piperidines and trioxifene

An estrogen receptor and progesterone receptor positive endometrial carcinoma (EnCa101) will grow in response to either estradiol or tamoxifen when transplanted into athymic mice. We have tested several antiestrogens with different properties to determine their ability to support endometrial tumor growth. Trioxifene, enclomiphene and nafoxidine are all as active as tamoxifen whereas the antiestrogen keoxifene, that has reduced estrogen-like properties, will partially inhibit tamoxifen-stimulated growth. Furthermore, the pure antiestrogen ICI 164,384 will block tamoxifen-stimulated growth without having any effect itself on tumor growth rate. Overall, the ability of antiestrogens to stimulate the growth of human endometrial carcinoma EnCa101 appears to be related to their intrinsic estrogenic activity.

Topics: Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Clomiphene; Enclomiphene; Endometrium; Estradiol; Estrogen Antagonists; Female; Humans; Mice; Mice, Inbred BALB C; Nafoxidine; Neoplasm Transplantation; Piperidines; Polyunsaturated Alkamides; Pyrrolidines; Raloxifene Hydrochloride; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Uterine Neoplasms

The non-steroidal antioestrogens tamoxifen, 4-hydroxytamoxifen, trioxifene, LY 117018 and LY 139481 have widely divergent affinities for oestrogen receptors from rat mammary tumours. The latter two compounds have much reduced partial agonist activity in rat uterus, compared to tamoxifen, but were less effective antitumour agents than tamoxifen. No direct correlation was established between receptor affinity and biological response in rat uterus or rat mammary carcinoma. However, in in vitro studies of growth inhibition of human breast cancer cells (MCF7), the order of potency was the same as the order of relative binding affinity. Differences in in vivo activity of these antioestrogens may be related to biological "half-life" which is dependent on the dose, route of administration and metabolic stability of the antioestrogens. Growth inhibition in MCF 7 cells did not correlate with affinity for tamoxifen-specific binding sites, nor was there any evidence for differences between antioestrogens in their mechanism of action on the rat uterus. It is concluded that the primary effects of antioestrogens are mediated by binding to oestrogen receptors.

Topics: Animals; Breast Neoplasms; Cell Line; Estrogen Antagonists; Female; Humans; Mammary Neoplasms, Experimental; Piperidines; Pyrrolidines; Raloxifene Hydrochloride; Rats; Receptors, Estrogen; Tamoxifen; Thiophenes; Uterus

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.

Topics: Animals; Estradiol; Estrogen Antagonists; Female; Mammary Neoplasms, Experimental; Organ Size; Piperidines; Pyrrolidines; Raloxifene Hydrochloride; Rats; Rats, Inbred Strains; Tamoxifen; Thiophenes; Uterus