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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1993 Feb;84(2):139–146. doi: 10.1111/j.1349-7006.1993.tb02847.x

Influence of Aging on Multi‐organ Carcinogenesis in Rats Induced by N‐Methyl‐N‐nitrosourea

Masae Mizoguchi 1,✉, Hatsumi Naito 1, Yasushi Kurata 1, Masa‐Aki Shibata 1,4, Hiroyuki Tsuda 2, Christopher P Wild 3, Ruggero Montesano 3, Shoji Fukushima 4
PMCID: PMC5919123  PMID: 8463131

Abstract

The effects of aging on the multi‐organ Carcinogenesis induced in rats by N‐methyl‐N‐nitrosourea (MNU), a direct carcinogen which does not need metabolic activation to exert carcinogenicity, were examined in male F344 rats. In the first experiment, rats at 6, 52, and 98 weeks of age were treated with MNU (20 mg/kg body weight, i.p.) twice weekly for 6 weeks and then maintained without any further treatment for 24 weeks in the case of young and middle‐aged rats and for 18 weeks in the case of the old rats. In young rats, malignant lymphomas, particularly thymic types, were observed at significantly high incidence. A striking result in the middle‐aged rats was the significantly higher incidence of adenocarcinomas in the small intestine than in young or old animals. The induction of proliferative and neoplastic lesions of the large intestine also tended to be increased in middle‐aged rats. In addition, epithelial hyperplasia of the tongue, but not the forestomach, occurred at the highest incidence in the middle‐aged group. There were no differences in the induction of epithelial lesions in the urinary bladder among the groups. In a second experiment, investigation of DNA synthesis in the tongue, small and large intestines, urinary bladder and lymph nodes did reveal significant increases or tendency for increase in the MNU‐treated groups, hut without differences with age. In contrast, the thymus of young rats showed significantly increased incorporation of BrdU label after administration of MNU, whereas it was markedly reduced in middle‐aged rats. In a third experiment, O′‐methyldeoxyguanine (O6‐medG) DNA adduct formation was immunohistochemically detected in various organs including the thymus, forestomach, and small intestine without any differences with age. Thus, the results demonstrated that while the target organs of MNU are modified by the age of the animals, levels of DNA synthesis and O6‐medG DNA adduct formation in most cases can not explain the observed differences in carcinogenic susceptibility.

Keywords: Aging and cancer, Multi‐organ Carcinogenesis, N‐Methyl‐N‐nitrosourea, O6‐Methyldeoxyguanine, Cell proliferation

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REFERENCES

  • 1. ) Smulow , J. B. , Konstantinidis , A. K. and Sonnenschein , C.Age‐dependent odontogenic lesions in rats after a single i.p. injection of N‐nitroso‐N‐methylurea . Carcinogenesis , 4 , 1085 – 1088 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Anisimov , V. N.Carcinogenesis and aging. I. Modifying effects of aging on N‐methyl‐N‐nitrosourea‐induced carcinogenesis in female rats . Exp. Pathol. , 19 , 81 – 90 ( 1981. ). [PubMed] [Google Scholar]
  • 3. ) Anisimov , V. N. and Turusov , V. S.Modifying effect of aging on chemical Carcinogenesis. A Review . Mech. Ageing Dev. , 15 , 399 – 414 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Watanabe , H. , Nakagawa , Y. , Takahashi , T. and Ito , A.Effect of age and strain on N‐methyl‐N'‐nitro‐N‐nitrosoguanidine tumorigenesis in ACI and Wistar Furth rats . Carcinogenesis , 9 , 1317 – 1318 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Vesselinovitch , S. D. , Koka , M. , Mihailovich , N. and Rao , K. V. N.Carcinogenicity of diethylnitrosamine in newborn, infant, and adult mice . J. Cancer Res. Clin. Oncol. , 108 , 60 – 65 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 6. ) Ebbesen , P.Aging increases susceptibility of mouse skin to DMBA Carcinogenesis independent of general immune status . Science , 183 , 217 – 218 ( 1974. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Hasegawa , R. , Takahashi , S. , Imaida , K. , Yamaguchi , S. , Shirai , T. and Ito , N.Age‐dependent induction of preneoplastic liver cell foci by 2‐acetylaminofluorene, phenobarbital and acetaminophen in F344 rats initially treated with diethylnitrosamine . Jpn. J. Cancer Res. , 82 , 293 – 297 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. ) Kimura , M. , Fukuda , T. and Sato , K.Effect of aging on the development of gastric cancer in rats induced by N‐methyl‐N'‐nitro‐N‐nitrosoguanidine . Gann , 70 , 521 – 525 ( 1979. ). [PubMed] [Google Scholar]
  • 9. ) Reuber , M. D.Effect of age and sex on lesions of the esophagus in Buffalo strain rats ingesting diethylnitrosamine . Exp. Cell Biol. , 44 , 65 – 72 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Toth , B.Critical review of experiments in chemical Carcinogenesis using newborn animals . Cancer Res. , 28 , 727 – 738 ( 1968. ). [PubMed] [Google Scholar]
  • 11. ) Ward , J. M. and Henneman , J. R.Naturally‐occurring age‐dependent glutathione S‐transferase π immunoreactive hepatocytes in aging female F344 rat liver as potential promotable targets for non‐genotoxic carcinogens . Cancer Lett. , 52 , 187 – 195 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Stenback , F. , Peto , R. and Shubik , P.Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low‐dose tumor risks . Br. J. Cancer , 44 , 24 – 34 ( 1981. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Fukushima , S. , Shibata , M. A. , Tamano , S. , Ito , N. , Suzuki , E. and Okada , M.Aging and urinary bladder Carcinogenesis induced in rats by N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine . J. Natl. Cancer Inst. , 79 , 263 – 267 ( 1987. ). [PubMed] [Google Scholar]
  • 14. ) Shibata , M. A. , Tamano , S. , Kurata , Y. , Hagiwara , A. and Fukushima , S.Participation of urinary Na+, K+, pH, and L‐ascorbic acid in the proliferative response of the bladder epithelium after the oral administration of various salts and/or ascorbic acid to rats . Food Chem. Toxicol. , 27 , 403 – 413 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Asamoto , M. , Mikheev , A. M. , Jiang , Y. Z. , Wild , C. P. , Hall , J. and Montesano , R.Immunohistochemical detection of DNA alkylation adducts in rat and hamster liver after treatment with dimethylnitrosamine . Exp. Pathol. , 41 , 71 – 78 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Kurihara , M. , Aoki , K. and Tominaga , S.Death rates for malignant neoplasms for selected sites, by sex and age‐group, for 1978–79 in 39 countries . In “ Cancer Mortality Statistics in the World ,” pp. 85 – 119 ( 1984. ). The University of Nagoya Press; , Nagoya . [Google Scholar]
  • 17. ) Goth , R. and Rajewsky , M. F.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. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Lewis , J. G. and Swenberg , J. A.The kinetics of DNA alkylation, repair and replication in hepatocytes, Kupffer cells, and sinusoidal endothelial cells in rat liver during continuous exposure to 1,2‐dimethylhydrazine . Carcinogenesis , 4 , 529 – 536 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Lu , S.‐J. , Chaulk , E. J. and Archer , M. C.Formation and repair of O6‐methylguanine and methylation of the Ha‐ras proto‐oncogene by N‐methyl‐N‐nitrosourea are not associated with mammary tumor resistance in the Copenhagen rat . Carcinogenesis , 13 , 857 – 861 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Ishikawa , T. and Sakurai , J.In vivo studies on age dependency of DNA repair with age in mouse skin . Cancer Res. , 46 , 1344 – 1348 ( 1986. ). [PubMed] [Google Scholar]
  • 21. ) Tice , R. R.Aging and DNA‐repair capability . In “ The Genetics of Aging ,” ed. Schneider E. L. , pp. 53 – 89 ( 1987. ). Plenum Press; , New York . [Google Scholar]
  • 22. ) Woodhead , A. D. , Merry , B. J. , Cao , E. H. , Holehan , A. M. , Grist , E. and Carison , C.Levels of O6‐methylguanine acceptor protein in tissues of rats and their relationship to carcinogenicity and aging . J. Natl. Cancer Inst. , 75 , 1141 – 1145 ( 1985. ). [PubMed] [Google Scholar]
  • 23. ) Yarosh , D.The role of O6‐methylguanine‐DNA methyl‐transferase in cell survival, mutagenesis and carcinogenesis . Mutat. Res. , 145 , 1 – 16 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Cohen , S. M. and Ellwein , L. B.Cell proliferation in carcinogenesis . Science , 249 , 1007 – 1011 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Shirai , T. , Nakamura , A. , Fukushima , S. , Takahashi , S. , Ogawa , K. and Ito , N.Effects of age on multiple organ carcinogenesis induced by 3,2′‐dimethyl‐4‐aminobiphenyl in rats, with particular reference to the prostate . Jpn. J. Cancer Res. , 80 , 312 – 316 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Shirai , T. , Fukushima , S. , Kawabe , M. , Shibata , M. A. , Iwasaki , S. , Tada , M. and Ito , N.Selective induction of rat urinary bladder tumors by simultaneous administration of 3,2′‐dimethyl‐4‐aminobiphenyl (DMAB) and butylated hydroxyanisole or butylated hydroxytoluene associated with increased DMAB‐DNA adduct formation . Carcinogenesis , 12 , 1335 – 1339 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 27. ) Sukumar , S. , Notario , V. , Martin‐Zanca , D. and Barbacid , M.Induction of mammary carcinomas in rats by nitro‐somethylurea involves malignant activation of H‐ras‐1 locus by single point mutations . Nature , 305 , 658 – 661 ( 1983. ). [DOI] [PubMed] [Google Scholar]

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