Idoxifene is equipotent to tamoxifen in inhibiting mammary carcinogenesis but forms lower levels of hepatic DNA adducts

Abstract

Summary 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 Mmethyinitrosourea (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-'), 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.

Anti‐breast cancer potential of SS1020, a novel antiestrogen lacking estrogenic and genotoxic actions

“…4‐Hydroxytamoxifen (4‐OHTAM) is a principal metabolite, showing ∼100‐fold more antiestrogenic activity than TAM in vitro 29. The 4‐OH moiety is expected to confer high antiestrogenic activity.…”

OXIDATION OF TAMOXIFEN BY HUMAN FLAVIN-CONTAINING MONOOXYGENASE (FMO) 1 AND FMO3 TO TAMOXIFEN-N-OXIDE AND ITS NOVEL REDUCTION BACK TO TAMOXIFEN BY HUMAN CYTOCHROMES P450 AND HEMOGLOBIN

“…Despite these potential drawbacks, TAM is still considered to be the most useful triphenylethyleneamine (TPE) agent for the endocrine treatment of breast cancer, and its safety as a therapeutic drug for up to 5 years of treatment has been established. Nevertheless, relatively novel TPEs, such as droloxifene, toremifene, and idoxifene, that apparently do not form DNA adducts as avidly as TAM are being investigated as potential second generation endocrine therapeutic agents (Hasmann et al, 1994;Pace et al, 1997;Williams and Jeffrey, 1997).…”

Synthesis and DNA Reactivity of α-Hydroxylated Metabolites of Nonsteroidal Antiestrogens

“…In contrast, the presence of a 4-iodo substituent in idoxifene renders the R-hydroxylated metabolite 9 less reactive to DNA, and correspondingly fewer adducts are seen. Almost undetectable levels of DNA adducts were observed in rats treated with idoxifene, whereas tamoxifen produces abundant adducts (22). The lower reactivity of 9 toward DNA may explain the lack of adduct formation.…”