On the promoting action of tamoxifen in a model of hepatocarcinogenesis induced by p-dimethylaminoazobenzene in CF1 mice.
OBJECTIVE
Tamoxifen (TMX) has proven to be an effective palliative treatment for advanced breast cancer with low reported incidence of side effects. TMX has been demonstrated to be an initiator and/or a promoter in the rat model of hepatocarcinogenesis. To document the long-term effect of TMX in mice treated with p-dimethylaminoazobenzene (DAB), we have investigated the time response action of these drugs on different biochemical parameters.


METHODS
A group of animals was placed on dietary DAB (0.5%, w/w) during a period of 28 weeks. Control animals received a standard laboratory diet. Two other groups of non-treated and DAB-treated animals received TMX citrate (0.025%, w/w) in the diet since day 20.


RESULTS
The activities of the enzymes involved in heme synthesis and degradation as evaluated in the DAB group was not further affected by TMX. DAB and/or TMX treatment significantly increased the content of total cytochrome P450 and also the activity of glutathione S-transferase indicating liver damage. In all treated groups oxidative stress and an adaptive response of the natural defense system (catalase and superoxide dismutase) were demonstrated. Histological and morphological studies revealed liver cell hyperplasia in DAB treated group; however, only in the DAB+TMX group solid, trabecular and acinar hepatocellular carcinoma was confirmed at the end of the experimental trial.


CONCLUSIONS
We have demonstrated that TMX produced changes in hepatic enzyme activities which may be relevant for the metabolism and disposition of this and/or other drugs. Because liver tumors could be initiated and promoted by several agents which need to be activated, the possible hazard of TMX should be considered. This study reports that long-term treatment with TMX enhances hepatocarcinogenesis induced by DAB. The widespread use of TMX as an anticancer agent adds to the significance of this study.
Caballero
F
F
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP) (CONICET-FCEN, UBA), Ciudad Universitaria, Pabellón II, 2do piso, 1428, Buenos Aires, Argentina.
Gerez
E
E
Oliveri
L
L
Falcoff
N
N
Batlle
A
A
Vazquez
E
E
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D013629:Tamoxifen / Q000633:toxicity*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors; D004124:p-Dimethylaminoazobenzene / Q000633:toxicity*
D002273:Carcinogens; D017392:Thiobarbituric Acid Reactive Substances; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System; D004124:p-Dimethylaminoazobenzene; D002374:Catalase; D006419:Heme Oxygenase (Decyclizing); D013482:Superoxide Dismutase; D000624:5-Aminolevulinate Synthetase; D005982:Glutathione Transferase