The role of cell death and cell proliferation in the promotion of rat liver tumours by tamoxifen

Administration of tamoxifen to rats results in liver tumours with a latency time that is dependent on the strain of rat used. Wistar and Lewis rats develop liver tumours more rapidly than Fischer rats. Significant increases in the number of apoptotic hepatocytes were found in the Wistar and Lewis strains of rats after they were fed tamoxifen for up to 6 months, but not in Fischer rats. By 6 months of exposure to tamoxifen there were liver tumours in the Wistar and Lewis rats, but not the Fischers. Sustained elevations of the PCNA labelling index were found in the livers of tamoxifen-treated Wistar and Lewis rats, over the first 6 months of tamoxifen treatment, but not Fischers. It is proposed that sustained cell death by apoptosis may play a role in the mechanism of promotion of tamoxifen-induced liver tumours, by causing liver hyperplasia. To support this concept it has been shown that cyloheximide, which causes apoptosis but not necrosis in the rat liver, causes DNA synthesis and cell division in hepatocytes.