DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation

Tamoxifen was administered in the diet (420 p.p.m.) to femaleF344 (Fischer), Wistar (LAC-P) and LEW (Lewis) rats to determinefor each strain the early morphological and biochemical changesassociated with the subsequent development of liver cancer.Hepatic DNA damage, as determined by ³²P-postlabelling, showeda cumulative increase with time from 500 adducts/10⁸ nucleotidesat 30 days to almost 3000 adducts/10⁸ nucleotides after 180days, with little difference between strains at this time point.A significant strain difference was found in the number of adductspresent in the Fischer rats at 90 days, compared to the Wistarand Lewis strains. There was a marked strain differences inthe time to development of liver tumours. After 6 months treatment,both Wistar and Lewis rats had tumours while none were seenin the Fischer animals. After 11 months, all of the Wistar andLewis rats had developed liver carcinoma, while the Fischerrats developed liver carcinoma by 20 months. Depression in cellproliferation, relative to age-matched controls, was seen inthe livers of Fischer rats after six months of exposure to tamoxifen,in contrast to an increase in the Wistar and Lewis rats. Thisobservation is consistent with the promotion of foci to tumoursand the subsequent progression of tumours to carcinomas in thelatter two strains. These data may assist in establishing thepossible risk factors, such as extent of DNA damage and increasedliver cell proliferation, to women with long-term prophylacticexposure to tamoxifen.