Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1998 Apr;89(4):371–376. doi: 10.1111/j.1349-7006.1998.tb00573.x

Suppressive Effect of Irsogladine Maleate on Diethylnitrosamine‐initiated and Phenobarbital‐promoted Hepatocarcinogenesis in Male F344 Rats

Shigeyuki Sugie 1,2,✉, Kiyohisa Okamoto 1, Fusao Ueda 3, Tomoyuki Watanabe 1, Takuji Tanaka 4, Hideki Mori 1
PMCID: PMC5921819  PMID: 9617341

Abstract

Modifying effects of irsogladine maleate (IRG) on diethylnitrosamine (DEN)‐induced hepatocarcinogenesis were examined in male F344 rats. Six‐week‐old rats were divided into 8 groups. Groups 1 through 4 were given a single i.p. injection of DEN (200 mg/kg body weight) at the start of the experiment, whereas groups 5 through 8 received a single i.p. injection of saline as the vehicle treatment. Groups 1 and 8 were kept on the basal diet and distilled water throughout the experiment (36 weeks). Groups 2 and 7 were exposed to 500 ppm phenobarbital (PB) in the drinking water, starting one week after the carcinogen or vehicle treatment. Groups 3 and 5 were fed the diet mixed with 125 ppm IRG from one week after DEN or vehicle treatment. Groups 4 and 6 were given 125 ppm IRG‐containing diet and drinking water with 500 ppm PB after the carcinogen or vehicle treatment. Liver neoplasms developed in groups 1 (1/15 rats, 7%) and 2 (14/14 rats, 100%). However, no liver tumors were found in rats of groups 3 through 8. Incidence and average number of liver neoplasms in group 4 (0/14 rats, 0%) were less than those in group 2 (P<0.0001). The number of glutathione S‐transferase placental form (GST‐P)‐positive liver cell foci in group 3 or 4 was significantly smaller than that in the appropriate control (P<0.01, P<0.001, respectively). The average and unit areas of these foci in group 4 were also significantly smaller than those in group 2 (P<0.001, P<0.05, respectively). These results suggest that IRG could be a chemopreventive agent for rat liver carcinogenesis.

Keywords: Irsogladine maleate, Hepatocarcinogenesis, Chemoprevention

Full Text

The Full Text of this article is available as a PDF (104.5 KB).

REFERENCES

  • 1. ) Wattenberg , L. W.Chemoprevention of cancer . Cancer Res. , 45 , 1 – 8 ( 1985. ). [PubMed] [Google Scholar]
  • 2. ) Tanaka , T. , Nishikawa , A. , Shima , H. , Sugie , S. , Shinoda , T. , Yoshimi , N. , Iwata , H. and Mori , H.Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E‐5166), or coffee on hepatocarcinogenesis in rats and hamsters . In“Antimutagenesis and Anticarcinogenesis Mechanisms ,” ed. Kuroda Y. , Shankel D. M. and Waters M. D. , pp. 429 – 440 ( 1990. ). Plenum Press; , New York . [DOI] [PubMed] [Google Scholar]
  • 3. ) Salt , D. B. and Farber , E.New principle for the analysis of chemical carcinogenesis . Nature , 263 , 701 – 703 ( 1976. ). [Google Scholar]
  • 4. ) Pitot , H. C. , Barsness , L. , Goldsworthy , T. and Kitagawa , T.Biochemical characterization of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine . Nature , 271 , 456 – 458 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Ito , N. , Tatematsu , M. , Nakanishi , K. , Hasegawa , R. , Takano , T. , Imaida , K. and Ogiso , T.The effects of various chemicals on the development of hyperplastic liver nodules in hepatectomized rats treated with N‐nitrosodiethylamine or N‐2‐fluorenylacetamide . Jpn. J. Cancer Res. , 71 , 832 – 842 ( 1980. ). [PubMed] [Google Scholar]
  • 6. ) Dragan , Y. P. and Pitot , H. C.The role of the stages of initiation and promotion in phenotypic diversity during hepatocarcinogenesis in the rat . Carcinogenesis , 13 , 739 – 750 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Loewenstein , W. R.Junctional intercellular communication and the control of growth . Biochim. Biophys. Acta , 560 , 1 – 65 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Yamasaki , H. , Krutovskikh , V. , Mesnil , M. , Columbano , A. , Tsuda , H. and Ito , N.Gap junction intercellular communication and cell proliferation during rat liver carcinogenesis . Environ. Health Perspect. , 101 , 191 – 198 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Tsuda , H. , Asamoto , M. , Baba , H. , Iwahori , Y. , Matsumoto , K. , Iwase , Y. , Nishida , Y. , Nagao , S. , Hakoi , K. , Yamaguchi , S. , Ozaki , K. and Yamasaki , H.Cell proliferation and advancement of hepatocarcinogenesis in the rat are associated with a decrease in connexin 32 expression . Carcinogenesis , 16 , 101 – 105 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Trosko , J. E. and Chang , C. C.Potential role of intercellular communication in the rate‐limiting step in carcinogenesis . J. Am. Coll. Toxicol. , 2 , 5 – 22 ( 1983. ). [Google Scholar]
  • 11. ) Saez , J. C. , Conner , J. A. , Spray , D. C. and Bennett , M. V. L.Hepatocyte gap junctions are permeable to a second messenger, inositol 1,4,5‐triphosphate and to calcium ions . Proc. Natl. Acad. Sci. USA , 86 , 2708 – 2712 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Paul , D. L.Molecular cloning of cDNA for rat liver gap junction protein . J. Cell Biol. , 103 , 123 – 134 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Zhang , J.‐T. and Nicholson , B. J.Sequence and tissue distribution of a second protein of hepatic gap junctions, Cx26, as deduced from its cDNA . J. Cell Biol. , 109 , 3391 – 3401 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Sakamoto , H. , Oyamada , M. , Enomoto , K. and Mori , M.Differential changes in expression of gap junction proteins connexin 26 and 32 during hepatocarcinogenesis in rats . Jpn. J. Cancer Res. , 83 , 1210 – 1215 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Sugie , S. , Mori , H. and Takahashi , M.Effect of in vivo exposure to the liver tumor promoters phenobarbital or DDT on the gap junctions of rat hepatocytes; a quantitative freeze‐fracture analysis . Carcinogenesis , 8 , 45 – 51 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Ueda , F. , Kyoi , T. , Mimura , K. and Yamamoto , M.Intercellular communication in cultured rabbit gastric epithelial cells . Jpn. J. Pharmacol. , 57 , 321 – 328 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Ueda , F. , Kameda , Y. , Yamamoto , O. and Shibata , Y.Beta‐Adrenergic regulation of gap‐junctional intercellular communication in cultured rabbit gastric epithelial cells . J. Pharmacol. Exp. Ther. , 271 , 397 – 402 ( 1994. ). [PubMed] [Google Scholar]
  • 18. ) Ueda , F. , Ban , K. and Ishima , T.Irsogradine activates gap‐junctional intercellular communication through M1 muscarinic acetylcholine receptor . J. Pharmacol. Exp. Ther. , 274 , 815 – 819 ( 1995. ). [PubMed] [Google Scholar]
  • 19. ) Hosokawa , T. , Ogawa , K. , Otani , Y. and Kajiwara , T.Two cases of gastric cancer remarkably reduces with a combined dosage of irsogladine maleate preparation and UFT . Oncol. Rep. , 1 , 93 – 95 ( 1994. ). [PubMed] [Google Scholar]
  • 20. ) Sumi , N. , Yoshida , M. , Nishiguchi , Y. , Tawaratani , T. , Fujimoto , S. , Ishibashi , S. , Yoshifusa , H. , Kameyama , K. and Nomura , A.Twelve‐months oral toxicity study of 2,4‐diamino‐6‐(2,5‐dichlorophenyl)‐s‐triazine maleate (MN‐1695) in rats followed by two‐months recovery test . Pharmacometrics , 32 , 347 – 386 ( 1986. ). [Google Scholar]
  • 21. ) Sugie , S. , Reddy , B. S. , El‐Bayoumy , K. and Tanaka , T.Inhibition by dietary benzylselenocyanate of hepatocarcinogenesis induced by azoxymethane in Fischer 344 rats . Jpn. J. Cancer Res. , 80 , 952 – 957 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Sato , K. , Kitahara , A. , Satoh , K. , Ishikawa , T. , Tatematsu , M. and Ito , N.The placental form of glutathione S‐transferase as a new marker protein for preneoplasia in rat chemical hepatocarcinogenesis . Gann , 75 , 199 – 202 ( 1984. ). [PubMed] [Google Scholar]
  • 23. ) Satoh , K. , Kitahara , A. , Soma , Y. , Inaba , Y. , Hayama , I. and Sato , K.Purification, induction and distribution of placental glutathione transferase: a new marker enzyme for preneoplastic cells in the rat chemical carcinogenesis . Proc. Natl. Acad. Sci. USA , 82 , 3964 – 3968 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. ) Williams , G. M.The pathogenesis of rat liver cancer caused by chemical carcinogenesis . Biochim. Biophys. Acta , 605 , 167 – 189 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Stein , L. S. , Boonstra , J. and Burghardt , R. C.Reduced cell‐cell communication between mitotic and nonmitotic coupled cells . Exp. Cell Res. , 198 , 1 – 7 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Eghbali , B. , Kessler , J. A. , Reid , L. M. , Roy , C. and Spray , D. C.Involvement of gap junctions in tumorigenesis: transfection of tumor cells with connexin 32 cDNA retards growth in vivo . Proc. Natl. Acad. Sci. USA , 88 , 10701 – 10705 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. ) Naus , C. C. G. , Elisevich , K. , Zhu , D. , Belliveau , D. J. and Del Maestro , R. F.In vivo growth of C6 glioma cells transfected with connexin 43 cDNA . Cancer Res. , 52 , 4208 – 4213 ( 1992. ). [PubMed] [Google Scholar]
  • 28. ) Zhu , D. , Caveney , S. , Kidder , G. M. and Naus , C. C. G.Transfection of C6 glioma cells with connexin 43 cDNA: analysis of expression, intercellular coupling, and cell proliferation . Proc. Natl. Acad. Sci. USA , 88 , 1883 – 1887 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Mehta , P. P. , Hotz‐Wagenblatt , A. , Rose , B. , Shalloway , D. and Loewenstein , W. R.Incorporation of the gene for a cell‐cell channel protein into transformed cells leads to normalization of growth . J. Membr. Biol. , 124 , 207 – 225 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Rose , B. , Mehta , P. P. and Loewenstein , W. R.Gap‐junction protein gene suppresses tumorigenicity . Carcinogenesis , 14 , 1073 – 1075 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Mesnil , M. , Krutovskikh , V. , Piccoli , C. , Elfgang , C. , Traub , O. , Willecke , K. and Yamasaki , H.Negative growth control of HeLa cells by connexin genes: connexin species specificity . Cancer Res. , 55 , 629 – 639 ( 1995. ). [PubMed] [Google Scholar]
  • 32. ) Sato , Y. , Morimoto , A. , Kiue , A. , Okamura , K. , Hamanaka , R. , Kohno , K. , Kuwano , M. and Sakata , T.Irsogladine is a potent inhibitor of angiogenesis . FEBS Lett. , 322 , 155 – 158 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Sato , Y. , Okamura , K. , Morimoto , A. , Hamanaka , R. , Hamaguchi , K. , Shimada , T. , Ono , M. , Kohno , K. , Sakata , T. and Kuwano , M.Indispensable role of tissue‐type plasminogen activator in growth factor‐dependent tube formation of human microvascular endothelial cells in vitro . Exp. Cell Res. , 204 , 223 – 229 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Larson , D. M. and Haudenschild , C. C.Junctional transfer in wounded cultures of bovine aortic endothelial cells . Lab. Invest. , 59 , 373 – 379 ( 1988. ). [PubMed] [Google Scholar]
  • 35. ) Pepper , M. S. and Meda , P.Basic fibroblast growth factor increases junctional communication and connexin 43 expression in microvascular endothelial cells . J. Cell. Physiol. , 153 , 196 – 205 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Sipos , E. P. , Tamargo , R. J. , Weingart , J. D. and Brem , H.Inhibition of tumor angiogenesis . Ann. NY Acad. Sci. , 732 , 263 – 272 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Russel , M. , Wintz , S. and Johnson , G. L.Acethylcholine muscarinic ml receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity . Mol. Cell. Biol. , 14 , 2343 – 2351 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES