Carcinogenesis, Vol 18, 649-655, Copyright © 1997 by Oxford University Press
P Rissler, UB Torndal and LC Eriksson
Compounds exerting a mitoinhibitory effect on normal hepatocytes are potent
promoters in the resistant hepatocyte model of chemical carcinogenesis in
combination with stimulation of regenerative growth by partial hepatectomy
or treatment with carbon tetrachloride. 2- Acetylaminofluorene (2-AAF)
almost completely inhibits liver cell regeneration after partial
hepatectomy, allowing only resistant cells to participate in regenerative
growth. After initiation by diethylnitrosamine and promotion with 2-AAF and
partial hepatectomy (PH), focal growth of initiated cells generates liver
lesions which occupy 40% of the hepatic volume three weeks after PH. In
this work the mechanism for the anti promoting effects of phenobarbital and
3- methylcholantrene were investigated as well as their effects on the
development of malignant hepatocellular carcinoma in the resistant
hepatocyte model. Treatment with phenobarbital or, especially, 3-
methylcholanthrene rendered normal rat hepatocytes resistant to the
mitoinhibitory effect of 2-AAF. In combination with 2-AAF/PH, 3-
methylcholanthrene shortened the regenerative growth period to less than
one week. In the Solt-Farber protocol for experimental
hepatocarcinogenesis, treatment with phenobarbital or 3- methylcholanthrene
during promotion with 2-AAF/PH permitted hepatocytes surrounding the focal
lesions to respond with regenerative growth. The foci and surrounding liver
grew until the liver/body mass index reached the control value. With
phenobarbital treatment the total focal volume was 20% of the liver volume
three weeks after PH, whereas the corresponding value in the case of
3-methylcholanthrene was only 1%. Labelling index data supported the
conclusion that growth of the liver lesions in the resistant hepatocyte
model was dependent on differential inhibition of normal hepatocyte growth
by the promoter and that the size of the foci obtained was related to the
length of time after PH required to complete liver regeneration.
3-methylcholanthrene induced 2- AAF resistance prevented the development of
large persistent nodules and hepatocellular carcinoma while phenobarbital
delayed cancer development with several month. The data thus supports the
idea that the degree of clonal expansion during promotion determines the
size of the population at risk for malignant transformation, as well as the
final frequency of carcinomas.
ARTICLES
Induced drug resistance inhibits selection of initiated cells and cancer development
Department of Immunology, Microbiology, Pathology and Infectious Diseases, Karolinska Institutet, Huddinge University Hospital, Sweden.
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