Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1983 Apr;47(4):517–525. doi: 10.1038/bjc.1983.82

Promotion mechanism of phenobarbital and partial hepatectomy in DENA hepatocarcinogenesis cell kinetics effect.

H Barbason, C Rassenfosse, E H Betz
PMCID: PMC2011340  PMID: 6849796

Abstract

Diethylnitrosamine (DENA, 10 mg kg-1 per day) was fed to rats for 2, 4 and 6 weeks. One week after the cessation of DENA, animals were submitted either to partial hepatectomy or to phenobarbital administration. Partial hepatectomy did not promote neoplastic transformation, except after a 6-week DENA treatment. A minimum of phenobarbital was required to reach a significant promoting effect in DENA carcinogenesis. A too-limited treatment was ineffectual but could be compensated for by prolonged DENA administration. The phenobarbital treatment became unnecessary when neoplastic nodules were present. Phenobarbital continuously given after the carcinogen administration promoted neoplastic transformation even after a subcarcinogenic DENA treatment (2 weeks). It accelerated the pathological evolution and increased the tumour incidence. In these conditions, phenobarbital increased the proliferation advantage of preneoplastic cells over normal cells. In the different experimental modalities, the promoting effect was associated with the induction of chronic cell proliferation, the inhibition of the rapid response to the 2/3 partial hepatectomy and the mitotic circadian rhythm normally present during liver regeneration. It is concluded that the promotion mechanism could consist in disturbing the mitotic control in order to maintain, for a long time, a chronic low level of cell proliferation permitting the selective growth of preneoplastic cells and their subsequent transformation.

Full text

PDF
517

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Argyris T. S. Additive effects of phenobarbital and high protein diet on liver growth in immature male rats. Dev Biol. 1971 Jun;25(2):293–309. doi: 10.1016/0012-1606(71)90032-7. [DOI] [PubMed] [Google Scholar]
  2. Argyris T. S., Magnus D. R. The stimulation of liver growth and demethylase activity following phenobarbital treatment. Dev Biol. 1968 Feb;17(2):187–201. doi: 10.1016/0012-1606(68)90060-2. [DOI] [PubMed] [Google Scholar]
  3. BUCHER N. L., SWAFFIELD M. N., DITROIA J. F. THE INFLUENCE OF AGE UPON THE INCORPORATION OF THYMIDINE-2-C14 INTO THE DNA OF REGENERATING RAT LIVER. Cancer Res. 1964 Apr;24:509–512. [PubMed] [Google Scholar]
  4. Bannasch P. Cytology and cytogenesis of neoplastic (hyperplastic) hepatic nodules. Cancer Res. 1976 Jul;36(7 Pt 2):2555–2562. [PubMed] [Google Scholar]
  5. Barbason H., Betz E. H. Liver cell control after discontinuation of DENA feeding in hepatocarcinogenesis. Eur J Cancer. 1981 Feb;17(2):149–154. doi: 10.1016/0014-2964(81)90029-3. [DOI] [PubMed] [Google Scholar]
  6. Barbason H., Betz E. H. Proliferation of preneoplastic lesions after discontinuation of chronic DEN feeding in the development of hepatomas in rat. Br J Cancer. 1981 Oct;44(4):561–566. doi: 10.1038/bjc.1981.226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Barbason H., Fridman-Manduzio A., Betz E. H. Activité mitotique lors de la période prénéoplasique précédant la cancérisation du foie par la diethylnitrosamine. Experientia. 1976 Jan 15;32(1):106–108. doi: 10.1007/BF01932649. [DOI] [PubMed] [Google Scholar]
  8. Barbason H., Fridman-Manduzio A., Betz E. H. Long term effects of a single dose of dimethylnitrosamine on the rat liver. Z Krebsforsch Klin Onkol Cancer Res Clin Oncol. 1975 Oct 27;84(2):135–142. doi: 10.1007/BF00304039. [DOI] [PubMed] [Google Scholar]
  9. Barbason H., Fridman-Manduzio A., Lelievre P., Betz E. H. Variations of liver cell control during diethylnitrosamine carcinogenesis. Eur J Cancer. 1977 Jan;13(1):13–18. doi: 10.1016/0014-2964(77)90223-7. [DOI] [PubMed] [Google Scholar]
  10. Barbason H., Smoliar V., Fridman-Manduzio A., Betz E. H. Effects of discontinuation of chronic feeding of diethylnitrosamine on the development of hepatomas in adult rats. Br J Cancer. 1979 Aug;40(2):260–267. doi: 10.1038/bjc.1979.174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Becker F. F., Klein K. M. The effect of L-asparaginase on mitotic activity during N-2-fluorenylacetamide hepatocarcinogenesis: subpopulations of nodular cells. Cancer Res. 1971 Feb;31(2):169–173. [PubMed] [Google Scholar]
  12. Emmelot P., Scherer E. The first relevant cell stage in rat liver carcinogenesis. A quantitative approach. Biochim Biophys Acta. 1980 May 6;605(2):247–304. doi: 10.1016/0304-419x(80)90006-2. [DOI] [PubMed] [Google Scholar]
  13. Farber E. The sequential analysis of liver cancer induction. Biochim Biophys Acta. 1980 May 6;605(2):149–166. doi: 10.1016/0304-419x(80)90002-5. [DOI] [PubMed] [Google Scholar]
  14. Hughes P. E. Liver cell responses to the carcinogen 3'-methyl-4-dimethylaminoazobenzene. Chem Biol Interact. 1970 Feb;1(3):301–305. doi: 10.1016/0009-2797(70)90016-5. [DOI] [PubMed] [Google Scholar]
  15. Kitagawa T., Pitot H. C., Miller E. C., Miller J. A. Promotion by dietary phenobarbital of hepatocarcinogenesis by 2-methyl-N,N-dimethyl-4-aminoazobenzene in the rat. Cancer Res. 1979 Jan;39(1):112–115. [PubMed] [Google Scholar]
  16. Peraino C., Fry R. J., Staffeldt E., Christopher J. P. Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat. Cancer Res. 1975 Oct;35(10):2884–2890. [PubMed] [Google Scholar]
  17. Peraino C., Fry R. J., Staffeldt E. Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene. Cancer Res. 1971 Oct;31(10):1506–1512. [PubMed] [Google Scholar]
  18. Pitot H. C., Barsness L., Goldsworthy T., Kitagawa T. Biochemical characterisation of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine. Nature. 1978 Feb 2;271(5644):456–458. doi: 10.1038/271456a0. [DOI] [PubMed] [Google Scholar]
  19. Pitot H. C., Sirica A. E. The stages of initiation and promotion in hepatocarcinogenesis. Biochim Biophys Acta. 1980 May 6;605(2):191–215. doi: 10.1016/0304-419x(80)90004-9. [DOI] [PubMed] [Google Scholar]
  20. Rabes H. M., Szymkowiak R. Cell kinetics of hepatocytes during the preneoplastic period of diethylnitrosamine-induced liver carcinogenesis. Cancer Res. 1979 Apr;39(4):1298–1304. [PubMed] [Google Scholar]
  21. Rabes H., Hartenstein R., Scholze P. Specific stages of cellular response to homeostatic control during diethylnitrosamine-induced liver carcinogenesis. Experientia. 1970 Dec 15;26(12):1356–1359. doi: 10.1007/BF02113030. [DOI] [PubMed] [Google Scholar]
  22. Scherer E., Emmelot P. Foci of altered liver cells induced by a single dose of diethylnitrosamine and partial hepatectomy: their contribution to hepatocarcinogenesis in the rat. Eur J Cancer. 1975 Mar;11(3):145–154. doi: 10.1016/0014-2964(75)90109-7. [DOI] [PubMed] [Google Scholar]
  23. Scherer E., Emmelot P. Kinetics of induction and growth of enzyme-deficient islands involved in hepatocarcinogenesis. Cancer Res. 1976 Jul;36(7 Pt 2):2544–2554. [PubMed] [Google Scholar]
  24. Squire R. A., Levitt M. H. Report of a workshop on classification of specific hepatocellular lesions in rats. Cancer Res. 1975 Nov;35(11 Pt 1):3214–3223. [PubMed] [Google Scholar]
  25. Taper H. S. The effect of estradiol-17-phenylpropionate and estradiol benzoate on N-nitrosomorpholine-induced liver carcinogenesis in ovariectomized female rats. Cancer. 1978 Aug;42(2):462–467. doi: 10.1002/1097-0142(197808)42:2<462::aid-cncr2820420213>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  26. Van Cantfort J., Barbason H. Influence of a chronic administration of diethylnitrosamine on the relation between specific tissular and division functions in the rat liver. Eur J Cancer. 1975 Aug;11(8):531–536. doi: 10.1016/0014-2964(75)90124-3. [DOI] [PubMed] [Google Scholar]
  27. Weisburger J. H., Madison R. M., Ward J. M., Viguera C., Weisburger E. K. Modification of diethylnitrosamine liver carcinogenesis with phenobarbital but not with immunosuppression. J Natl Cancer Inst. 1975 May;54(5):1185–1188. doi: 10.1093/jnci/54.5.1185. [DOI] [PubMed] [Google Scholar]
  28. Williams G. M., Klaiber M., Farber E. Differences in growth of transplants of liver, liver hyperplastic nodules, and hepatocellular carcinomas in the mammary fat pad. Am J Pathol. 1977 Nov;89(2):379–390. [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES