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- less than 2-(1-pyrrolidinyl) ethoxyphenyl
ketone (
LY 117018) and 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- less than 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.