Skip to main content
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1999 Jan;90(1):101–107. doi: 10.1111/j.1349-7006.1999.tb00672.x

Natural Killer Activity in a Medium‐term Multi‐organ Bioassay for Carcinogenesis

Ana Lúcia Tozzi Spinardi 1, Ramon Kaneno 3, Maria Aparecida Marchesan Rodrigues 1, Daisy Maria Fávero Salvadori 1, Noeme Sousa Rocha 2, Luís Fernando Barbisan 4, Lúcia Regina Ribeiro 1, João Lauro Viana de Camargo 1,
PMCID: PMC5925978  PMID: 10076572

Abstract

Natural killer (NK) cell activity was evaluated after the initiation and promotion steps in a medium‐term multi‐organ bioassay for carcinogenesis. NK cell activity was assessed in vitro by Cr51 release assay at the 4th and 30th weeks of the experiment. Male Wistar rats were sequentially initiated with N‐diethylnitrosamine (DEN i.p.), N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN drinking water), N‐methyl‐N‐nitrosourea (MNU i.p.), dihydroxy‐di‐N‐propylnitrosamine (DHPN drinking water) and N, N′‐dimethylhydrazine (DMH s.c.) at subcarcinogenic doses for 4 weeks (DMBDD initiation). One group was evaluated at the 4th week and the other was maintained without any further treatment until the 30th week. Two initiated groups were exposed through the diet to 2‐acetylaminofluorene (2‐AAF) or phenobarbital (PB), from the 6th until the 30th week. Five additional groups were studied to evaluate the effects of each initiator on NK activity. All groups submitted to initiation only, initiation plus promotion, or promotion only, developed significantly more preneoplastic lesions than the untreated control group. The main target organs for tumor development in the initiated animals were the liver and the colon, irrespective of treatment with 2‐AAF or PB. NK cell activity was not affected by exposure to genotoxic carcinogens after initiation, at the 4th week. Treatments only with PB or 2‐AAF did not change NK cell activity. However, decreased NK cell activity was registered in the group only initiated with DMBDD and in the group given DMBDD+2‐AAF. This late depression of NK cell activity at the 30th week could be related to the production of suppressing molecules by the tumor cells.

Keywords: NK cell activity, Immune response, Multi‐organ carcinogenesis, Chemical carcinogens

Full Text

The Full Text of this article is available as a PDF (121.8 KB).

REFERENCES

  • 1. ) Koller , L. D.Effect of chemical sensitivity on the immune system . Immunol. Allergy Pract. , 7 , 13 – 25 ( 1985. ). [Google Scholar]
  • 2. ) Koller , L. D.Immunotoxicology today . Toxicol. Pathol. 15 , 346 – 351 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Talcott , P. A. , Exon , J. H. and Koller , L. D.Alteration of natural killer cell‐mediated cytotoxicity in rats treated with selenium, diethylnitrosamine and ethylnitrosourea . Cancer Lett. , 23 , 313 – 322 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Luster , M. I. , Germolec , D. R. and Rosenthal , G. J.Immunotoxicology: review of current status . Ann. Allergy , 64 , 427 – 432 ( 1990. ). [PubMed] [Google Scholar]
  • 5. ) Krzystyniak , K. , Tryphonas , H. and Fournier , M.Approaches to the evaluation of chemical‐induced immunotoxicity . Environ. Health Perspect. , 103 , 17 – 22 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Luster , M. I. and Rosenthal , G. J.Chemical agents and the immune response . Environ. Health Perspect. , 100 , 219 – 236 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Woodruff , M. F. A.The cytolytic and regulatory role of natural killer cells in experimental neoplasia . Biochim. Biophys. Acta , 865 , 43 – 57 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Kurosawa , S. , Harada , M. , Matsuzaki , G. , Shinomiya , Y. , Terao , H. , Kobayashi , N. and Nomoto , K.Early‐appearing tumour‐infiltrating natural killer cells play a crucial role in the generation of anti‐tumour T lymphocytes . Immunology , 85 , 338 – 346 ( 1995. ). [PMC free article] [PubMed] [Google Scholar]
  • 9. ) Miller , K.Immunotoxicology . Clin. Exp. Immunol. , 61 , 219 – 223 ( 1985. ). [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Altmann , G. G. and Lala , P. K.Initiated stem cells in murine intestinal carcinogenesis: prolonged survival, control by NK cells, and progression . Int. J. Cancer , 59 , 569 – 579 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Altmann , G. G. , Parhar , R. S. and Lala , P. K.Hyperplasia of mouse duodenal crypts and its control by NK cells during the initial phase of DMH carcinogenesis . Int. J. Cancer , 46 , 695 – 702 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Ito , N. , Shirai , T. and Hasegawa , R.Medium‐term bioassays for carcinogens . In“Mechanisms of Carcinogenesis in Risk Identification ” ed. Vainio H. , Magee P. N. , McGregor D. B. and McMichael A. J. , pp. 356 – 388 ( 1992. ). International Agency for Research on Cancer; , Lyon , France . [Google Scholar]
  • 13. ) IARC. “Long‐term and Short‐term Assays for Carcinogens: A Critical Appraisal ” ed. Montesano R. , Bartsch H. , Vainio J. , Wilbourn H. and Yamasaki H. , pp . 1 – 546 ( 1986. ). Lyon , France .
  • 14. ) Ito , N. , Hasegawa , R. , Imaida , K. , Hirose , M. and Shirai , T.Medium‐term liver and multi‐organ carcinogenesis bioas‐says for carcinogens and chemopreventive agents . Exp. Toxicol. Pathol. , 48 , 113 – 119 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Takahashi , S. , Hasegawa , R. , Masui , T. , Misoguchi , M. , Fukushima , S. and Ito , N.Establishment of multi‐organ carcinogenesis bioassay using rats treated with a combination of five different carcinogens . J. Toxicol. Pathol. , 5 , 151 – 156 ( 1992. ). [Google Scholar]
  • 16. ) Brazilian Institute of Environmental and Renewable Natural Resources (IBAMA) . Normative Act no. 84, October 15 ( 1996. ) ( In Portuguese ).
  • 17. ) Reynolds , C. W. , Timonen , T. and Herberman , R. B.Natural killer (NK) cell activity in the rat. I. Isolation and characterization of the effector cells . J. Immunol. , 127 , 282 – 287 ( 1981. ). [PubMed] [Google Scholar]
  • 18. ) Hagiwara , A. , Tanaka , H. , Imaida , K. , Tamano , S. , Fukushima , S. and Ito , N.Correlation between medium‐term multi‐organ carcinogenesis bioassay data and long‐term observation results in rats . Jpn. J. Cancer Res. , 84 , 237 – 245 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Pitot , H. C. and Dragan , Y. P.Facts and theories concerning the mechanisms of carcinogenesis . FASEB J. , 5 , 2280 – 2286 ( 1991. ). [PubMed] [Google Scholar]
  • 20. ) Pitot , H. C.The molecular biology of carcinogenesis . Cancer , 72 , 962 – 970 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Munson , A. E. , McCay , J. A. and Cao , W.Approaches to immunotoxicologic studies with emphasis on chemical‐induced immunomodulation . Ann. Allergy , 66 , 505 – 518 ( 1991. ). [PubMed] [Google Scholar]
  • 22. ) Locniskar , M. , Nauss , K. M. and Newberne , P. M.Natural killer cell activity and autologous mixed lymphocyte response of splenic, mesenteric lymphnode, and colonic lymphocytes during DMH‐induced colon carcinogenesis in the rat . Digest. Dis. Sci. , 32 , 747 – 752 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Talcott , P. A. , Exon , J. H. and Koller , L. D.The effects of methylnitrosourea (MNU) on natural killer (NK) cell cytotoxicity and cytokine production in rats . Carcinogenesis , 11 , 829 – 834 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Brittenden , J. , Heys , S. D. , Ross , J. and Eremin , O.Natural killer cells and cancer . Cancer , 77 , 1226 – 1243 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 25. ) Kimber , I. , Griffin , A. C. and Jones , K.The influence of chemical carcinogens on natural killer cell function in rats. A comparison of 2‐acetylaminofluorene with 4‐acetylaminofluorene . Cancer Lett. , 30 , 41 – 48 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Hong , W. S. , Hong , S. I. and Jang , J. J.Natural killer activity in a rat multi‐organ carcinogenesis model . Korean J. Immunol. , 13 , 43 – 51 ( 1991. ). [Google Scholar]
  • 27. ) Marana , H. R. C. , Andrade , J. M. and Silva , J. S.Natural killer cells and interleukin‐12 in patients with advanced cervical cancer under neoadjuvant chemotherapy . Braz. J. Med. Biol. Res. , 29 , 473 – 477 ( 1996. ). [PubMed] [Google Scholar]
  • 28. ) Coca , S. , Piqueras , J. P. , Martinez , D. , Colmenarejo , A. , Saez , M. A. , Vallejo , C. , Martos , J. A. and Moreno , M.The prognostic significance of intramural natural killer cells in patients with colorectal carcinoma . Cancer , 79 , 2320 – 2328 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Tamura , Y. , Takashima , S. , Cho , J.‐M. , Qi , W. , Kamiguchi , K. , Torigoe , T. , Takahashi , S. , Hirai , I. , Sato , N. and Kikuchi , K.Inhibition of natural killer cell cytotoxicity by cell growth‐related molecules . Jpn. J. Cancer Res. 87 , 623 – 630 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. ) Liao , N. S. , Bix , M. , Zijlstra , M. , Jaenisch , R. and Raulet , D.MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK cell activity . Science , 253 , 199 – 202 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Kärre , K.Express yourself or die: peptides, MHC molecules, and NK cells . Science , 267 , 978 – 979 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Malnati , M. S. , Peruzzi , M. , Parker , K. C. , Biddison , W. E. , Ciccone , E. , Moretta , A. and Long , E. O.Peptide specificity in the recognition of MHC class I by natural killer clones . Science , 267 , 1016 – 1018 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Kaufman , D. S. , Schoon , R. A. and Leibson , P. J.MHC class I expression on tumor targets inhibits natural killer cell‐mediated cytotoxicity without interfering with target recognition . J. Immunol. , 150 , 1429 – 1436 ( 1993. ). [PubMed] [Google Scholar]
  • 34. ) MacDonald , H. R.NK1.1+ T cell receptor‐α/β+cells: new clues to their origin, specificity, and function . J. Exp. Med. , 182 , 633 – 638 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. ) MacDonald , H. R.Development and function of natural killer I+T‐cells . Biochem. Soc. Trans. , 25 , 696 – 699 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Williams , N. S. , Moore , T. A. , Schatzle , J. D. , Puzanov , I. J. , Sivakumar , P. V. , Zlotnik , A. , Bennett , M. and Kumar , V.Generation of lytic natural killer 1.1+, Ly‐49– cells from multipotential murine bone marrow progenitors in a stroma‐free culture: definition of cytokine requirements and developmental intermediates . J. Exp. Med. , 186 , 1609 – 1614 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. ) Santoni , A. and Palmeri , G.NK receptors and signalling . Res. Immunol. , 148 , 184 – 190 ( 1997. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES