Antioestrogenic and antitumour activities of a series of non-steroidal antioestrogens

Abstract

The relative oestrogenic and antioestrogenic activities in the immature rat uterus of the antioestrogens tamoxifen, trioxifene, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- <2-(1-pyrrolidinyl) ethoxyphenyl ketone (LY 117018) and 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- <2-(1-piperidinyl) ethoxyphenyl ketone (LY 139481) were compared. The efficacy of these compounds in inhibiting the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinomas was also measured. Tamoxifen and trioxifene were equipotent antioestrogens (ED50 =dose required to produce 50% reduction in oestradiol-stimulated uterine growth = 0·1 mg/kg); both compounds also demonstrated a maximal partial agonist (uterotrophic) effect of 40% that of oestradiol. LY 117018 and LY 139481 were less potent antioestrogens (ED50 = 0·7 and 0·25 mg/kg respectively) than tamoxifen but both compounds were also less oestrogenic (partial agonist activities 20 and 10% respectively compared with oestradiol). The differences in partial agonist activity were reflected by differences in maximum antioestrogenic effects. High doses of tamoxifen or trioxifene produced 60% inhibition of oestradiol-induced uterine growth whereas LY 117018 (80% inhibition) and LY 139481 (90% inhibition) were both more antioestrogenic because of their reduced partial agonist activity. In rats bearing DMBA-induced mammary tumours tamoxifen was the most effective inhibitor of tumour growth. In tamoxifen-treated animals only 7% (8/111) of hormone-dependent tumours showed progressive growth, compared to 60% in controls. The other antioestrogens were less effective; in trioxifene-treated animals 42% (18/43) of tumours continued to grow during treatment. Similarly, for LY 117018, 39% (14/36) and for LY 139481, 26% (10/38) of tumours showed progression. High doses of trioxifene and LY 117018 were markedly less efficacious than low doses. The increased separation between oestrogenic and antioestrogenic activity in the rat uterus, exemplified by LY 117018 and LY 139481 compared to tamoxifen and trioxifene, did not lead to increased antitumour efficacy.