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 271 records · Page 15Linked to original sources

PubMed1995

Multi-generational carcinogenesis from diethylstilbestrol investigated by blastocyst transfers in mice.

Previous studies have shown that a carcinogenic effect can be transmitted from female mice exposed prenatally to diethylstilbestrol (DES) to their female offspring. Furthermore, male mice exposed pre-natally to DES can transmit a carcinogenic effect to their offspring through their germ cells. To study how multi-generational carcinogenesis is transmitted through females exposed pre-natally to DES, the technique of blastocyst transfer was utilized. Blastocysts from strain CD-1 mice exposed pre-natally to vehicle were transferred to mice exposed pre-natally to DES. Among 143 offspring from these transfers, there were 10 ovarian adenomas and 10 uterine adenocarcinomas. Among 92 offspring from blastocyst transfers between mice exposed pre-natally to vehicle only, there was 1 ovarian adenoma and 1 uterine adenocarcinoma. Thus the pre-natal exposure of the host to DES produced a maternal environment which increased the incidence of ovarian and uterine tumors. The reverse type of transfer was also performed, in which blastocysts from female mice exposed pre-natally to DES were transferred into mice exposed to vehicle only pre-natally. Among 99 offspring derived from DES-exposed germ cells, 6 developed ovarian adenomas and 16 developed uterine adenocarcinomas. Thus DES also has a multi-generational effect transmitted through the blastocyst, which is consistent with fetal germ cell mutation from DES.

Abnormalities, Drug-Induced↗

PubMed1987

Embryotoxicity induced by diethylstilbestrol in vitro.

The embryotoxic potential of diethylstilbestrol (DES) was examined in a whole embryo culture system containing a P-450-dependent bioactivating system. Sprague-Dawley rat embryos were explanted on day 10 and cultured for 24 hours. Concentration-dependent effects of DES on embryonic growth parameters, viability, and embryotoxicity were observed. Concentrations of DES greater than 0.26 mM (final concentration) produced 100% embryolethality, while those below 0.15 mM were without significant effects. At a final concentration of 0.19 mM, DES produced only a slight increase in embryolethality. The same concentration elicited a marked increase in observed embryotoxicity, including prosencephalic hypoplasia, incomplete axial rotation, and open neural tubes. In addition, reductions in embryonic length, somite number, and protein and DNA content were observed. An exogenous P-450-dependent hepatic biotransforming (catechol-generating) system failed to alter either the incidence of observed toxic effects or measured growth parameters. Likewise, exposure of cultured embryos to 20% carbon monoxide (CO) failed to reduce DES-induced embryotoxicity, indicating a lack of participation of an endogenous P-450-dependent embryonic bioactivating system. Arachidonic acid (0.20 mM) and/or indomethacin (0.50 mM) also had no observable effect on DES-induced embryotoxicity, suggesting that prostaglandin synthase was not involved in the embryotoxic activity of DES, as has been proposed to explain its carcinogenic effect. The antioxidants N-acetylcysteine (1.14 mM) and alpha-tocopherol (0.08 mM) failed to protect against DES-induced embryotoxicity, while the anti-estrogen tamoxifen (up to 0.85 mM) actually enhanced this effect of DES in culture. The DES analogs Z,Z-dienestrol (DIES, 0.10 mM) and hexestrol (HES, 0.48 mM) were both embryotoxic in vitro. The presence of an exogenous P-450-dependent hepatic biotransforming system appeared to protect against HES-induced embryolethality but had little effect upon DIES-induced embryotoxicity. The results were consistent with a direct effect of DES independent of either estrogenicity or exogenously generated metabolites.

Animals↗

PubMed1988

Inhibition of prostaglandin H synthase-catalyzed cooxidation of diethylstilbestrol by alpha-naphthoflavone and beta-naphthoflavone.

Prostaglandin H synthase (PHS) has gained interest as a drug-metabolizing enzyme and has been shown to cooxidize and metabolically activate diethylstilbestrol (DES) in vitro. Both 7,8-benzoflavone (alpha-naphthoflavone, ANF) and 5,6-benzoflavone (beta-naphthoflavone, BNF) have now been studied for their effects on PHS from ram seminal vesicle microsomes by means of several in vitro assays. The PHS-catalyzed cooxidation of DES, as measured by high-performance liquid chromatography (HPLC) analysis, is inhibited by BNF and ANF at micromolar concentrations, with median inhibitory concentrations (IC-50) of less than 20 and 40 microM, respectively. The oxidation of DES is inhibited whether it is initiated by arachidonic acid or by hydrogen peroxide, indicating that the benzoflavones inhibit PHS by a mechanism different from that of indomethacin. Monitoring of cyclooxygenase activity in an oxygraph also reveals an inhibition of PHS by BNF which depends only weakly on arachidonic acid concentration; inhibition by ANF is less pronounced under these conditions. Since PHS-catalyzed conversion of the benzoflavone compounds was detected under conditions permitting cooxidation, the inhibition of PHS by benzoflavones in vitro could either be a direct effect or possibly mediated via metabolites. Our data imply that ANF and BNF, in addition to their well-known role as modifiers of mixed-function oxidases, can affect the PHS-catalyzed metabolism of xenobiotics. This is discussed in the context of adverse effects caused by DES in vivo and in cell culture and must be taken into account when interpreting the modifying effect of benzoflavones on these endpoints.

Animals↗

PubMed1988

Altered activation/detoxication enzymology following neonatal diethylstilbestrol treatment.

The effects of neonatal exposure to diethylstilbestrol (DES) on hepatic activation/detoxication enzyme levels in the adult rat were investigated. Neonatal exposure of male rats to DES (DES males) decreased the endogenous levels of UDP-glucuronyltransferase as compared to control males. Female rats exposed neonatally to DES (DES females) had higher endogenous epoxide hydrolase and glutathione transferase activity levels than control females. Adult animals treated neonatally with DES also had altered metabolic potential following exposure to 3-methylcholanthrene and phenobarbital. The DES males treated in adulthood with 3-methylcholanthrene had higher benzo(a)pyrene hydroxylase activities and lower UDP-glucuronyl-transferase activity levels than did control males treated in adulthood with 3-methylcholanthrene. The DES males exposed in adulthood to phenobarbital had reduced cytochrome P-450 and glutathione transferase activity levels as compared with respective controls. The DES females treated in adulthood with 3-methylcholanthrene had lower benzo(a)pyrene hydroxylase and epoxide hydrolase activity levels than control females receiving 3-methylcholanthrene. The DES females challenged in adulthood with phenobarbital also had decreased benzo(a)pyrene hydroxylase, epoxide hydrolase, UDP-glucuronyltrasferase, and glutathione transferase activity levels as compared with respective controls. Our results demonstrated that neonatal exposure to DES changed the endogenous levels of specific hepatic enzymes and altered the metabolic response of these adult animals to a carcinogen and a drug.

Animals↗

PubMed1984

Immunotoxic effects of diethylstilbestrol on host resistance: comparison with cyclophosphamide.

To evaluate the usefulness of host resistance assays for measurement of immunotoxicologic effects of chemicals, the immunosuppressive effects of exposure to diethylstilbestrol (DES) were compared with the effects of treatment with the known immunosuppressive drug cyclophosphamide (CPS). A panel of six host resistance models was evaluated, including infection with the bacterium Listeria monocytogenes, herpes simplex virus type 2 (HSV-2), and encephalomyocarditis virus (EMC), the yeast Cryptococcus neoformans, the parasite Naegleria fowleri, and transplantation of the B16F10 melanoma tumor. The results demonstrate a general correlation between the effects of CPS and DES on host resistance. Acute treatment with CPS (200 mg/kg) markedly depressed resistance to the microbial infections with L. monocytogenes and HSV, and exposure to DES usually also decreased resistance in a dose dependent manner. Moreover, CPS had no marked effect on resistance to N. fowleri and EMC virus, and exposure to DES also had a neglible or slight effect. There were, however, two model systems in which the effects of CPS and DES diverged. Whereas treatment with DES produced no significant effect on resistance to C. neoformans, acute treatment with CPS prior to the fungal infection produced a marked increase in resistance. Also, while treatment with CPS markedly increased B16F10 lung metastases, treatment with DES significantly decreased the incidence and number of lung metastases. The data support the general validity of host resistance assays, particularly with models of short disease course, for measuring immunosuppression. However, the results also emphasize the complexity of interpreting effects of environmental chemicals on host resistance, because of the interplay of such factors as relative times of exposure to the chemical in relation to pathogenesis of infection, the length of the disease course, the nature of the operative host defense mechanisms, and the compensatory recovery of these mechanisms.

Amebiasis↗

PubMed1986

Effects of diethylstilbestrol on Propionibacterium acnes immunomodulation: inhibition of macrophage activation and antitumor activity.

Exposure of mice to diethylstilbestrol (DES) inhibited Propionibacterium acnes-induced antitumor activity in vivo against the B16F10 subcutaneous tumor. The inhibitory effect was associated with inhibition by DES of the characteristic P. acnes induced splenomegaly and changes in splenic and peritoneal macrophages (M phi) cell populations. The characteristic P. acnes induced reductions in M phi alkaline phosphodiesterase I (APD) ectoenzyme activity and in total RNA synthesis, proposed biochemical markers of tumoricidal M phi, were partially or completely reversed in DES-treated mice. As predicted from these in vivo and in vitro results, DES treatment significantly decreased P. acnes activation of M phi antitumor activity in vitro against B16F10 melanoma and Lewis lung carcinoma cells. These data suggest a macrophage activation defect may be involved in the reduced resistance that DES-treated animals exhibit to a variety of neoplastic and microbial challenges.

Animals↗

PubMed1977

Synthesis of 5-substituted 2-oxazolidinethiones and their antagonism to uterotropic effect of diethylstilbestrol.

5-(4-Aminophenoxymethyl)-2-oxazolidinethiones were synthesized by the cyclization of 1-(4-aminophenoxy)-3-amino-2-propanol in the presence of potassium hydroxide and carbon disulfide. This oxazolidinethione, on reaction with suitable isothiocyanates, yielded 5-[4-(substituted thiocarbamido)phenoxymethyl]-2-oxazolidinethiones. These compounds antagonized the uterotropic effects of diethylstilbestrol in female rats and possessed approximate LD50 values of 400-greater than 800 mg/kg.

Animals↗

PubMed1982

Effects of diethylstilbestrol diphosphate on serum and tissue ribonuclease levels in prostatic carcinoma.

Thirty-six patients with prostatic carcinoma and benign prostatic hyperplasia (BPH) were studied. Transurethral resection (TUR) was performed in all, and serum and tissue ribonuclease (RNase) levels were determined with the spectrophotometric method using yeast RNA as the substrate. In patients with untreated prostatic carcinoma, statistically significant increased RNase levels were found in serum and tissue. Treatment with diethylstilbestrol diphosphate (DESDP) led to a decrease in RNase levels. In the same patients RNase serum levels after DESDP treatments also showed a parallel decrease with serum prostatic acid phosphatase (sPAP) levels. We have concluded that the serum RNase measurement may be useful for TNM classification and immunostaging.

Acid Phosphatase↗

PubMed1990

Combined hormonal therapy with high-dose diethylstilbestrol diphosphate (DES-DP) intravenous infusion plus vindesine (VND) for the treatment of advanced prostatic carcinoma: a controlled study.

Fifty-one patients with stage D prostate cancer, who had failed primary hormone treatment, were treated with diethylstilbestrol diphosphate (DES-DP) 1.5 g 24 hr intravenous infusion from day 1 to day 7 (group A). In group B, patients were treated with DES-DP as in A, plus vindesine (VND) 3 mg/m2 intravenously on days 8, 15, and 22. Cycles were repeated every 28 days for six consecutive cycles. All 51 patients were evaluable for response, toxicity, time to progression, and survival. Pretreatment clinical and laboratory characteristics were comparable. The National Prostatic Cancer Project Criteria were used for evaluation. A minimum of two cycles were required for evaluation of response. No complete response was seen. In group A, 9 "partial response" and 7 "no change" (80%), and in group B, 11 "partial response" and 12 "no change" (74%) were registered. Median survival time was 40 weeks. Toxicity ranged from mild to moderate. DES-DP + VND seemed to improve duration of objective response compared to DES-DP alone, but the difference was not significant.

Aged↗

PubMed2001

Promoter CpG methylation of Hox-a10 and Hox-a11 in mouse uterus not altered upon neonatal diethylstilbestrol exposure.

Mouse abdominal B-like Hoxa genes are expressed and functionally required in the developing reproductive tracts. Mice lacking either Hoxa-10 or Hoxa-11, two of the AbdB Hoxa genes, exhibit abnormal uterine development similar to that induced by in utero diethylstilbestrol (DES) exposure. Indeed, uterine Hoxa-10 and Hoxa-11 expression is potently repressed by perinatal DES exposure, providing a potential molecular mechanism for DES-induced reproductive tract malformations. We have shown previously that DES can permanently alter uterine lactoferrin gene expression through modulation of the lactoferrin promoter methylation pattern. Here we ask whether a similar mechanism also functions to deregulate uterine Hoxa-10 or Hoxa-11 expression during neonatal DES exposure. We mapped the Hoxa-10 promoter by cloning a 1.485 kb DNA fragment 5' of the Hoxa-10 exon1a. A 5' rapid amplification of cDNA ends (RACE) experiment revealed a transcription start site for the a10-1 transcript. Functional analysis of the proximal 200-bp sequences demonstrated significant promoter activity, confirming the location of the Hoxa-10 promoter. Moreover, methylation assays performed on eight CpGs in Hoxa-10 and 19 CpGs in Hoxa-11 proximal promoters demonstrated that all these CpGs were highly unmethylated in both control and DES-dosed mice from postnatal day 5 to day 30. Significant methylation around Hoxa-10 and Hoxa-11 promoters was only observed in DES-induced uterine carcinomas in 18-mo-old mice. Our results suggest that DES-induced downregulations of Hoxa-10 or Hoxa-11 gene expression are not associated with methylation changes in their proximal promoters and that gene imprinting by developmental DES exposure may be a gene-specific phenomenon.

Animals↗

PubMed2003

Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus.

Perinatal exposure to diethylstilbestrol (DES) induces reproductive tract cancers later in life in both humans and animals. Because there is no clear evidence that perinatal DES exposure induces gene mutation, we proposed that perinatal DES exposure causes epigenetic methylation changes that result in persistent alterations in gene expression, leading to tumorigenesis. The proto-oncogene c-fos is one of the immediately induced genes in uterine epithelium after estrogen simulation and a key player in uterine carcinogenesis. Here, we investigated c-fos expression in mice neonatally exposed to DES (2 microg/pup/day on postnatal days 1-5). The mRNA levels of c-fos in uteri of neonatal DES-treated mice were persistently 1.4-1.9-fold higher than that in the control mice from day 5 to day 60. Overall, the uterine c-fos expression level in the neonatal DES-exposed group was significantly higher than that in the control group. After examination of the methylation status of the c-fos gene, we found that the CpGs in promoter and intron-1 regions were completely unmethylated. In exon-4, from day 17 to day 60, the percentage of unmethylated CpGs was higher in neonatal DES-exposed mice uteri than that in control (42%, 51%, 47%, and 42% in DES-exposed mice vs 33%, 34%, 33%, and 21% in control mice at day 17, 21, 30, and 60, respectively). These results suggest that perinatal DES exposure may permanently alter gene expression and methylation, and the methylation modification may occur in either the promoter regions or other regulatory sites in the gene.

Animals↗

PubMed1994

Use of representational difference analysis for the identification of mdm2 oncogene amplification in diethylstilbestrol-induced murine uterine adenocarcinomas.

Exposure in utero to the synthetic estrogen diethylstilbestrol (DES) is associated with the subsequent development of reproductive-tract malignancies in female offspring. To search for the genetic targets of DES, representational difference analysis was used to compare genomic DNA from DES-associated mouse uterine adenocarcinoma cells with genomic DNA from normal CD-1 mouse tissue. Several difference clones were obtained, all of which recognized rearranged and amplified sequences in tumor compared with normal DNA. One of these difference fragments mapped to a region of mouse chromosome 10 that includes the mdm2 oncogene. Amplification and overexpression of mdm2 was found in all three early-passage cell lines established from independent DES-associated cancers. These findings demonstrate the potential power of representational difference analysis in cancer research and suggest a genetic mechanism for DES-induced carcinogenesis.

Adenocarcinoma↗

PubMed1990

Diethylstilbestrol revisited in advanced breast cancer management.

Prior to the introduction of tamoxifen, diethylstilbestrol (DES) was widely used as the first-line endocrine therapy in postmenopausal women with advanced breast cancer. Since randomized trials reported that tamoxifen has a similar response rate but fewer side effects than DES, its use has declined markedly. We administered DES in a dose of 10-20 mg daily to 11 postmenopausal women with advanced breast cancer, all of whom had received previous endocrine and some cytotoxic therapy also. Four women showed tumour responses to DES (1 complete and 3 partial), 5 had stable disease, and 2 progressive disease. Amongst the patients who responded, 2 had previously been unresponsive to other endocrine treatments. Of the women with stable disease, 3 had prolonged relief of symptoms. No withdrawal responses were noted. The major side effects were nausea (severe in 2 patients, mild in 1) and cardiac failure (2 patients). We conclude that DES remains a useful, active agent in the management of advanced breast cancer in postmenopausal women, even in patients with tumours unresponsive to other endocrine therapy.

Aged↗

PubMed2002

Toxicogenomic effects of neonatal exposure to diethylstilbestrol on mouse testicular gene expression in the long term: a study using cDNA microarray analysis.

We examined the effect of neonatal exposure to diethylstilbestrol (DES) on mouse testicular gene expression, using in-house mouse fetus (day 14.5) cDNA microarrays. Newborn male ICR mice were exposed to DES (50 microg/mouse/day) from neonatal day 1 to 5. Differential expression was detected in 14 genes in 4-week-old (day 28) mouse testes by cDNA microarray analysis; 11 genes (AI035263, AU080565, AU080361, AU080678, AI131681, AU080631, AA986882, AI037066, AA986537, AI156816, and AI596237) were up-regulated and three genes (AI131656, AI118968, and AI117606) were down-regulated in DES-treated mouse testes. Higher expression levels of the former eight genes, out of the up-regulated genes picked-up by the microarray, were also confirmed by reverse transcription and real-time polymerase chain reaction (real-time RT-PCR) analysis. However, the differential expression of other genes could not be confirmed. Real-time RT-PCR analysis also revealed that expression levels of the eight genes were still higher in DES-treated testes at 8 and 12 weeks of age. Our results suggest that cDNA microarray analysis is a useful method by which a large number of gene expressions are simultaneously detected and changes in gene expression are screened. In addition, our results suggest that these genes, whose expressions are changed in the testes of adult mice by fetal or neonatal exposure to exogenous chemicals, might be candidates for predictive biological markers.

Animals↗

PubMed2003

ADAM7 (a disintegrin and metalloprotease 7) mRNA is suppressed in mouse epididymis by neonatal exposure to Diethylstilbestrol.

We investigated whether neonatal exposure to diethylstilbestrol (DES) induces the alteration of mRNA expression in adult mouse epididymis, which plays an important role in sperm maturation. Using a cDNA subtraction method, we isolated 15 changed gene clones in neonatally DES-treated mouse epididymides, and we found a clone homologous with a disintegrin and metalloprotease (ADAM) 7 in the epididymis, as a suppressed gene, by means of neonatal DES treatment in 8-week-old mice. Indeed, it was confirmed by Northern blot analysis that the ADAM7 mRNA expression in the epididymis was at a lower level in neonatally DES-treated mice than in non-treated mice. Moreover, in situ hybridization analysis and real-time reverse transcription and polymerase chain reaction (real-time RT-PCR) revealed that ADAM7 expression was markedly reduced in the corpus region of the epididymis of DES-treated mice as compared with non-treated mice. Our results suggest that neonatal exposure to DES leads to the suppression of ADAM7 expression in the epididymis in the long term. ADAM7 gene expression might be a biological marker of fetal or neonatal exposure to estrogenic compounds, including endocrine disruptors.

Animals↗

PubMed2004

Toxicogenomic difference between diethylstilbestrol and 17beta-estradiol in mouse testicular gene expression by neonatal exposure.

In this study, we investigated the effects of neonatal exposure to exogenous estrogen (diethylstilbestrol: DES, 17beta-estradiol: E2) on testicular gene expressions. Male C57BL/6J mice, 1 day after birth, were subcutaneously injected with DES or E2 (3 micrograms/mouse/day) for 5 days, and then they were raised for 8 weeks. In morphological observation of 8-week-old mice testes, spermatozoa were absent from many seminiferous tubules in DES-treated mice testes, but there was no change in E2-treated mice testes. Analysis of in-house cDNA microarray (mouse cDNA 889 genes) revealed that 17 genes were altered in DES-treated mice testes at 8 weeks of age, compared to each control. Real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) analysis of these genes revealed that some genes, which were changed in E2-treated testis, were the same as in DES-treated testis, whereas in other cases there was a difference between DES-treated and E2-treated testis. The present results suggest that each exogenous estrogenic compound has both a common gene expression change pattern and its own testicular gene expression change pattern. Mol. Reprod. Dev. 67: 19-25, 2004.

Animals↗

PubMed2005

Association of increased type I collagen expression and relative stromal overgrowth in mouse epididymis neonatally exposed to diethylstilbestrol.

The aim of this study was to investigate the molecular changes that underlie morphological changes in the epididymis following neonatal exposure to potent synthetic estrogen, namely diethylstilbestrol (DES). Newborn male mice were subcutaneously injected with DES or endogenous estrogen, namely 17 beta-estradiol (E2) (5 microg/mouse/day), for the first 5 days. At the age of 2, 4, and 8 weeks, epididymides of the mice were dissected. Characteristic morphological abnormality, such as relative stromal overgrowth, was observed at the age of 2 weeks in the epididymis of DES-treated mice, but not in E2-treated mice. Microarray and real-time RT-PCR analyses revealed that the expression levels of procollagen type I alpha 1 (col1a1) and col1a2 genes were markedly upregulated at the age of 2 weeks in the epididymis of DES-treated mice in comparison with the control. Western blot analysis revealed that type I collagen protein expression level in epididymis of DES-treated mice was elevated at the age of 2 weeks. In situ hybridization analysis revealed that the signals of col1a1 mRNA were detected similarly throughout the stromal tissue of epididymis at the age of 2 weeks in control and DES- and E2-treated mice. The gene expression level of epididymal type III collagen (col3a1), which is found in many stromal connective tissues as well as type I collagen, did not change at the age of 2 weeks in all groups. These results suggest that the increased type I collagen expression is associated with the relative stromal overgrowth in the epididymis of DES-treated mice.

Animals↗

PubMed2006

Absence of Bcl-2 expression favors response to the short-term administration of diethylstilbestrol diphosphate in prostate Cancer.

BACKGROUND: Neoadjuvant hormone therapy remains a controversial issue in spite of multiple studies having been performed. METHODS: We performed short-term (10 days) treatment with diethylstilbestrol (DES) in 30 patients with stages T2 or T3 prostate cancer (PCa). All the patients underwent needle core prostate biopsy before and radical prostatectomy within a month after the start of the endocrine therapy. The histological effects in PCa and the changes in morphological and clinical parameters and their association were elucidated. RESULTS: Serum PSA (P < 0.001), Ki-67 PI (P = 0.022), and AR (P = 0.002) expression decreased after the treatment. An obvious effect (Grade 1-3) of endocrine treatment was seen in 11 of 30 patients and was associated with a prominent PSA decrease (P = 0.0274) and with older age (P = 0.0026). Pre-treatment specimens from a group without any effects of endocrine therapy had a higher frequency of Bcl-2 positivity (57.9%) compared to the group of Grade 1-3 effects (27.3%). Prostatectomy specimens presented with significantly higher AI in Bcl-2 negative cases (P = 0.0029) and pre treatment Bcl-2 was associated with a higher AI in Grade 1-3 patients (P = 0.0393). CONCLUSIONS: Older age is a predictor of histological effects in short-term hormone treatment of PCa. A lower Bcl-2 in biopsy specimens presented more frequently in the patients who experienced a prominent effect of endocrine therapy, and it was also useful to predict a significantly higher AI in Grade 1-3 patients. Histological effects are also associated with the PSA decrease, reflecting the clinically meaningful shrinkage of tumors and a decrease of tumor burden.

Aged↗