On the promoting action of tamoxifen in a model of hepatocarcinogenesis induced by p-dimethylaminoazobenzene in CF1 mice

Background and aims: Tamoxifen (TMX) has proven to be an effective palliati ve treatment for advanced breast cancer with low reported incidence of side effects. TMX has been demonstrated to be: an initiator and/or a promoter i n the rat model of hepatocarcinogenesis. To document the long-term effect o f TMX in mice treated with p-dimerhylaminuazobenzene (DAB), we have investi gated the time response action of these drugs on different biochemical para meters. Methods: A group of animals was placed on dietary DAB (0.5%, w/w) d uring 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 signifi cantly increased the content of total cytochrome P450 and also the activity of glutathione S-transferase indicating liver damage. In all treated group s oxidative stress and an adaptive response of the natural defense system ( catalase and superoxide dismutase) were demonstrated. Histological and morp hological studies revealed liver cell hyperplasia in DAB treated group: how ever. only in the DAB + TMX group solid. trabecular and acinar hepatocellul ar carcinoma was confirmed at the end of the experimental trial. Conclusion s: We have demonstrated that TMX produced changes in hepatic enzyme activit ies which may be relevant fur the metabolism and disposition of this and/or other drugs. Because liver tumors could be initiated and promoted by sever al agents which need to be activated. the possible hazard of TMX should be considered. This study reports that long-term treatment with TMX enhances h epatocarcinogenesis induced by DAB. The widespread use of TMX as an antican cer agent adds to the significance of this study. (C) 2001 Published by Els evier Science Ltd.