Tamoxifen is an effective agent preventing mammary
carcinogenesis in rats but causing liver tumours.
Idoxifene is a more potent antioestrogen and is effective in patients with advanced
breast cancer. We therefore compared the effects of
idoxifene with
tamoxifen on mammary
carcinogenesis and hepatic
DNA adduct formation. To do this, we undertook a study designed to compare
tamoxifen with
idoxifene as a chemopreventive agent in rats inoculated with N-
methylnitrosourea (MNU) and also measured hepatic adduct formation. We examined the time to mammary tumour development in 272 female Ludwig/Wistar/Olac rats treated with MNU followed by
tamoxifen (5 mg kg(-1)), equimolar
idoxifene or vehicle three times a week for up to 24 weeks. To determine duration of effect, a second study was carried out whereby all of the 129 animals surviving at the end of treatment were entered into a surveillance programme for 27 weeks after the end of the administration period. Hepatic
DNA adduct formation was examined by 32P-postlabelling in a group of rats after 24 weeks' treatment. In the first study, both
idoxifene and
tamoxifen were effective in preventing tumour growth as only 2 out of 21 (10%) MNU and vehicle-treated animals were alive and tumour free after 24 weeks compared with 13 out of 22 (59%) animals receiving MNU followed by
idoxifene or
tamoxifen (P < 0.001). The second study showed that, in both
idoxifene- and
tamoxifen-treated animals, a progressive regrowth of tumours occurred after cessation of
therapy, as by the end of the observation period only four
idoxifene-treated animals and one
tamoxifen-treated animal were free from disease. In the subset of animals tested,
tamoxifen-treated animals had approximately 100 times higher levels of
DNA hepatic adducts than
idoxifene-treated animals. Adducts were not seen in the control group. These results indicate that
idoxifene is as effective a chemopreventive agent as
tamoxifen in the rat while causing only very low levels of
DNA adducts in liver tissue and suggest that
idoxifene may be a well-tolerated chemopreventive agent in women who are at increased risk of
breast cancer.