Potent Antiestrogen Research Articles

Treatment of fibrocystic disease of the breast with gestrinone, a new trienic synthetic steroid with anti-estrogen, anti-progesterone properties

Twenty-eight patients with radiologically diagnosed fibrocystic disease were given twice weekly 5 mg tablets of Gestrinone, a synthetic contraceptive steroid with potent anti-estrogen, anti-progesterone properties, for periods ranging from 3 to 9 months. Treatment was discontinued when the nodularity disappeared and the patient became asymptomatic. Twelve patients had palpable nodules or masses in both breasts, while the remaining 16 had a single nodule or lump. In 12 patients, all with small nodules or lumps, complete elimination of nodularity occurred at the end of the first 3 months of treatment. In a further eight patients, five of whom had small nodules and three of whom had large ones, an additional 3 months of therapy were required to achieve complete elimination of nodularity. In two subjects, nodularity was eliminated at the end of 9 months of therapy, and in the remaining six subjects, although a reduction in nodularity greater than 50% occurred, masses remained palpable at the end of 9 months. Pain and tenderness were eliminated during the first 2 weeks of therapy in most cases. The most common complaints were acne and seborrhea (70% of patients) and a weight gain of between 2 and 5 kg in patients treated for 9 months. Main side effects encountered were acne and seborrhea.

Metabolites of tamoxifen in animals and man: identification, pharmacology, and significance.

Over the past decade, the non-steroidal antiestrogen tamoxifen has gained general acceptance for the palliative treatment of breast cancer. Although there has been much interest in the pharmacology of tamoxifen, our knowledge of its metabolism in laboratory animals and patients is incomplete and the precise mechanism of action within target tissue and breast tumor cells is unknown. This review briefly describes the pharmacology of tamoxifen in various laboratory species and patients. Several metabolites of tamoxifen are known and their relative potencies as estrogens and antiestrogens are compared with the parent compound. Apart from monohydroxytamoxifen, none of tamoxifen's metabolites are more potent antiestrogens, but a metabolite in the dog, Metabolite E, is fully estrogenic. Routine assays (tlc, HPLC, glc/ms) are available to detect tamoxifen, N-desmethyltamoxifen, monohydroxytamoxifen, and a newly identified metabolite, designated Metabolite Y, in biological fluids. Continuous therapy with tamoxifen (10 mg bid) produces steady-state levels (100-200 ng/ml serum) within 4 weeks. Levels of N-desmethyltamoxifen are often up to twice the levels achieved with tamoxifen, while levels of monohydroxytamoxifen and Metabolite Y are below 10 ng/ml. Although monohydroxytamoxifen has a high binding affinity for the estrogen receptor, the metabolic activation of tamoxifen is an advantage rather than a requirement for antiestrogenic activity. The action of tamoxifen in vivo is the net result of the individual actions of the parent compound and its metabolites competing for the occupation of receptors within target tissues and tumors.

Biological Potency and Uterine Estrogen Receptor Interactions of the Metabolites of the Antiestrogens CI628 and U23,469*

Previous studies from this laboratory have revealed that two potent nonsteroidal antiestrogens, CI628 [α-(p-(2-(1-pyrrolidino)ethoxy)phenyl)4-methoxy-α′-nitrostilbene] and U23,469 [cis-(3-(p-(l,2,3,4-tetrahydro-6-methoxy-2-phenyll-naphthyl)phenoxy)1,2-propanediol], are metabolized during their action in vivo to more polar metabolites. We have identified these metabolites as the demethylated forms of the parentantiestrogen and have synthesized them (CI628M and U23.469M). In studies reported here, we compare the potency of the metabolites and parent antiestrogens in terms of their 1) affinity for cytoplasmic estrogen receptor, 2) ability to translocate estrogen receptor to the nuclear fraction in whole uteri in organ culture in vitro and to prevent nuclear uptake of [3H]estradiol, 3) ability to prevent estradiol stimulation of induced protein synthesis in vitro, and 4) ability to inhibit estradiol stimulation of uterine weight gain and peroxidase activity in vivo. The antiestrogens compete with [3H]estradio...

Absence of correlation between antiestrogenic activity and binding affinity for the estrogen receptor

We have compared the binding to the estrogen receptor (R) of different androgens and antiestrogens with their antiestrogenic activities on uterine growth. We found that estradiol (E 2) 1 and hydroxytamoxifen, a potent antiestrogen, displayed the same affinity for R. Conversely, androgens which have a much lower affinity for R and a much higher dissociation rate than E 2, behave at high doses as full estrogens, with no significant antiestrogenic activity. We conclude that there is no correlation between the dissociation rate from R and the antiestrogenic activity of R ligands and that one cannot discriminate between estrogen and antiestrogen ligands by simply evaluating their in vitro binding to the cytosol R.

Nonsteroidal antiestrogens: Their biological effects and potential mechanisms of action

The uterotropic and antiuterotrapic effects of a variety of structural derivatives of the nonsteroidal antiestrogen tamoxifen have been determined in the rat and the mouse. One derivative, monohydroxytamoxifen, was found to be a potent antiestrogen in the rat, with a high affinity for the estrogen receptor. Various techniques of sucrose density gradient analysis were used to demonstrate that estradiol and tamoxifen bind to the rat uterine cytoplasmic estrogen receptor. Estrogens and antiestrogens provoke the translocation of estrogen receptors to the nucleus and deplete the cytoplasmic estrogen receptor pool for short or long periods depending on the dose administered. Estradiol stimulates endometrial hyperplasia with an increase in total uterine DNA content, whereas tamoxifen stimulates endometrial hypertrophy with only a slight increase in uterine DNA content. It is concluded that the molecular shape of the ligand that binds to the estrogen receptor determines antiestrogenic activity.

Spermatogenic arrest produced in the adult male rat by 19-norspiroxenone, a potent anti-estrogen.

19-Norspiroxenone, a potent anti-estrogen with no known estrogenic action, produces a striking arrest of spermatogenesis in the early stages of meiosis in the adult male rat with a complete block of fertility.