DNA-DAMAGE AS ASSESSED BY P-32 POSTLABELING IN 3 RAT STRAINS EXPOSED TO DIETARY TAMOXIFEN - THE RELATIONSHIP BETWEEN CELL-PROLIFERATION ANDLIVER-TUMOR FORMATION

Tamoxifen was administered in the diet (420 p.p.m,) to female F344 (Fi scher), Wistar (LAC-P) and LEW (Lewis) rats to determine for each stra in the early morphological and biochemical changes associated with the subsequent development of liver cancer, Hepatic DNA damage, as determ ined by P-32-postlabelling, showed a cumulative increase with time fro m 500 adducts/10(8) nucleotides at 30 days to almost 3000 adducts/10(8 ) nucleotides after 180 days, with little difference between strains a t this time point. A significant strain difference was found in the nu mber of adducts present in the Fischer rats at 90 days, compared to th e Wistar and Lewis strains. There was a marked strain differences in t he time to development of liver tumours, After 6 months treatment, bot h Wistar and Lewis rats had tumours while none were seen in the Fische r animals. After 11 months, all of the Wistar and Lewis rats had devel oped liver carcinoma, while the Fischer rats developed liver carcinoma by 20 months. Depression in cell proliferation, relative to age-match ed controls, was seen in the livers of Fischer rats after six months o f exposure to tamoxifen, in contrast to an increase in the Wistar and Lewis rats. This observation is consistent with the promotion of foci to tumours and the subsequent progression of tumours to carcinomas in the latter two strains. These data may assist in establishing the poss ible risk factors, such as extent of DNA damage and increased liver ce ll proliferation, to women with long-term prophylactic exposure to tam oxifen.