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PubMed1980

Synthesis of novel hexestrol and diethylstilbestrol derivatives as potential anticancer and estrogenic agents.

Two novel series of potential anticancer agents derived from hexestrol and diethylstilbestrol have been synthesized. The first includes several alkylating agents containing sulphonic esters and nitrogen mustard functions attached through various chains to only one phenolic group in hexestrol. The second contains the N1-acetyl-N4-substituted thiosemicarbazide moieties attached to one phenolic group hexestrol or to the two phenolic oxygens in diethylstilbestrol. The tests of some of the products for antileukemic activity in P 388 Lymphocytic Leukemia indicated no significant activity over the parent nuclei. The estrogenic activity of some representative examples of the thiosemicarbazides was found to be dependent on the nature of the N4-substituent in the thiosemicarbazide moiety.

Animals↗
PubMed1975

Reduction of enzyme efflux from skeletal muscle by diethylstilbestrol.

We have previously shown that oral diethylstilbestrol (DES) lowers the high serum enzyme levels characteristic of Duchenne's muscular dystrophy (DMD). The present studies were undertaken to assess the effect of DES on the efflux of enzymes from isolated mouse skeletal muscle. Thirty-four male mice were used. Half received daily subcutaneous injections of 10 mug diethylstilbestrol-diphosphate (DES-DP) in saline for up to 3 wk and half daily saline injections. Left gastrocnemii were isolated from control and treated mice, and placed in separate incubation media at 37 degrees C. The efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) from each was compared over a 4- to 5-hr period. In 15 of 18 there was a reduction in efflux of both enzymes from muscles isolated from DES-DP-treated mice. The greatest effect was noted during the second hour, when the mean efflux of each enzyme was reduced about 30%. Minor differences in muscle weight, water content, and enzyme activities did not explain the reduced efflux. These results suggest that DES has either reduced the permeability of the sarcolemma or enhanced the intracytoplasmic stability of these enzymes. This is the first drug reported to reduce the spontaneous enzyme efflux from isolated skeletal muscle. It remains to be established that a similar effect accounts for the reduction in serum enzyme levels when DES is administered to persons with DMD.

Animals↗
PubMed1993

Investigation of aneuploidy induction in mouse oocytes following exposure to vinblastine-sulfate, pyrimethamine, diethylstilbestrol diphosphate, or chloral hydrate.

The various causative and mechanistic phenomena associated with aneuploidy induction require considerable investigation to better understand the etiology of chromosome missegregation. We investigated the potential of vinblastine sulfate, pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate to induce numerical and structural chromosome changes in female mouse germ cells. Superovulated ICR mice were administered the compounds either by intraperitoneal injection or oral gavage, and oocytes were collected and processed for cytogenetic analysis 17 hr later. Vinblastine sulfate, administered i.p., induced a significant increase in the frequency of ovulated MI oocytes and of hyperploid MII oocytes compared to controls, but did not increase the frequency of structural aberrations. Pyrimethamine, diethylstilbestrol diphosphate, and chloral hydrate did not increase the frequency of numerical or structural chromosome changes in female mouse germ cells.

Aneuploidy↗
PubMed1980

Thrombocytopenia during diethylstilbestrol diphosphate (stilphostrol) infusion for carcinoma of the prostate.

Transient thrombocytopenia was noted to occur in ten of 13 patients with advanced carcinoma of the prostate undergoing intravenous diethylstilbestrol diphosphate therapy. This was not associated with abnormalities of the initial platelet count or other parameters of the hemogram. There was no evidence of disseminated intravascular coagulation in these patients. No serious bleeding episodes occurred secondary to the thrombocytopenia. Following diethylstilbestrol diphosphate infusion, platelet counts generally returned to pretreatment levels. While the mechanism of action of the thrombocytopenia is unclear, we hypothesize a transient bone marrow toxicity as the cause of this phenomenon.

Adenocarcinoma↗
PubMed2000

Clear cell carcinoma of the uterine cervix: pathology and prognosis in surgically treated stage IB-IIB disease in women not exposed in utero to diethylstilbestrol.

OBJECTIVE: The purpose of this research was to compare the clinical behavior, pathology findings, and prognosis of surgically treated FIGO stage IB-IIB clear cell carcinomas of the cervix with those of squamous cell carcinomas and non-clear cell adenocarcinomas. METHODS: Fifteen patients with clear cell adenocarcinomas of the cervix (8 FIGO stage IB, 7 FIGO stage IIB) were reviewed. The control group consisted of 444 squamous cell carcinomas and 59 non-clear cell adenocarcinomas. None of the patients had a history of in utero exposure to diethylstilbestrol. All patients underwent radical abdominal hysterectomy with systematic pelvic lymphadenectomy. All specimens were processed as serial giant frontal sections. The mean follow-up in the clear cell group was 83 (13-182) months. Statistical analysis was done with contingency tables, chi(2) tests, and Fisher's exact test. RESULTS: Twelve of the fifteen clear cell carcinomas (80%) were endophytic and tended toward deep cervical infiltration. Clear cell carcinomas extended to the uterine corpus significantly more often than squamous cell and non-clear cell adenocarcarcinomas (P < 0.001). The rates of parametrial involvement and pelvic lymph node involvement were 40 and 47%, respectively. Four patients (27%), all with positive pelvic nodes, developed recurrences an average of 14 (4-48) months after initial therapy. The extrapelvic sites of relapse were the lung, liver, and bone. Clear cell carcinomas had a worse 5-year survival rate (67%) than squamous cell carcinomas (80%) and non-clear cell adenocarcinomas (77%) but this was not statistically significant (P = 0.6). No significant differences were seen for age, growth pattern, parametrial and vaginal involvement, parametrial and pelvic lymph node metastases, frequency of recurrent disease, and time to first recurrence. CONCLUSION: The clinicopathologic findings and prognosis of surgically treated patients with stage IB-IIB clear cell carcinomas without exposure to diethylstilbestrol in utero are similar to those of patients with squamous cell carcinomas and non-clear cell adenocarcinomas.

Adenocarcinoma, Clear Cell↗
PubMed1981

The tumor-inhibiting effect of diethylstilbestrol-3,4-oxide.

Diethylstilbestrol-3,4-oxide, (DES-3,4-oxide), one of the possible cancerogenic metabolites of the well-known estrogen diethylstilbestrol (DES), is a potential estrophilic cytostatic compound. It shows a very good affinity to the estrogen receptor. The uterotrophic activity determined in the mouse uterine weight bioassay is nearly identical with that of DES. Potential alkylating properties could neither be detected in the p-NBP test not in the prophage induction test. DES-3,4-oxide [0.01-1.0 mg/kg body weight (b. wt.)] markedly inhibited the growth of the DMBA-induced hormone-dependent mammary carcinoma of the SD rat, as well as the growth of a hormone-dependent postmenopausal (but not of a premenopausal) human mammary carcinoma serially transplanted in nude mice. However, DES-3,4-oxide had no significantly better effect on the DMBA-induced mammary carcinoma of the SD rat than DES.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

[Enzyme immunoassay (EIA) for the estrogenic stilbene derivative diethylstilbestrol (DES) (author's transl)].

An enzyme immunoassay (EIA) for diethylstilbestrol (DES) is described, which is based on the competitive reaction between DES and peroxidase-labelled DES for an antibody, which has been bond to an insoluble support. The preparation of the enzyme-labelled DES necessitates the use of highly purified 4-O-(carboxypropyl)-diethylstilbestrol (CP-DES) to obtain a highly immunoreactive conjugate. CP-DES was synthesized from DES and ethyl-4-bromobutylate and was purified by a novel isolation procedure involving a simple solvent partition followed by hydrolysis of the ester. It was characterized by it's chemical and biological properties. The assay covers the range from 0.2 to 20 pmol/test (approximately equal to 0.05-5 ng/test). It has sufficient sensitivity and specificity compared with radio immuno assay to make it a potential method for controlling the misuse of this estrogenic substance in animal production.

Animals↗
PubMed1975

The effect of diethylstilbestrol on the rate of osseous repair, bone integrity, and plasma calcium in the adult avian.

The effect of diethylstilbestrol on healing experimental osseous defects in adult roosters was studied by means of I-125 photon absorptiometry. Although the two dose levels utilized in this study both resulted in elevated plasma calcium and lipid levels and significantly increased the mineral and organic fractions of femoral bone, diethylstilbestrol treatment over a six-week period had no effect on the rate or magnitude of mineralization in the repairing osseous defect.

Absorption↗
PubMed2005

Clear cell adenocarcinoma of the cervix in a child without in utero exposure to diethylstilbestrol: a case report and review of the literature.

We describe the case of a primary cervical tumor in a 6-year-old child that was originally suspected to be an embryonal rhabdomyosarcoma botryoides. Histologic analysis revealed a clear cell adenocarcinoma. Despite a direct search and questioning for maternal exposure to diethylstilbestrol, this was not documented. Clear cell adenocarcinoma is an extremely rare neoplasm that should be kept in the differential diagnosis of cervicovaginal lesions in children, even in the absence of a clinical history of in utero diethylstilbestrol exposure. We discuss the hypothesized pathogenesis and review the literature on this unusual tumor.

Adenocarcinoma↗
PubMed1984

Affinity chromatography of estrogen receptors on diethylstilbestrol-agarose.

Diethylstilbestrol was coupled to epoxy-activated agarose yielding an affinity resin which is highly efficient for the isolation of estrogen receptors. This resin, diethylstilbestrol-agarose (DES-agarose), bound two proteins (Mr = 50,000 and 65,000) from rabbit uterine cytosol that show a specific interaction with estradiol. A two step procedure--adsorption on DES-agarose followed by a selective elution with p-sec-amylphenol and NaSCN, yielded highly purified estrogen receptors which can be used in the studies of estradiol-receptor interactions with other cell constituents.

Animals↗
PubMed1981

Diethylstilbestrol treatment modulates the enzymatic activities of phosphatidylcholine biosynthesis in rooster liver.

The effect of diethylstilbestrol injection on the activities of phosphatidylcholine biosynthetic enzymes in rooster liver has been determined. Choline kinase activity was stimulated within 4 h after the first hormone injection. By the third day enzyme activity reached 5.47 nmol . min-1 . mg-1 protein compared to control values (1.83 nmol . min-1 . mg-1 protein) which were unchanged during the the experiment. CTP : phosphocholine cytidylyltransferase activity was unaffected until Day 3 when its activity was 50% that of control values. When assayed in the presence of exogenous phospholipid, no significant change was noted in cytidylyltransferase activity. The activity of CDPcholine : 1,2-diacylglycerol phosphocholinetransferase was not altered by the hormone injections. The activity of phosphatidylethanolamine-N-methyltransferase gradually increased so that by Day 3, the enzyme activity was elevated 2-fold (0.12 to 0.24 nmol methyl group transferred per mg microsomal protein). These results are consistent with earlier in vivo studies (Vigo, C. and Vance, D.E. (1981) Eur. J. Biochem., in the press) that indicated a stimulation of phosphatidylcholine biosynthesis via CDPcholine during the first 2 days of diethylstilbestrol injection and inhibition on the third day.

Animals↗
PubMed1985

In vitro metabolism of diethylstilbestrol by hepatic, renal and uterine microsomes of rats and hamsters. Effects of different inducers.

In order to elucidate possible differences in the metabolism of the synthetic estrogen diethylstilbestrol (DES) by target and non-target tissues for DES carcinogenicity, the biotransformation of [14C]DES has been studied in vitro with hepatic and renal microsomes of male and female hamsters and rats, and from hamster and rat uterus. Of these tissues, only the male hamster kidney is susceptible to the carcinogenic effect of DES. Moreover, the effect of various inducers on the in vitro metabolism of DES has been investigated. It was found that male hamster kidney microsomes produced a markedly different pattern of DES metabolites as compared to renal microsomes from female hamster or male and female rats. Pretreatment with phenobarbital markedly increased oxidative DES metabolism by renal microsomes from female rat but not from male rat. Diethylstilbestrol metabolism by hepatic microsomes was different between hamster and rat, but was not sex-dependent and could not be significantly affected by pretreatment with phenobarbital, DES, 3-methylcholanthrene and 7:8-benzoflavone. The differences in DES metabolism between target and non-target organs and its modulation by inducers may help to gain further insight into the mechanism of DES tumorigenesis.

Animals↗
PubMed1993

A 125I-radioimmunoassay for diethylstilbestrol in serum of patients with prostatic cancer treated with stilphostrol.

A new radioimmunoassay for determining diethylstilbestrol in serum using N-(4'-OH-[3'-125I]iodophenethyl)-6-(4-O-diethylstilbestryl)-hex anamide as a radiotracer and a double antibody as a separation reagent is described. The radiotracer is prepared by synthesizing 6-(4-O-diethylstilbestryl)-hexanoic acid and coupling its succinimidyl ester with mono-[125I]tyramine in tetrahydrofuran (16 h, 20-22 degrees C). The standard curve is linear (semi-log transformation) and the assay is sensitive (< 0.022 pmol/tube), reproducible (intra- and interassay coefficient of variation values, 5.3 and 8.1%, respectively), and accurate (recovery values, 95-101%), with a non-specific binding less than 3.2%. Diethylstilbestrol concentrations measured in sera of nine patients with prostatic cancer by the proposed assay ranged from 0.170 to 2.517 mumol/l, which corresponded to an only three-fold dosage variation. In all cases tested, dosing was adequate to retain markers of prostatic cancer in serum within accepted limits; nevertheless, individualization of dosing may be necessary to minimize toxicity.

Aged↗
PubMed1981

Uptake in vivo of 45Ca in male accessory sex organs of the rat: effect of estramustine phosphate and diethylstilbestrol diphosphate.

The radioactivity following a single i.v. injection of 45Ca into male rats was found to be significantly higher in seminal vesicles, dorsolateral prostate, coagulating glands and ventral prostate than in muscle. The acute effect of a single dose given intraperitoneally of estramustine phosphate (Estracyt) and diethylstilbestrol diphosphate (Honvan) were examined on 45Ca uptake. Generally, the 45Ca concentration in the accessory sex organs with the exception of the dorsolateral prostate increased after administration of estramustine phosphate. Diethylstilbestrol phosphate treatment also significantly increased 45Ca uptake in the ventral prostate when measured on the basis of tissue wet weight but not on the basis of protein. The implications of these findings are discussed in relation to the therapeutic action of Estracyt in prostatic carcinoma.

Absorption↗
PubMed1993

Mutagenic and recombinagenic effects of diethylstilbestrol quinone.

Estrogens are believed to be major contributors to many cancers of the human female genital tract, but the mechanism of their carcinogenic action is not well-understood. While a tumor-promoting role for estrogens is well-supported, whether they also act as tumor initiators has remained controversial. Here, we have sought to examine the mutagenic potential of diethylstilbestrol, a synthetic estrogen that is a powerful carcinogen in hamsters, and is suspected to be a human carcinogen. Phage M13 single-stranded DNA was treated in vitro with diethylstilbestrol quinone (DES Q: 1.25 mM) and transfected into Escherichia coli cells. DES Q treatment resulted in an apparent enhancement of mutagenesis in the LacZ(alpha) gene segment. DNA sequence analysis of LacZ(alpha) mutants obtained by transfection of DES Q-treated DNA revealed that the major effect of DES Q treatment has been a 6-fold elevation of recombination between the phage-borne LacZ(alpha) sequence and the LacZ delta M15 sequence on the E. coli fertility plasmid F. To confirm whether DES Q treatment is recombinagenic, we used an experimental system that allows the detection of recombination between a defective E. coli chromosomal LacY gene and a normal counterpart borne on a plasmid. Transfection of DES Q (0.06-12 mM) treated plasmid DNA showed significant enhancement (2-100-fold) in recombination, but not in mutagenesis. These results raise the possibility that estrogen quinones may induce recombinagenic DNA damage.

Bacteriophage M13↗
PubMed1986

Diethylstilbestrol on urinary catecholamines and on food intake in castrated male rats.

Moderate changes in food intake produced by diethylstilbestrol in rats were not well correlated with changes in urinary norepinephrine, vanillylmandelic acid or epinephrine. Apparently moderate dietary restrictions are not capable of decreasing adrenergic activity, and the decreased urinary norepinephrine produced by diethylstilbestrol is not associated with decreased availability of dietary precursors.

Animals↗
PubMed1982

Deuterium labeling of diethylstilbestrol and analogues.

E-2,2,3',3'',5,5,5',5''-octadeuteriodiethylstilbestrol (DES-d8) and Z-2,3'3'',4,5,5,5',5''-octadeuterio-3,4-bis(p-hydroxyphenyl)-2-hexene (psi-DES-d8) were synthesized from E-diethylstilbestrol (DES) by hydrogen/deuterium exchange in a mixture of methanol-d and deuterium chloride in deuterium oxide. The structures, isotopic purity, and positions of uptake of deuterium were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Additional confirmation of the positions of deuterium exchange in stilbestrols was obtained from an analysis of the oxidation of dES-d8 to Z,Z-2,3',3'',5,5',5''-hexadeuteriodienestrol (beta-DIES-d6) and of the hydrogen/deuterium exchange reaction of hexestrol (HEX) to 3',3'',5',5''-hexestrol, (HEX-d4). Structural analysis and the determination of isotopic purity of the latter two compounds were also carried out by NMR and MS. The uptake of eight deuterium atoms by DES is postulated to proceed via two different reactions occurring simultaneously: 1. acid catalyzed deuteration of all four phenolic ortho-positions (3',3'',5',5''); 2. acid catalyzed deuteration of the olefin bridge with subsequent formation of deuterated psi-DES (3 or 4). Due to the equilibration between DES, psi-DES, and Z-diethylstilbestrol (cis-DES) in the acidic reaction mixture at 85 degrees C, the deuterated psi-DES is thought to rapidly rearrange to deuterated DES. Repeated deuteration will eventually form DES-d8 fully labeled in the 2,2,5,5 methylene positions.

Deuterium↗