SEARCH · PubMed Health

Results for “DIETHYLSTILBESTROL”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources

PubMed2002

Phenotypic variations and dynamic topography of transformed cells in an experimental model of diethylstilbestrol-induced renal tumour in male Syrian hamster.

This work explores the phenotypic changes affecting transformed cells in an experimental model of diethylstilbestrol (DES)-induced renal tumours in male Syrian hamster. This estrogen-induced neoplasm presents an important cytological pleomorphism and its origin remains largely controversial. In order to characterize phenotypic variations during tumour progression, the occurrence of seven lineage markers was analysed by a morphometric approach in kidney sections of DES-exposed hamsters (6-11 months). S100 protein, neuron-specific enolase (NSE) and vimentin are expressed by a large percentage of malignant cells during tumour development. Glial fibrillary acidic protein (GFAP), protein gene product 9.5 (PGP 9.5) and desmin are mostly evidenced in advanced neoplasm whereas Leu 7 always presents a focal expression. As evidenced by double-label immunofluorescence, the coexpression of three important neuroectodermal lineage markers (S100, NSE and PGP 9.5) in earliest tumour buds points to a peripheral nerve sheath origin for this neoplasm thus confirming previously published data. For each marker, the fluctuations of expression levels during tumour progression as well as the spatial heterogeneity of distribution suggest variable phenotypic differentiation of transformed cell populations. This observation is largely corroborated by double-label immunofluorescence showing coexpression modification of several markers during tumour progression. This points to a complex dynamic and spatial self-organization of different phenotypes within neoplasms. Altogether, these results support the concept that DES-induced kidney tumours are not made of unstructured cell populations but represent adaptive complex dynamic biosystems.

Animals↗

PubMed2005

Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer.

Diethylstilbestrol (DES) is a synthetic oestrogen, and its anticancer effects are exerted in androgen-dependent prostate cancer. The administration of DES decreases serum testosterone to castration levels. However, in androgen-independent prostate cancer patients, who are already orchiectomised, the administration of DES improves symptoms and decreases prostate-specific antigen (PSA). The mechanisms responsible for these direct inhibitory effects have been explained as biological actions not mediated by oestrogen receptors. We assessed the gene expression profiles of prostate cancer cells treated with DES, and investigated direct inhibitory effects of DES. DES inhibited the proliferation of LNCaP and PC-3 cells. cDNA microarray analysis showed that expression of many genes was downregulated by DES. However, insulin-like growth factor binding protein 6 (IGFBP-6) gene expression levels were upregulated in PC-3 cells. IGFBP-6 gene expression and protein levels significantly increased after DES treatment. Recombinant IGFBP-6 inhibited cell proliferation, and the inhibitory effect of DES was neutralised by anti-IGFBP-6 antibody. From the immunohistochemical analysis of IGFBP-6 using biopsy samples from androgen-independent prostate cancer, we found IGFBP-6 expression in androgen independent prostate cancer, and that DES treatment increased the IGFBP-6 staining intensity of the cancer cells in one sample. These findings suggested that DES induces IGFBP-6, which inhibits cell proliferation in an androgen-independent prostate cancer cell line, PC-3. IGFBP-6 therefore might be involved in the direct effects of DES in androgen-independent prostate cancer.

Antineoplastic Agents, Hormonal↗

PubMed2004

Estrogen-independent activation of erbBs signaling and estrogen receptor alpha in the mouse vagina exposed neonatally to diethylstilbestrol.

Growth factors and estrogen receptor (ER) signaling cooperate to play essential roles in cell proliferation, differentiation and tumor progression in mouse reproductive organs. Treatment of neonatal mice with diethylstilbestrol (DES) induces an estrogen-independent persistent proliferation and cornification of the vaginal epithelium, which results in cancerous lesions later in life. However, the mechanisms of the estrogen-dependent and -independent pathways essentially remain unknown. We characterized the expression of epidermal growth factor (EGF)-like growth factors (EGF, transforming growth factor alpha (TGF-alpha), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (APR), epiregulin (EPR) and neuregulin (NRG) 1) and erbB receptors (EGF receptor (EGFR), erbB2/neu, erbB3 and erbB4) in the vaginae of mice treated either neonatally (0-4 day) or as adults (55-59 day) with estrogens. EGFR and erbB2 were activated in the vaginal epithelium of mice by estrogen treatment. This activation was also encountered in vaginae from neonatally DES-exposed mice, along with the expression of EGF, TGF-alpha, HB-EGF, BTC, APR, EPR and NRG1. Immunohistochemical analysis indicated that erbB2 was primarily expressed in vaginal epithelium. Finally, we found that serine 118 and 167 located in the AF-1 domain of ERalpha were phosphorylated in these vaginae. AG825, AG1478 or ICI 182,780 administration blocked proliferation of vaginal epithelium induced by neonatal DES exposure. Thus, signal transduction via EGFR and erbB2 could be related to the estrogen-induced vaginal changes and persistent erbBs phosphorylation and sustained expression of EGF-like growth factors, leading to ERalpha activation that may result in cancerous lesions in vaginae from neonatally DES-exposed mice later in life.

Animals↗

PubMed2004

Effect of neonatal exposure to diethylstilbestrol on testicular gene expression in adult mouse: comprehensive analysis with cDNA subtraction method.

Summary In utero or neonatal exposure to high levels of exogenous steroid hormones, such as the potent synthetic diethylstilbestrol (DES), incurs an increased risk of malfunctional male reproduction. In this study, we investigated whether neonatal exposure to DES induces the alteration of mRNA expression in adult mouse testis. Using a cDNA subtraction method, we isolated seven gene clones whose expression was changed in neonatally DES-treated mouse testis. Northern blot analysis revealed that five up-regulated genes (AF326230, AF356521, AK004975, AK006136 and BM237156) and two down-regulated genes (AK017044, AK017130) were predominantly expressed in testes of 8-week-old mice. Moreover, we confirmed that the expression of these seven genes was altered by neonatal DES-exposure using Northern blot analysis. Our results suggest that neonatal exposure to DES leads to the alteration of gene expression in the testis in the long term. These genes might be useful as biological markers of foetal or neonatal exposure to exogenous steroid hormones, such as DES.

Aging↗

PubMed2002

Development of the blood-testis barrier in the mouse is delayed by neonatally administered diethylstilbestrol but not by beta-estradiol 3-benzoate.

A group of newborn mice were treated with 1 micro g dose-1 individual-1 of diethylstilbestrol (DES) on alternate days, from days 1 to 11 postnatally. Another group of mice were treated similarly with 125 ng dose-1 individual-1 of beta-estradiol 3-benzoate (E2B). The testes were sequentially examined up to 84 days of age using light and electron microscopy. Spermatogenic cells in the DES-treated mice differentiated normally from birth until 17 days of age, when they differentiated into pachytene spermatocytes and remained at this meiotic prophase for the next 10 days approximately. The cells then began to differentiate further, ultimately forming spermatozoa by 49 days of age. Confocal and electron microscopy showed that the blood-testis barrier did not form until 28 days of age in the DES-treated mice, and a delay in the functional maturation of this structure, as the blood-testis barrier, was confirmed by intercellular tracer experiments. The arrest of spermatogenesis at the meiotic prophase may have been attributable to the DES-induced defective formation of the blood-testis barrier. No delay of the blood-testis barrier formation was detected in the E2B-treated mice. Thus, DES and E2B, both of which are known as potent oestrogenic compounds, had different effects on the Sertoli cells.

Animals↗

PubMed2001

The pharmacokinetics of fosfestrol and diethylstilbestrol in chronic hemodialysis patients with prostate cancer.

BACKGROUND: Fosfestrol drip infusion therapy is an available endocrinotherapy for prostate cancer. But since there have been few reports of its use in chronic dialysis patients, the pharmacokinetics of fosfestrol in these patients remains unclear. We conducted fosfestrol drip infusion therapy as an induction therapy in chronic hemodialysis patients with prostate cancer. METHODS: Two male patients were included in this study. One was a 68-year-old man who had been in hemodialysis for 15.7 years and had stage B2 prostate cancer. The other was a 74-year-old man who had been in hemodialysis for 4.4 years and had stage C prostate cancer. A total of 250 mg of fosfestrol was dissolved in 250 mL of 5% glucose solution and administered by drip infusion. The drug was given subcutaneously during 14 consecutive days and a luteinizing hormone-releasing hormone agonist was injected on day 15. RESULTS: Serum fosfestrol levels increased rapidly after the drip infusion was started and remained at high levels during infusion, but fell quickly after the treatment ended. Diethylstilbestrol (DES) was also detected in blood after the infusion was started and its levels peaked when infusion ended. But on the next day, neither fosfestrol nor DES were detected in the blood of the patients. Moreover, neither fosfestrol nor DES was detected in the blood of the two patients before administering fosfestrol on day 15. Fosfestrol was quickly eliminated from the blood after hemodialysis was started, while DES remained in the blood during hemodialysis. The adverse reactions were mild hepatic dysfunction and gynecomastia. CONCLUSIONS: Fosfestrol drip infusion therapy appeared to be safe as an endocrinotherapy for prostate cancer in chronic hemodialysis patients.

Aged↗

PubMedDate not supplied

Concurrent primaries of vaginal clear cell adenocarcinoma and endometrial adenocarcinoma in a 39-year old woman with in utero diethylstilbestrol exposure.

Diethylstilbestrol (DES) was used widely in the late 1940s in an attempt to prevent adverse pregnancy outcomes. In 1971 the US Food and Drug Administration proscribed its use for pregnancy support secondary to its association with clear cell adenocarcinoma of the vagina. Several studies in animal models demonstrated an association with endometrial cancer among offspring following in utero DES exposure. To date, there is only one case report of endometrial cancer in women exposed to DES in utero. We present the first case, to our knowledge, of a woman exposed to DES in utero who presented with double primaries of clear cell cancer of the vagina concomitant with endometrial cancer.

Adenocarcinoma↗

PubMed2001

Long-term cancer risk in women given diethylstilbestrol (DES) during pregnancy.

From 1940 through the 1960s, diethylstilbestrol (DES), a synthetic oestrogen, was given to pregnant women to prevent pregnancy complications and losses. Subsequent studies showed increased risks of reproductive tract abnormalities, particularly vaginal adenocarcinoma, in exposed daughters. An increased risk of breast cancer in the DES-exposed mothers was also found in some studies. In this report, we present further follow-up and a combined analysis of two cohorts of women who were exposed to DES during pregnancy. The purpose of our study was to evaluate maternal DES exposure in relation to risk of cancer, particularly tumours with a hormonal aetiology. DES exposure status was determined by a review of medical records of the Mothers Study cohort or clinical trial records of the Dieckmann Study. Poisson regression analyses were used to estimate relative risks (RR) and 95% confidence intervals (CI) for the relationship between DES and cancer occurrence. The study results demonstrated a modest association between DES exposure and breast cancer risk, RR = 1.27 (95% CI = 1.07-1.52). The increased risk was not exacerbated by a family history of breast cancer, or by use of oral contraceptives or hormone replacement therapy. We found no evidence that DES was associated with risk of ovarian, endometrial or other cancer.

Breast Neoplasms↗

PubMed1996

Expression of estrogen receptor and proto-oncogene messenger ribonucleic acids in reproductive tracts of neonatally diethylstilbestrol-exposed female mice with or without post-puberal estrogen administration.

Perinatal treatment of female mice with natural and synthetic estrogens including diethylstilbestrol (DES) results in estrogen-independent persistent proliferation and cornification of the vaginal epithelium. The dynamics of the induction of estrogen receptor (ER), c-jun, c-fos and c-myc mRNAs by 17 beta-estradiol (E2) was examined in the uterus and vagina of neonatally DES-exposed and -unexposed ovariectomized adult mice. In the uterus of neonatally DES-unexposed ovariectomized mice, the expression of ER mRNA increased within 1 h after E2 administration and declined by 12 h thereafter. ER mRNA in the vagina decreased within 1 h after the stimulation and recovered by 12 h thereafter. In the uterus, c-jun and c-fos mRNAs increased in concentration within 1 h after E2 administration, showing a peak 3 h after the stimulation; they decreased with time thereafter. In the vagina, the concentration of c-jun and c-fos mRNAs increased rapidly, reaching a peak within 1 h after the stimulation. However, the expression of c-myc in uterus and vagina was not changed by postpuberal E2. These results suggest that estrogen regulation of ER and proto-oncogene mRNAs in the vagina differs from those in the uterus. In the neonatally DES-exposed ovariectomized adult mice, uterine ER mRNA expression levels were significantly higher than in the unexposed ovariectomized controls; however, vaginal levels were drastically lower than in the controls. Expression of c-jun and c-fos mRNAs was greater in both the uterus (3- and 6-fold, respectively) and the vagina (18- and 4-fold) of neonatally DES-exposed mice than in controls. The ER mRNA and the increased levels of c-fos and c-jun mRNAs in both uterus and vagina of neonatally DES-exposed ovariectomized mice were not further altered by post-puberal E2 and may be related to ovary-independent persistent changes in the genital tract.

Animals↗

PubMed1978

A twenty-five-year follow-up study of women exposed to diethylstilbestrol during pregnancy.

To assess the long-term effects of diethylstilbestrol we conducted a health survey among 693 mothers who had taken the drug during pregnancy and a comparable group of 668 who had not. These women had participated in a study during 1951-52 to evaluate the drug. There were 32 (4.6 per cent) breast cancers among the 693 exposed and 21 (3.1 per cent) among the 668 unexposed, but the difference was not statistically significant (P = 0.16). No statistically significant differences occurred between the groups in any of the other categories of disease. The occurrence of breast cancer in both groups was compared to the Connecticut State Tumor Registry for 1963-65. Compared to the registry data, a significantly (P less than 0.01) higher incidence of breast cancer occurred in both the exposed and unexposed groups at ages over 50. The reason for this increase is not known, but effects linked to the selection of mothers participating in the original clinical study cannot be excluded.

Breast Neoplasms↗

PubMed1980

Fertility and outcome of pregnancy in women exposed in utero to diethylstilbestrol.

Fertility and outcome of pregnancy were examined in women participating in the National Cooperative Diethylstilbestrol Adenosis (DESAD) Project. We compared 618 subjects who had prenatal exposure to DES with 618 control subjects. Fertility, measured in terms of pregnancies achieved, did not differ between the women exposed to DES and the controls. An increased risk of unfavorable outcome of pregnancy was associated with DES exposure (the relative risk of any unfavorable outcome of pregnancy was 1.69; P less than 0.001). Speculation on biologic mechanisms that might produce this difference is premature, since additional data about these subjects must be collected. Among DES-exposed women who became pregnant, 81 per cent had at least one full-term live birth.

Abnormalities, Drug-Induced↗

PubMed1981

Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer.

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

Aged↗

PubMed1984

Leuprolide versus diethylstilbestrol for metastatic prostate cancer.

We compared the efficacy and safety of the gonadotropin-releasing hormone analogue, leuprolide (1 mg subcutaneously daily), with diethylstilbestrol (DES, 3 mg by mouth daily) in patients with prostate cancer and distant metastases (Stage D2) who had not previously received systemic treatment. Initial therapy (leuprolide or DES) was continued for as long as an objective response was noted; cross-over to the alternative arm occurred at the time of disease progression or intolerable adverse reactions. Ninety-eight patients were randomly assigned to leuprolide, and 101 to DES. Suppression of testosterone and dihydrotestosterone and decreases in acid phosphatase were comparable in the two groups. Patients receiving DES experienced more frequent painful gynecomastia (P less than 0.00001), nausea and vomiting (P = 0.02), edema (P = 0.008), and thromboembolism (P = 0.065) than those receiving leuprolide. The leuprolide group reported more "hot flashes" (P = 0.00001). Overall, 86 per cent of the leuprolide group had an objective response (complete response, 1 per cent; partial response, 37 per cent; stable disease, 48 per cent), as compared with 85 per cent of the DES group (complete, 2 per cent; partial, 44 per cent; stable, 39 per cent). Actual survival rates at one year were 87 per cent for the leuprolide group and 78 per cent for the DES group (P = 0.17). We conclude that leuprolide offers an important alternative treatment that is therapeutically equivalent to and causes fewer side effects than DES for the initial systemic management of metastatic prostate cancer.

Acid Phosphatase↗

PubMed2004

Diethylstilbestrol induces fish oocyte maturation.

An endocrine-disrupting chemical, diethylstilbestrol (DES), a nonsteroidal estrogen, triggers oocyte maturation in fish. The morphology (the time course of the change in germinal vesicle breakdown) and an intracellular molecular event (the de novo synthesis of cyclin B) induced by DES were indistinguishable from those induced by a natural maturation-inducing hormone, 17alpha,20beta-dihydroxy-4-pregnen-3-one (17,20beta-DHP). A synergistic action of DES on 17,20beta-DHP-induced oocyte maturation was observed. Both 17,20beta-DHP- and DES-induced oocyte maturation was inhibited by an antibody against the maturation-inducing hormone receptor. The structural requirement for the action of DES is discussed based on results obtained with DES analogs.

Animals↗

PubMed1990

Cloning and expression of the delayed-rectifier IsK channel from neonatal rat heart and diethylstilbestrol-primed rat uterus.

cDNAs encoding a delayed-rectifier-type K+ channel were cloned from both neonatal rat heart and ovariectomized, diethylstilbestrol-primed rat uterus by using the polymerase chain reaction. Both clones have nucleotide sequences identical to that encoding the rat kidney IsK channel [Takumi, T., Ohkubo, H. & Nakanishi, S. (1988) Science 242, 1042-1045] and encode a putative protein of 130 amino acids. Injection of RNA transcripts of the cDNAs into Xenopus oocytes resulted in the expression of a slowly activating, voltage-dependent K+ current. An antisense oligonucleotide, derived from the sequence of the clone, specifically inhibited the expression of the slow, outward current observed in cells injected with mRNAs isolated from the parent tissues (i.e., kidney, heart, and uterus), indicating that the cloned gene underlies the major K+ current expressed from RNA isolated from these tissues.

Amino Acid Sequence↗

PubMed1997

Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses.

On the basis of results of studies using high doses of estrogens, exposure to estrogen during fetal life is known to inhibit prostate development. However, it is recognized in endocrinology that low concentrations of a hormone can stimulate a tissue, while high concentrations can have the opposite effect. We report here that a 50% increase in free-serum estradiol in male mouse fetuses (released by a maternal Silastic estradiol implant) induced a 40% increase in the number of developing prostatic glands during fetal life; subsequently, in adulthood, the number of prostatic androgen receptors per cell was permanently increased by 2-fold, and the prostate was enlarged by 30% (due to hyperplasia) relative to untreated males. However, as the free serum estradiol concentration in male fetuses was increased from 2- to 8-fold, adult prostate weight decreased relative to males exposed to the 50% increase in estradiol. As a model for fetal exposure to man-made estrogens, pregnant mice were fed diethylstilbestrol (DES) from gestation days 11 to 17. Relative to controls, DES doses of 0.02, 0.2, and 2.0 ng per g of body weight per day increased adult prostate weight, whereas a 200-ng-per-g dose decreased adult prostate weight in male offspring. Our findings suggest that a small increase in estrogen may modulate the action of androgen in regulating prostate differentiation, resulting in a permanent increase in prostatic androgen receptors and prostate size. For both estradiol and DES, prostate weight first increased then decreased with dose, resulting in an inverted-U dose-response relationship.

Animals↗

PubMed1996

Diethylstilbestrol-DNA interaction studied by Fourier transform infrared and Raman spectroscopy.

The interaction of diethylstilbestrol (DES) with calf thymus DNA was investigated at physiological pH with drug/DNA (phosphate) molar ratios (r) of 1:40, 1:20, 1:10, 1:4, 1:2, and 1. Fourier transform infrared and laser Raman difference spectroscopy were used to establish correlations between spectral changes and drug binding mode, sequence selectivity, DNA conformation, and structural properties of DES.DNA complexes in aqueous solution. Spectroscopic results indicated that DES is a weak intercalator with affinity for A-T-rich regions. It is also a groove binder with a major interaction with the thymine O-2 atom. At low drug concentration (r = 1:40), the A-T-rich region is the main target of drug intercalation, while at a higher drug content (r > 1:5), external binding to the G-C bases also occurs with a partial helix destabilization. Evidence for this comes from the spectral alterations of the A-T vibrational frequencies at 1661 cm-1 (Raman) and 1663 and 1609 cm-1 (IR) and of the G-C vibrations at 1581 and 1491 cm-1 (Raman) and 1717 and 1492 cm-1 (IR). Drug intercalation leads to a major reduction of B-DNA structure in favor of A-DNA.

DNA↗

PubMed1997

RNA-diethylstilbestrol interaction studied by Fourier transform infrared difference spectroscopy.

Diethylstilbestrol (DES), a synthetic estrogen, is known to be a carcinogen in human and in animals. This study was designed to examine the interaction of DES with yeast RNA in aqueous solution at physiological pH with drug/RNA-phosphate (P) molar ratios of 1/80, 1/40, 1/20, 1/10, 1/4, and 1/2. Fourier transform infrared (FTIR) difference spectroscopy was used to determine the drug binding mode, the binding constant, the sequence selectivity, and RNA secondary structure in the RNA.DES complexes. Spectroscopic evidence showed that at low drug concentration (1/80 and 1/40), DES is intercalating through both Gua-Cyt and Ade-Urd base pairs with minor interaction with the backbone PO2 group (external binding). The calculated binding constant of K approximately 8.5 x 10(4) M-1 at a drug concentration of 3.12 x 10(-4) M shows that DES is a weaker intercalator than those of the methylene blue, acridine orange, and ethidium bromide. At high drug content (r > 1/40, where r represents the DES/RNA-phosphate molar ratio), a partial helix destabilization occurs with no alteration of RNA conformation upon drug complexation. However, a comparison with DNA.DES complexes showed that drug intercalation causes major reduction of the B-DNA structure in favor of A-DNA with no participation of the backbone PO2 group in the DES. DNA complexation.

DNA↗