoogle Scholar
  76. Sugimura, T., Tanaka, N., Kawachi, T., Kogure, K., Fujimura, S., and Shimosato, Y., 1971, Production of stomach cancer in dogs byN-methyl N’-nitro N-nitrosoguanidine, Gann 62: 67.PubMedGoogle Scholar
  77. Sugimura, T., Kawachi, T., Kogure, K., Nagao, M., Tanaka, N., Fujimura, S., Takayama, S., Shimosato, Y., Noguchi, M., Kuwabara, N., and Yamada, T., 1972, Induction of stomach cancer by N-methyl-N’-nitro-N-nitrosoguanidine: Experiments on dogs as clinical models and metabolism of this carcinogen, in: Topics in Chemical Carcinogenesis ( W. Nakahara, S. Takyama, T. Sugimura, and S. Odashima, eds.), pp. 105–119, University of Tokyo Pkess, Tokyo.Google Scholar
  78. Sugimura, T., Nagao, M., Kawachi, T., Honda, M., Yahagi, T., Seino, Y., Matsushima, T., Shirai, A., Sawamura, M., Sato, S., Matsumoto, H. and Matsukura, N., 1977, Mutagen-carcinogens in food with special reference to highly mutagenic pyrolytic products in broiled foods, in: Origins of Human Cancer (J. D. Watson and H. Hiatt, eds.), Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.Google Scholar
  79. Tabuchi, Y., Mitsumo, T., and Sugiyama, T., 1975, Mucosal damage induced by various gastric carcinogens in the glandular stomach of the rat, J. Natl. Cancer Inst. 55: 1395–1401.PubMedGoogle Scholar
  80. Taguchi, T., Fujita, M., and Usugane, M., 1975, Heterotransplantation of a cinine gastric cancer induced by N-methyl-N’-nitro-N-nitrosoguanidine into nude mice, Bitren J. 18: 175–177.Google Scholar
  81. Tahara, E., and Haizuka, S., 1975, Effect of gastro-entero-pancreatic endocrine hormones on the histogenesis of gastric cancer in rats induced by N-methyl-N’-nitro-N-nitrosoguanidine; with special reference to development of scirrhous gastric cancer, Gann 66: 421–426.PubMedGoogle Scholar
  82. Takahashi, M., 1970, Effect of alkylbenzenesulfonate as a vehicle for 4-nitroquinoline 1-oxide on gastric carcinogenesis in rats, Gann 61: 27–33.PubMedGoogle Scholar
  83. Takahashi, M., Shirai, T., Fukushima, S., Hananouchi, M., Hirose, M., and Ito, N., 1976, Effect of fundic ulcers induced by iodoacetamide on development of gastric tumors in rats treated with N-methyl-N’-nitro-N-nitrosoguanidine, Gann 67: 47–54.PubMedGoogle Scholar
  84. Tatematsu, M., Takahashi, M., Fukushima, S., Hanaouchi, M., and Shirai, T., 1975, Effects in rats of sodium chloride on experimental gastric cancers induced by N-methyl-N’-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide, J. Natl. Cancer Inst. 55: 101–106.PubMedGoogle Scholar
  85. Tatematsu, M., Takahashi, M., Hananouchi, M., Shirai, T., Hirose, M., Fukushima, S., and Ito, N., 1976, Protective effect of mucin on experimental gastric cancer induced by Nmethyl-N’-nitro N-nitrosoguanidine plus sodium chloride in rats, Gann 67: 223–229.PubMedGoogle Scholar
  86. Yamada, T., 1977, Studies on the evaluation of mass screening of gastric cancer, Report to the Ministry of Health and Welfare, Japan.Google Scholar

Copyright information

© Springer Science+Business Media New York 1978

Authors and Affiliations

  • Takashi Sugimura
    • 1
  • Takashi Kawachi
    • 1
  1. 1.National Cancer Research InstituteTokyoJapan

Personalised recommendations