Detection of the 8 S oestrogen-binding component in human uterine endometrium during the menstrual cycle.
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Adult↗
Biomedical subjects
V C Jordan
Publications and source records attributed to V C Jordan.
Relation of steroids and prostaglandin at vaginal delivery and cesarean section.
The simultaneous determination of estradiol, estrone, progesterone, and prostaglandins E and F has been made in fetal and maternal compartments in patients with and without the onset of labor. The decidua rather than the fetus or placenta was considered to be the site of prostaglandin synthesis, and prostaglandins present in the amniotic fluid during labor were thought to be a byproduct by myometrial activity rather than the factor initiating the onset of labor. Progesterone levels in the maternal plasma were lower during labor but estradiol levels were elevated. It was concluded that the steroid environment may contribute to the clinical course of labor by facilitating the local uterine production of prostaglandins. Whereas estradiol was high and estrone low in maternal circulation, the ratio was reversed in the fetus. This reversal may serve to protect the fetus from high maternal levels of estradiol.
Amniotic Fluid↗
Anti-oestrogenic activity in compounds related to ethamoxytriphetol (MER 25), clomiphene and MRL 37.
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Animals↗
Is it time to develop an optimal endocrine therapy for premenopausal patients with axillary node positive and negative breast cancer?
One hundred years ago ovarian ablation was shown to be an effective treatment for advanced breast cancer in premenopausal women. Since that time many different treatment modalities have been advocated to improve patient survival. The value of adjuvant ovarian ablation, however, has recently been established in the overview of breast cancer clinical trials. In fact, comparison of the efficacy of combination chemotherapy with earlier trials of oophorectomy demonstrate the superiority of oophorectomy. The effectiveness of chemotherapy may largely be the result of partial ovarian ablation produced in premenopausal patients. Based on this position, we propose a clinical trial that would establish the optimal therapy for premenopausal breast cancer. In addition, the beneficial effects of long-term tamoxifen as it pertains to serum lipids and bone density are highlighted. The use of tamoxifen maintenance in oophorectomized women might provide an optimal therapy for the control of breast cancer recurrence.
Antineoplastic Agents, Hormonal↗
Tamoxifen for the prevention of breast cancer in the high-risk woman.
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Adult↗
The role of tamoxifen in the treatment and prevention of breast cancer.
Tamoxifen is a nonsteroidal antiestrogen that has found successful applications for each stage of breast cancer in the treatment of selected patients. Tamoxifen was originally introduced for the treatment of advanced disease in postmenopausal women; however, the drug is now also available for the palliative treatment of premenopausal women with estrogen receptor (ER) positive disease. The proven efficacy of tamoxifen and the low incidence of side effects made the drug an ideal agent to test as an adjuvant therapy for women with node-positive breast cancer. Laboratory studies indicate that long-term treatment schedules may provide maximal benefit in preventing recurrence, and recent analysis of clinical trials demonstrates that between 2 and 5 years of adjuvant tamoxifen therapy provides a survival advantage for postmenopausal women with node-positive disease. Similarly, adjuvant studies in node-negative breast cancer have demonstrated an increase in the disease-free survival of both pre- and postmenopausal patients with ER-positive tumors. However, the extended use of tamoxifen has raised questions about the long-term safety of antiestrogen therapy. Of special concern is the impact of tamoxifen on ovarian function in premenopausal women and the potential risks to the fetus if pregnancy occurs. Fortunately, there are no reports about the teratogenicity of tamoxifen in the human, but it is important that physicians counsel women about the risk of pregnancy. Tamoxifen should not be used if a patient is pregnant. Initial concerns that the long-term administration of an antiestrogen would increase bone loss and increase the risks of coronary heart disease appear to be unwarranted. Tamoxifen has some estrogen-like activities in postmenopausal women and causes a preservation of bone in the lumbar spine and a decrease in circulating cholesterol. Indeed, a reduction in fatal myocardial infarction (MI) has been noted during 5 years of tamoxifen therapy, possibly the direct result of a prolonged reduction in circulating cholesterol. However, the estrogen-like qualities of tamoxifen that could be valuable as a hormone replacement therapy for all postmenopausal women following a diagnosis of breast cancer may also increase the risk for developing endometrial carcinoma. To date, there are only a few reports of endometrial carcinoma being diagnosed during adjuvant therapy with tamoxifen; however, any instances of uterine bleeding or spotting should be followed up with an endometrial biopsy. There are some concerns about large doses of tamoxifen promoting liver cancer in rats. These results are of particular concern if tamoxifen is to be used as a preventive in normal women.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Control of the estrogen-like actions of the tamoxifen-estrogen receptor complex by the surface amino acid at position 351.
Tamoxifen is a valuable therapeutic agent with applications in the treatment and prevention of breast cancer. However, the development of drug resistance limits the usefulness of tamoxifen therapy. One form of drug resistance in breast cancer is tamoxifen-stimulated growth. We have addressed a mechanism how the tamoxifen-estrogen receptor (ER) complex can convert from being a blocking to stimulatory signal in breast cancer. We have described an effective assay system to study the action of antiestrogen-ER complex through the activation of transforming growth factor alpha gene in situ. The MDA-MB-231 breast cancer cells were stably transfected with cDNAs for wtER (D351), mutant Asp351Tyr ER (D351Y) and mutant Asp351Gly ER (D351G). The D351Y ER can enhance the estrogenic properties of 4OHT and change the pharmacology of raloxifene by converting it from antiestrogen to estrogen. We hypothesized that alterations in the charge of amino acid (aa) 351, and changes in the interaction with the side chain of an antiestrogen, are critical for the subsequent estrogenicity of the complex. Our goal was (1) to modulate the estrogenicity of the antiestrogen-ER complex by different aa substitutions at position 351 and (2) to examine the role of alterations in the side chain of antiestrogens on the estrogenicity of the complex. Substitution of tyrosine for aspartate at aa351 results in increased estrogenicity for a series of tamoxifen derivatives-ER complexes and the conversion of EM 652-ER and GW 7604-ER complexes from antiestrogenic to estrogen-like. Substitution of glycine for aspartate at aa 351 results in the conversion of 4OHT-ER complex from estrogen-like to antiestrogenic. We propose that the side chain of antiestrogens either neutralizes or displaces the charge at aspartate 351 thereby removing a charged site for the opportunistic binding of a novel coactivator. If no charge is present (D351G) then no coactivator can bind and the complex with any antiestrogen is not estrogen-like. However, if the charge is extended beyond the reach of an antiestrogen side chain (D351Y), then the coactivators bind and compounds are estrogen-like. The establishment of a relationship between the structure of the antiestrogen-ER complex and its function will enhance the development of novel compounds with unique biological activities and potentially avoid premature drug resistance.
Amino Acids↗
Antiestrogens: clinical applications of pharmacology.
Selective estrogen receptor modulators (SERMs) appear to reduce the incidence of breast cancer in high-risk women. Five years of tamoxifen administration after the diagnosis of breast cancer results in a 50% reduction in the incidence of contralateral breast cancer. This reduction is maintained for 5 years after therapy is discontinued. The Study of Tamoxifen And Raloxifene (STAR), presently ongoing, will address the questions of breast cancer prevention, risk of endometrial cancer, the incidence of bone fractures, and coronary artery disease in women treated with these SERMs.
Breast Neoplasms↗
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.
Animals↗
Laboratory studies on the mode of action and application of antiestrogen for breast cancer therapy.
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Animals↗
Metabolites, pharmacodynamics, and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient.
The metabolism of tamoxifen was examined in the rat, mouse, and human breast cancer patient. Large oral doses of tamoxifen (200 mg/kg) in the immature ovariectomized rat and mature mouse produced circulating levels of the parent compound, N-desmethyltamoxifen, and 4-hydroxytamoxifen quantifiable by HPLC separation, UV activation, and fluorescence detection. N-Desmethyltamoxifen and 4-hydroxytamoxifen serum levels in the mature ovariectomized mouse paralleled tamoxifen levels throughout a 96-hr time course after a single dose of tamoxifen. On the other hand, N-desmethyltamoxifen was the predominant serum metabolite after an equivalent dose of tamoxifen to the immature rat, but there was little 4-hydroxytamoxifen. Peak levels of tamoxifen occurred 3-6 hr after oral administration of tamoxifen in both species, whereas peak levels of N-desmethyltamoxifen in the immature rat did not occur until 24-48 hr. AUCs for tamoxifen and N-desmethyltamoxifen were approximately 4 times greater in the rat (57.5 and 111 micrograms.hr/ml, respectively) than the mouse (15.9 and 26.3 micrograms.hr/ml, respectively) after equivalent doses of tamoxifen (200 mg/kg). AUC of 4-hydroxytamoxifen for the rat (8.9 micrograms.hr/ml), however, was similar to that for the mouse (13.9 micrograms.hr/ml). The rate of elimination from serum was similar for tamoxifen, N-desmethyltamoxifen, and 4-hydroxytamoxifen in both the rat (t1/2 = 10.3, 12.1, and 17.2 hr, respectively) and the mouse (t1/2 = 11.9, 9.6, and 6 hr, respectively). Administration of large oral doses of tamoxifen (200 mg/kg) every 24 hr to mature ovariectomized mice or immature ovariectomized rats resulted in accumulation for the first 4 days.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The biological significance of the interaction of estrogen agonists and antagonists with the estrogen receptor.
The identification and isolation of a soluble estrogen receptor protein from estrogen target tissues, e.g., uterus, more than 25 years ago provided a unique opportunity for the biochemical pharmacologist to study the interaction of agonist and antagonist molecules in a well-defined organ. Nonsteroidal antiestrogens have proved to be valuable research tools to study cell replication or estrogen specific protein synthesis, e.g., prolactin synthesis or progesterone receptor induction. During the past two decades the antiestrogen tamoxifen has become the endocrine treatment of choice for all stages of breast cancer. This fact has provided an additional incentive to study breast cancer cell replication. In the laboratory breast cancer cells can be used to study the direct actions of antiestrogens without the complicating aspects of pharmacokinetics and metabolism. Studies of the structure-activity relationships of antiestrogens compliment the current investigation of steroid hormone receptors as part of a superfamily of transcription factors. Antiestrogens will, in the future, provide valuable information (from X-ray crystallography) about the three-dimensional folding required if a steroid receptor complex is to prevent cell replication. Clearly this information, and the description of additional transcription factors in hormone-independent cells may prove to be critical for the development of new therapeutic opportunities.
Animals↗
Pharmacology of tamoxifen in laboratory animals.
This paper reviews the recent laboratory findings about the nonsteroidal antiestrogen, tamoxifen, and its more potent major metabolite, monohydroxytamoxifen. Both compounds stimulate progesterone receptor synthesis in the rat uterus, and there is an inhibition of cell division in the uterine luminal epithelial cells. The effects of tamoxifen in vivo may be a result of the net effects of the parent compound and monohydroxytamoxifen. In rats with dimethylbenzanthracene (DMBA)-induced rat mammary carcinomata, young tumors that are estrogen receptor- and progesterone receptor-rich respond more favorably to tamoxifen that do older estrogen receptor- and progesterone receptor-poor tumors. However, the antitumor effect of tamoxifen in the DMBA-induced rat mammary carcinoma model is probably a result of the blockade of tumor estrogen receptors, a reduction in circulating gonadotropins, lower circulating estrogen levels, and lower circulating prolactin levels. The 30-days treatment of rats with tamoxifen 30 days after DMBA resulted in a dose-related decrease in the appearance and numbers of mammary tumors; however, only continuous therapy maintained animals in a tumor-free state. Monohydroxytamoxifen was a less-potent antitumor agent, probably because it is cleared from the rat more rapidly than tamoxifen. The present laboratory findings support the clinical use of tamoxifen as a treatment of endometrial carcinoma and the resultant metastases and as an adjuvant therapy after surgery for breast cancer.
9,10-Dimethyl-1,2-benzanthracene↗
Should adjuvant tamoxifen therapy be stopped at 5 years?
Toxifen, a nonsteroidal antiestrogen, is currently the most widely used adjuvant therapy for the treatment of breast cancer. Though the efficacy of tamoxifen has been well documented in clinical trials, the certainty over the duration of therapy is less clear. Clinical and laboratory evidence suggests that longer therapy is better; however, whether this means 5 years, 10 years, or indefinite therapy has not been established in clinical trials. Essential to any study of long-term tamoxifen therapy is consideration of its effects not only on breast cancer but also on other estrogen target tissues. The estrogenic effect of tamoxifen that lowers serum lipids results in fewer hospital admissions for heart disease and a reduction in fatal myocardial infarction. Similarly, tamoxifen maintains bone mass that may ultimately result in fewer fractures. The effects of tamoxifen appear to parallel the effects of estrogen, so results from clinical trials of estrogen replacement therapy will provide a useful guide of what to expect with tamoxifen. The negative aspect of the therapy is a modest increase in the incidence of endometrial cancer. However, the incidence of endometrial cancer after stopping either estrogen or tamoxifen remains elevated for at least 5 years after the drug is stopped. Nevertheless, it is important to stress that the overall prognosis remains unaffected. We conclude that it will be difficult to demonstrate survival differences between 5 and 10 years of tamoxifen in clinical trials unless significant tamoxifen-stimulated recurrences occur with continued therapy. The benefits of tamoxifen must be calculated using estimates of the decreased rates of heart disease, contralateral cancers, decreased hospitalizations for fractures, and reduced cancer relapses.
Animals↗