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PubMed1983

Non-estrogenic metabolites of diethylstilbestrol produced by prostaglandin synthase mediated metabolism.

Incubation of trans-diethylstilbestrol (E-DES) with prostaglandin synthase (PGS) in vitro leads to the formation of the metabolites cis, cis-dienestrol (Z,Z-DIES) and cis-diethylstilbestrol (Z-DES) which have considerably decreased estrogenic activity compared to their parent compound. Incubations of (14C)-E-DES with PGS in the presence of arachidonic acid (AA) predominantly catalyze formation of the oxidative metabolite Z,Z-DIES, accompanied by the formation of protein bound radioactivity. Inhibition of peroxidative metabolism through addition of indomethacin or absence of AA favors isomerization of E-DES to Z-DES without concomitant formation of protein bound radioactivity. Isomerization is inhibited by phenidone (1-phenyl-3-pyrazolidone). Since PGS activity is present in uterine tissue, these pathways may play a role in the metabolism of DES in its target tissue.

Animals↗

PubMed1975

Management of adenocarcinoma of prostate with diethylstilbestrol diphosphate and cyclophosphamide.

Eleven patients with terminal metastatic prostatic carcinoma were selected for a pilot study to evaluate how effective diethylstilbestrol diphosphate (Stilphostrol) and cylcophosphamide (Cytoxan) are in this disease. Six of 7 patients had a good response when treated with diethylstilbestrol diphosphate. The mean duration of response was 6.4 months. All 6 patients given cyclophosphamide had marked relief of pain and increased mobility. Of these, 3 died twelve, sixteen, and nineteen weeks, respectively, following initiation of therapy while still benefiting from pain relief. The mean duration of response was 14.8 weeks.

Adenocarcinoma↗

PubMed1976

Regression of prostatic cancer metastasis by high doses of diethylstilbestrol diphosphate.

Diethylstilbestrol diphosphate (DES-P) has shown effective symptomatic relief in patients with metastatic carcinoma of the prostate. Although there is little known about its role in soft tissue metastasis, our experience in 3 patients with advanced carcinoma of the prostate infiltrating the trigone and ureterovesical junction revealed significant improvement of hydronephrosis. All patients failed to respond to conventional doses of stilbestrol. Diethylstilbestrol diphosphate is recommended in the treatment of advanced carcinoma of the prostate with soft tissue metastasis. It is safe and effective, and the tumor responses outweigh the side effects of the drug. The mechanism of action of this compound is discussed.

Aged↗

PubMed1976

Comparison of flutamide (SCH-13521) and diethylstilbestrol in untreated advanced prostatic cancer.

A double-blind study comparing the efficacy of flutamide (SH-13521) and diethylstilbestrol in 15 patients with advanced, previously untreated adenocarcinoma in the prostate in herein presented. Patients receiving diethylstilbestrol, 1 mg. daily, remained stable without evidence of progression of their disease for an average of 25.6 weeks while those receiving either high-or low-dose flutamide showed no objective progression for an average of thirty weeks. There were no complete remissions, and no signficant side effects were seen with either of these agents. In this small series of hormonally untreated Stage D prostatic cancer patients, neither agent displayed significant superiority.

Aged↗

PubMed1992

Treatment of castration-induced menopausal symptoms with low dose diethylstilbestrol in men with advanced prostate cancer.

Menopausal symptoms manifesting as hot flashes and sweats occur in up to 75 percent of patients following either orchiectomy or treatment with a luteinizing hormone-releasing hormone agonist for prostate cancer. As many as one third of these patients will experience symptoms severe enough to seek palliation. We treated 12 such patients with low dose diethylstilbestrol (1/3 mg daily). Nine patients demonstrated both objective and subjective improvement in their menopausal symptoms. Five patients experienced toxicity including new onset of gynecomastia or breast soreness although no patient discontinued treatment on this basis. No cardiovascular complications were noted. We conclude that low dose diethylstilbestrol is an inexpensive, effective means of controlling troublesome postorchiectomy menopausal symptoms in carefully selected patients.

Aged↗

PubMed1991

Rapid screening method for the determination of diethylstilbestrol in edible animal tissue by column liquid chromatography with electrochemical detection.

A rapid and sensitive screening method for the determination of residues of diethylstilbestrol in edible animal tissue is described. The analyte was extracted from the tissue with tert.-butyl methyl ether, reextracted with 1 M sodium hydroxide and further cleaned up by solid-phase extraction with C18 cartridges. Analysis was performed by isocratic elution with a phosphate-buffered mobile phase, methanol-0.05 M phosphate buffer pH 3.5 (67:33), on a Nucleosil 5-microns C18 column with electrochemical detection at +0.90 V. The average recovery of trans-diethylstilbestrol in spiked samples is 66%, with a standard deviation of 14% (n = 22) in the range 0.5-2.0 microgram/kg. The detection limit is 0.1-0.2 microgram/kg, although at this level other compounds may interfere and give rise to false positive results.

Animals↗

PubMed2004

[Obstetrical prognosis improvement in patients exposed in utero to diethylstilbestrol with specific care management].

OBJECTIVE: To define the interest of a specific care management of pregnancies in patients exposed in utero to diethylstilbestrol, with the intention of reducing the number of spontaneous miscarriage and prematurity. PATIENTS AND METHODS: One hundred and three pregnancies in 49 patients exposed in utero to diethylstilbestrol were followed during a 4-year study, while establishing a specific care management of pregnancies in those women. RESULTS: Spontaneous miscarriage rate was 18.5%, among which 16.5% before 15 weeks of pregnancy and 2% after 15 weeks of pregnancy. Premature birth rate was 41.9%, among which 10.8% of great premature birth (before 32 weeks of pregnancy), 13.5% of moderate premature birth (between 32 and 36 weeks of pregnancy), and 17.6% of minor prematurity (after 36 weeks of pregnancy). The patients' average delivery term was 36 +/-3.6 weeks. DISCUSSION AND CONCLUSION: As compared with the literature data, our miscarriage and prematurity rates are found to be lower. Our specific care management seems thus to be effective.

Abortion, Spontaneous↗

PubMed1987

Management of the diethylstilbestrol-exposed pregnant patient: a prospective study.

Over a 5-year period we have managed 63 diethylstilbestrol-exposed pregnant patients with a standardized protocol requiring weekly cervical examination and decreased physical activity of the patient. Twenty-six patients (42%) underwent a prophylactic cerclage for a history of second-trimester loss or a hypoplastic cervix on initial clinical examination (group I). Thirty-six patients (58%) were followed expectantly (group II). Sixteen patients (44%) in group II demonstrated cervical change and required an emergency cerclage. Twenty-one patients were managed expectantly with no cerclage. The gestational age at delivery for group I was 37.7 +/- 2.80 versus 34.5 +/- 6.9 weeks for patients without a cerclage (p = 0.04). There were no perinatal deaths if a cerclage was performed, whereas there were five deaths (24%) in the group without cerclage. The five deaths occurred at a mean gestational age of 24.40 +/- 4.0 weeks and a mean birth weight of 614.00 +/- 441.73 gm. Patients with a hypoplastic cervix or prior reproductive loss had a better outcome with early cerclage than patients with a normal cervix followed expectantly. We presently lack a reliable method to detect the diethylstilbestrol-exposed patient at greatest risk for perinatal loss. Based on our experience we believe that placement of a cerclage early in pregnancy should be a strong consideration.

Adult↗

PubMed2001

Interaction of sheep liver cytosolic aldehyde dehydrogenase with quercetin, resveratrol and diethylstilbestrol.

The effects of quercetin and resveratrol (substances found in red wine) on the activity of cytosolic aldehyde dehydrogenase in vitro are compared with those of the synthetic hormone diethylstilbestrol. It is proposed that quercetin inhibits the enzyme by binding competitively in both the aldehyde substrate binding-pocket and the NAD(+)-binding site, whereas resveratrol and diethylstilbestrol can only bind in the aldehyde site. When inhibition is overcome by high aldehyde and NAD(+) concentrations (1 mM of each), the modifiers enhance the activity of the enzyme; we hypothesise that this occurs through binding to the enzyme-NADH complex and consequent acceleration of the rate of dissociation of NADH. The proposed ability of quercetin to bind in both enzyme sites is supported by gel filtration experiments with and without NAD(+), by studies of the esterase activity of the enzyme, and by modelling the quercetin molecule into the known three-dimensional structure of the enzyme. The possibility that interaction between aldehyde dehydrogenase and quercetin may be of physiological significance is discussed.

Aldehyde Dehydrogenase↗

PubMed1982

Rapid, specific method for diethylstilbestrol analysis using an in-line photochemical reactor with high-performance liquid chromatography and fluorescence detection.

Low ppb levels of diethylstilbestrol in biological samples of human and animal origin can be determined using a unique in-line separation-photoreaction-fluorescence detection analytical system. After a very simple extraction procedure, the diethylstilbestrol is separated from interfering substances by high-performance liquid chromatography, photoconverted to a fluorescent product, and detected by fluorescence spectroscopy at optimised excitation-emission wavelengths. A sample can be extracted and analysed in less than 1 h.

Animals↗

PubMed1988

The combination of cyproterone acetate and low dose diethylstilbestrol in the treatment of advanced prostatic carcinoma.

Cyproterone acetate is a steroidal antiandrogen with weak progestational activity that results in the partial suppression of pituitary gonadotropin. We demonstrate that the associated decrease in serum testosterone is more complete and prolonged if cyproterone acetate (200 mg. daily) is combined with a low dose of diethylstilbestrol (0.1 mg. daily). The effectiveness of the combination in the treatment of prostatic carcinoma was investigated in 51 patients with stage D2 malignancy. From an initial concentration of 360 +/- 23 ng. per dl. (mean +/- standard error), serum testosterone decreased to 56 +/- 5 ng. per dl. after 1 week and reached a plateau of approximately 30 ng. per dl. after 2 months. This was accompanied by a decrease in serum prostatic acid phosphatase from a mean starting concentration of 43 +/- 11 ng. per ml. to a low of 3 +/- 1 ng. per ml. at 12 months; the proportion of normal values increased from 10 to 80 per cent. A complete response was observed in 7 patients (13 per cent), partial response in 35 (69 per cent) and stable disease in 8 (16 per cent), yielding an over-all objective response rate of 98 per cent (1980 National Prostatic Cancer Project criteria). The actuarial median time to progression was 17 months and the median survival time was 23.5 months. In 26 patients who subsequently had signs of progressive carcinoma the relapse rate in bone (85 per cent) far exceeded that in nonskeletal sites (23 per cent). The incidence of cardiovascular toxicity was 12 per cent. These results indicate that cyproterone acetate and low dose diethylstilbestrol may be co-administered to achieve a synergistic and potent androgen withdrawal effect in the treatment of advanced prostatic carcinoma.

Acid Phosphatase↗

PubMed2001

Effect of diethylstilbestrol (DES) on intracellular Ca(2+) levels in renal tubular cells.

The effect of the estrogen diethylstilbestrol (DES) on intracellular Ca(2+) concentrations ([Ca(2+)](i)) in Madin Darby canine kidney (MDCK) cells was investigated, using the fluorescent dye fura-2 as a Ca(2+) indicator. DES (10-50 microM) evoked [Ca(2+)](i) increases in a concentration-dependent manner. Extracellular Ca(2+) removal inhibited 45 +/- 5% of the Ca(2+) response. In Ca(2+)-free medium, pretreatment with 50 microM DES abolished the [Ca(2+)](i) increases induced by 2 microM carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler) and 1 microM thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor); and pretreatment with CCCP and thapsigargin partly inhibited DES-induced [Ca(2+)](i) signals. Adding 3 mM Ca(2+) increased [Ca(2+)](i) in cells pretreated with 50 microM DES in Ca(2+)-free medium, suggesting that DES may induce capacitative Ca(2+) entry. 17beta-Estradiol (2-20 microM) increased [Ca(2+)](i), but 100 microM diethylstilbestrol dipropionate had no effect. Pretreatment with the phospholipase C inhibitor U73122 (1 microM) to abolish inositol 1,4,5-trisphosphate formation inhibited 30% of DES-induced Ca(2+) release. DES (20 microM) also increased [Ca(2+)](i) in human normal hepatocytes and osteosarcoma cells. Cumulatively, this study shows that DES induced rapid and sustained [Ca(2+)](i) increases by releasing intracellular Ca(2+) and triggering extracellular Ca(2+) entry in renal tubular cells.

Animals↗

PubMed2001

The role of diethylstilbestrol in the treatment of prostate cancer.

OBJECTIVES: Diethylstilbestrol administration was a classic form of androgen deprivation therapy (ADT) that gradually fell out of favor because of its cardiovascular toxicity, economic disinterest on the part of manufacturers, and the emergence of novel therapeutic agents with a superior safety profile. The cost of contemporary agents and the efficacy of diethylstilbestrol (DES) have perpetuated the evaluation of this agent, especially in the circumstance of early hormone-refractory (clinical stage D2.5) disease. The objective of this study is to evaluate the status of DES-based therapies, and assess their efficacy and toxicity as a viable form of ADT. METHODS: Current research from single-institution and group studies, as well as basic scientific investigations related to DES, were assessed with regard to the population studied, dosage, criteria for response, response rate, duration of response, and toxicity. RESULTS: Contemporary basic research has demonstrated a direct apoptotic effect of DES on prostate cancer cells. There is also evidence to support the ability of DES to suppress testosterone production at extratesticular sites and inhibit dihydroepiandrosterone sulfate serum levels. Contemporary cooperative group trials for stage D2 disease incorporating a DES arm have demonstrated therapeutic efficacy and equivalence to orchiectomy, which is marred by significant cardiovascular toxicity. In smaller single-institution studies (n = 17 to 38) of patients with D2.5 disease, an average response rate of 55% is noted with a mean time to clinical progression of 6.4 months (2 to 18). Cardiovascular toxicity occurred in 10% to 30% of patients, with events including deep vein thrombosis, myocardial infarction, and transient ischemic attack. Edema and gynecomastia was also noted. Strategies to reduce thromboembolic events, such as dose reduction or the use of warfarin sodium were unsuccessful, whereas the use of low-dose aspirin (100 mg daily) resulted in only 1 of 38 vascular events. CONCLUSIONS: In contemporary studies of DES as an agent for ADT in D2.5 patients, a reasonable response rate (40% to 60%) of modest duration (5 to 8 months) is noted. Cardiovascular complications still persist, requiring the development of safe, effective antithrombolic therapy to take advantage of this phenomenon.

Androgen Antagonists↗

PubMed1985

Application of a capillary gas chromatographic-selected-ion recording mass spectrometric technique to the analysis of diethylstilbestrol and its phosphorylated precursors in plasma and tissues.

A method for the analysis of diethylstilbestrol (DES) which is suitable for pharmacokinetic studies has been developed using capillary gas chromatographic (GC) separation and detection with selected-ion mass spectrometry (MS). This technique has been applied to a variety of samples including human plasma samples and extracts of animal tissues including prostate and liver. To investigate the pharmacokinetics of stilphostrol (diethylstilbestrol diphosphate) we have modified the GC-MS method in two ways. One modification involves a dual assay for DES; the first a direct assay, and the second after hydrolysis of a sample with alkaline phosphatase. The difference in these values is the amount of phosphorylated DES present. The other modification separates stilphostrol and DES using a reversed-phase, ion-paired high-performance liquid chromatographic method followed by alkaline phosphatase hydrolysis followed by the GC-MS method. The details of these three methods are described and some representative data are shown.

Alkaline Phosphatase↗

PubMed1999

Effects of diethylstilbestrol on mouse hippocampal evoked potentials in vitro.

1. Several steroids and related compounds can bind to central opiate receptors in whole-brain mouse homogenates. Among these drugs, the synthetic estrogen, diethylstilbestrol (DES), exhibits one of the highest affinities in binding experiments labeling opiate receptors with the nonselective opiate antagonist, [3H]diprenorphine. 2. In the search for a functional correlate to this biochemical finding, we have studied the effects of DES on the mouse hippocampal slice in vitro preparation. 3. Previously, binding studies were performed in hippocampal homogenates, labeling opiate receptors with [3H]diprenorphine or with the mu-selective opiate agonist, [3H]DAGO. DES inhibited [3H]diprenorphine and [3H]DAGO binding, the IC50 values obtained being (1.03 +/- 0.16) x 10(-5) and (1 +/- 0.8) x 10(-5) M, respectively. 4. In mice hippocampal slices, we measured the extracellular evoked potentials obtained in the CA1 pyramidal cell layer of the hippocampi and the field excitatory postsynaptic potentials (EPSP) obtained in the stratum radiatum. The presence of DES (10(-5) M) induced an increase in the amplitude of the population spikes measured in the pyramidal layer without modifying the field EPSP. This effect is similar to that obtained in the presence of DAGO in this preparation. The effect produced by DES was not modified by the presence of the opiate competitive antagonist, naloxone (10(-5) M), or by the opiate alkylating agent, beta-chlornaltrexamine (10(-5) M). Conversely, in the presence of the transcription inhibitor, actinomycin D (5 micrograms/ml), the effect produced by DES was inhibited. 5. Our results with DES support the general idea that estrogens increase central excitability. Although diethylstilbestrol can bind to opiate receptors in the hippocampus, the effect induced by this estrogen on hippocampal excitability seems unrelated to a direct action on opiate receptors, and an intracellular effect is suggested.

Animals↗

PubMed2003

Melatonin inhibits growth of diethylstilbestrol-induced prolactin-secreting pituitary tumor in vitro: possible involvement of nuclear RZR/ROR receptors.

Melatonin exerts a marked antiproliferative action in numerous experimentally-induced tumors in vivo as well as in both animal and human cell lines in vitro. However, the mechanisms of oncostatic action of melatonin is not clear, and the involvement of both membrane and nuclear receptors are suggested. Therefore, the aim of this study was to investigate effects of melatonin, and both agonist (CGP 52608), and antagonist (CGP 55644) of RZR/ROR nuclear receptors on the growth of diethylstilbestrol-induced rat prolactin-secreting pituitary tumor cells in vitro. Pituitary tumors were induced by subcutaneous implantation of a single silastic capsule containing 10 mg of diethylstilbestrol in 4-wk-old male Fischer 344 rats. Four months after the implantation of capsules the animals were killed by decapitation, pituitary tumors were aseptically removed, mechanically dispersed, and enzymatically digested with 0.2% collagenase and 0.2% hyaluronidase. The cells (6 x 105 cells/well) were incubated for 24 hr in the presence of melatonin, CGP 52608, CGP 55644 and CGP 55644 plus melatonin (at the concentrations of 107 and 10-9 m) at 37 degrees C in the humidified atmosphere of 95% air and 5% CO2. The group with the addition of solvent only served as control. The growth of cell was measured using the EZ4U system. Statistical analysis was performed using ANOVA followed by LSD test. Both melatonin and CGP 52608 significantly suppressed growth of tumor cells in vitro in both used concentrations. CGP 55644 stimulated growth of tumor cells and blocked the inhibitory effects of melatonin in vitro. Results of the present study as well as other experimental evidence strongly support the hypothesis that both membrane and nuclear receptors are involved in the oncostatic action of melatonin, and indicate that nuclear signalling plays an important role in this process.

Animals↗

PubMed1989

The permeability of lysosomes to sugars. Effect of diethylstilbestrol on the osmotic activation of lysosomes induced by glucose.

We have investigated the effect on the osmotic activation of rat liver lysosomes, by glucose penetration, of different substances known to inhibit the glucose transport through the plasma membrane. Diethylstilbestrol is the most efficient, particularly when purified lysosomes are used. It has no effect on osmotic activation induced by hypo-osmotic sucrose or by iso-osmotic KCl. It is proposed that diethylstilbestrol reacts with specific sites involved in the glucose translocation through the lysosomal membrane. These sites could not be identified by binding experiments, presumably owing to the considerable unspecific binding of the compound to the membrane.

Acetylglucosaminidase↗

PubMed1978

Estrogenic activity in vivo and in vitro of some diethylstilbestrol metabolites and analogs.

The diethylstilbestrol (DES) metabolite (beta-dienestrol), which had been identified in mouse, rat, monkey, and human urine, and two proposed metabolic intermediates (diethylstilbestrol alpha,alpha'-epoxide and alpha,alpha'-dihydroxy DES) were synthesized and their estrogenic activities determined. In addition, three DES analogs, alpha-dienestrol, DES-dihydroxy diethyl phenanthrene (DES-phenanthrene), and 1-(alpha-ethyl, 4alpha-hydroxyphenyl)indanyl-5-ol (indanyl-DES), were studied. Estrogenic activities of the compounds in vivo were determined by the immature mouse uterine weight bioassay; in vitro, their estradiol receptor binding activity (competitive equilibrium binding, sucrose gradient analysis, and association rate inhibition assays) was determined. Results of the mouse uterine weight bioassay gave the following order of estrogenicity: DES > alpha-dienestrol >/= DES-epoxide > indanyl-DES > dihydroxy DES > beta-dienestrol > DES-phenanthrene. Results of competitive equilibrium binding analyses of these compounds with estradiol-17beta for the mouse uterine cytosol receptor followed the same order seen for the bioassay, except for indanyl-DES. DES, indanyl-DES, and alpha-dienestrol had the greatest affinities (K(a) values approximately 0.5-19.1 x 10(10) M(-1)), while DES-phenanthrene had the lowest (K(a) = 3.5 x 10(7) M(-1) +/- 1.2). Sucrose gradient analysis of the above competition preparations illustrated the displacement of [(3)H]estradiol from the receptor peak. This displacement was receptor specific and concentration dependent and correlated with the equilibrium binding concentrations. In addition, the most hormonally active substances demonstrated the greatest rate inhibition in the estradiol cytosol receptor association rate reaction (V(0)). The rank order of estrogenicity of the compounds determined in this study should be useful in evaluating alternative metabolic pathways of DES as well as distinguishing biologically active metabolites from relatively inactive ones.

Binding, Competitive↗