Diethylstilbestrol Diphosphate Research Articles

Effect of Diethylstilbestrol Diphosphate on Activity of 5α-Reductase in Human Prostate

Following the intravenous drip infusion of diethylstilbestrol diphosphate (DES-DP), the diethylstilbestrol (DES) concentrations both in plasma and prostatic tissue obtained from patients with prostatic carcinoma were measured by radioimmunoassay and the effects of DES on the activity of 5 alpha-reductase in the prostate obtained from BPH patients were determined in vitro. Further, the changes in the activity of 5 alpha-reductase in the prostate from the BPH patients who received DES-DP infusion were also determined. The plasma and prostatic tissue concentrations of DES rapidly declined from 2.3 micrograms/ml and 1.6 micrograms/g wet weight 1 h after DES-DP infusion to 0.8 microgram/ml and 0.25 microgram/g wet weight 3 h after DES-DP infusion, respectively, and decreased gradually thereafter until 24 h. In in vitro study progressed by BPH specimens, the 5 alpha-reduction rate was completely inhibited by an addition of 5 x 10(-4) M of DES and the DES concentration on the inhibition rate of 50% was 4 x 10(-5) M. In in vivo study, the mean production rate of 5 alpha-dihydrotestosterone (DHT) in the control specimens of BPH without infusion of DES-DP was 14.0 +/- 3.4 nmol/15 min/mg protein and the production rate of DHT in the DES-DP infused specimens of BPH was 14.7 nmol/15 min/mg protein at 3 h and 15.2 nmol/15 min/mg protein at 12 h after the termination of DES-DP infusion. These results indicated that intravenously administered DES-DP did not act via the inhibition of 5 alpha-reductase in the prostatic cells for producing the clinical effects.

Effect of estrogen treatment on testicular gonadotropin receptors in prostatic cancer patients.

Effects of estrogen treatment on testicular human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH) receptors in man were investigated. Ten patients (aged 58 to 75, mean 67 years) with prostatic cancer were treated with diethylstilbestrol diphosphate (DESDP) (300 mg daily, oral administration). They were divided into two groups: 5 of them (aged 58 to 74, mean 67 years) were orchiectomized after 7 days of treatment and the remainder (aged 60-75, mean 67 years) after 6 months of treatment. hCG and FSH receptors in the resected testes of each group were measured and compared with those of age-matched prostatic cancer patients without any treatment (controls). After 7 days and 6 months of DESDP treatment, the number of hCG receptors decreased to approximately 53% and 24%, respectively, of that of the controls. FSH receptors in the testes of the patients treated with DESDP did not differ significantly from those of the controls.

2 New results on the pharmacokinetics of fosfestrol

2 New results on the pharmacokinetics of fosfestrol

3 High dose estrogens (diethyL stilbestrol diphosphate, DES-P) in prostate cancer

3 High dose estrogens (diethyL stilbestrol diphosphate, DES-P) in prostate cancer

Effects of diethylstilbestrol diphosphate (DES-P) and alpha-interferon on natural killer cell activity in vitro

リン酸ジエチルスチルベストロール (diethylstilbestrol diphosphate, DES-P) の in vitro における natural killer (NK) 細胞活性に与える影響を検討した. 8例の健康成人男子よりフィコール比重遠沈法を用いて分離した末梢血リンパ球を0.1mg/mlのDES-Pと16時間, 37℃下にて培養したところ, NK細胞活性はコントロール群 (48.6±10.5%) と比較すると有意に低下し (25.6±9.2%, p<0.001), 更にDES-PによるNK細胞活性の抑制効果は濃度および培養時間に依存した. また, 0.1mg/mlのDES-Pと16時間の培養により低下したNK細胞活性 (25.0±13.3%) は, 600IU/mlのα型インターフェロン (IFN-α) の添加により増強された (58.3±16.0%, p<0.001).われわれは, DES-Pにより低下したNK細胞活性が, IFN-αとの混合培養により回復する結果を得た. 今後, これら基礎的実験結果に基づき, エストロゲン療法時におけるIFNなどの Biological Response Modifiers の併用投与により, 宿主の免疫能の保持が期待される.

Relationships Between Estrogen Intake, Serum Testosterone, and Tumor Androgen, Estrogen, and Progesterone Receptor Levels in Diethylstilbestrol-Treated Rats Bearing the R3327 Prostatic Adenocarcinoma

The relationships between intake of diethylstilbestrol (DES), serum testosterone, prostate weight, and the tumor steroid receptor content were investigated in male Copenhagen x Fischer F1 hybrid rats bearing the R3327H tumor after treatment for 20 days with graded doses of diethylstilbestrol diphosphate. It was found that the wet weights of the ventral and dorsolateral prostate glands were positively linearly related to the log of the serum testosterone level (P < 0.001). The cellular distribution of androgen receptor (AR) in the tumors of the treated animals was consistent with the androgen deprivation brought about by the treatment, and nuclear AR concentrations were also linearly related to the log of the serum testosterone levels (P < 0.001). Although nuclear estrogen receptor could not be consistently demonstrated in these tumors, cytosol progesterone levels were linearly related to the amount of DES ingested during the treatment period (P < 0.001).

A phase II study of high-dose estrogens (diethylstilbestrol diphosphate) in prostate cancer.

Twenty-five patients with metastatic prostate cancer resistant to primary hormone therapy, received high-dose intravenous diethylstilbestrol diphosphate (Stilphostrol [Miles Pharm], DES-P) in a Phase II study using established response criteria. Objective response rate was 17%, while 22% of the patients were subjectively improved. Moderate gastrointestinal toxicity was reported in 10 patients (40%). Thromboembolic complications were seen in 2 (8%). The role of high-dose Stilphostrol in the treatment of hormone-resistant prostate cancer is limited.

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.

Direct inhibitory effects of natural and synthetic oestrogens on testosterone release from human testicular tissue in vitro.

Human testicular slices were incubated in vitro in order to examine the direct effects of natural and synthetic oestrogens on testosterone secretion. In the presence of human chorionic gonadotrophin (10 IU per ml), oestradiol-17 beta (1 or 10 micrograms per ml) and ethinyl oestradiol (0.1, 1 or 10 micrograms per ml) inhibited testosterone release into the media in a dose dependent manner. The addition of estramustine phosphate, estromustine, diethylstilboestrol or diethylstilboestrol diphosphate in comparable concentrations produced no significant effects on testosterone release.

Characterization of estrogen-induced progestin binding in cytosol of the R3327 prostatic carcinoma of the rat

High affinity binding of the synthetic steroids methyltrienolone (R1881) and promegestone (R5020) to cytosol protein from the Dunning (R3327) experimental prostatic carcinoma of the rat was investigated. Animals bearing tumours of approx 1.5 cm mean diameter were either left untreated, or were administered diethylstilbestrol diphosphate (DESP) in the drinking water in doses close to those used clinically for the treatment of human prostatic carcinoma. Tumours were excised after 10–40 days, and binding of [3H]R1881 and [3H]R5020 to tumour cytosol was characterized using Scatchard analysis, sucrose density gradient centrifugation, and steroid competition, under conditions optimal for the conservation and assay of progesterone receptor. Both ligands were bound in much higher concentrations by cytosol from DESP-treated tumours than from untreated tumours. Binding was of high affinity (Kd ∼- 1 nM), was specific for progestins, and sedimented in peaks at ~ 8S and ~ 4S in sucrose density gradients. We conclude the DESP treatment of rats bearing the R3327 prostatic carcinoma induces synthesis of progesterone receptor in this tumour.

Relationships between estrogen intake, serum testosterone, and tumor androgen, estrogen, and progesterone receptor levels in diethylstilbestrol‐treated rats bearing the R3327 prostatic adenocarcinoma

AbstractThe relationships between intake of diethylstilbestrol (DES), serum testosterone, prostate weight, and the tumor steroid receptor content were investigated in male Copenhagen x Fischer F1 hybrid rats bearing the R3327H tumor after treatment for 20 days with graded doses of diethylstilbestrol diphosphate. It was found that the wet weights of the ventral and dorsolateral prostate glands were positively linearly related to the log of the serum testosterone level (P &lt; 0.001). The cellular distribution of androgen receptor (AR) in the tumors of the treated animals was consistent with the androgen deprivation brought about by the treatment, and nuclear AR concentrations were also linearly related to the log of the serum testosterone levels (P &lt; 0.001). Although nuclear estrogen receptor could not be consistently demonstrated in these tumors, cytosol progesterone levels were linearly related to the amount of DES ingested during the treatment period (P &lt; 0.001).

Decreased Serum Phosphate Levels after High-Dose Estrogens in Metastatic Prostate Cancer. Possible Implications

Hypophosphatemia and osteomalacia have been described in patients with metastatic prostate cancer. The mechanism of hypophosphatemia in prostate cancer is not known. A decrease in serum phosphate levels was observed in 16 of 18 patients with metastatic prostate cancer treated with high-dose diethylstilbestrol diphosphate. To determine if the fall in serum phosphate was indeed due to diethylstilbestrol diphosphate, the data from several similar groups of patients treated with chemotherapy and combined chemohormonal therapy that included diethylstilbestrol diphosphate were re-examined. Fifty-eight patients were treated with doxorubicin, doxorubicin plus cis-platinum, doxorubicin plus diethylstilbestrol diphosphate, or diethylstilbestrol diphosphate alone. A significant decrease in serum phosphate levels was seen only in patients treated with diethylstilbestrol diphosphate. Hypophosphatemia and possibly osteomalacia in metastatic prostate cancer may be related to estrogen therapy.

Decreased serum phosphate levels after high-dose estrogens in metastatic prostate cancer: Possible implications

Hypophosphatemia and osteomalacia have been described in patients with metastatic prostate cancer. The mechanism of hypophosphatemia in prostate cancer is not known. A decrease in serum phosphate levels was observed in 16 of 18 patients with metastatic prostate cancer treated with high-dose diethylstilbestrol diphosphate. To determine if the fall in serum phosphate was indeed due to diethylstilbestrol diphosphate, the data from several similar groups of patients treated with chemotherapy and combined chemohormonal therapy that included diethylstilbestrol diphosphate were re-examined. Fifty-eight patients were treated with doxorubicin, doxorubicin plus cis-platinum, doxorubicin plus diethylstilbestrol diphosphate, or diethylstilbestrol diphosphate alone. A significant decrease in serum phosphate levels was seen only in patients treated with diethylstilbestrol diphosphate. Hypophosphatemia and possibly osteomalacia in metastatic prostate cancer may be related to estrogen therapy.

Radioimmunoassay of diethylstilbestrol in plasma of patients with prostatic carcinoma.

A method for the radioimmunoassay of diethylstilbestrol (DES) was established and it was used to measure the plasma concentration of DES in patients with prostatic carcinoma receiving intravenous drip infusion of 500 mg of diethylstilbestrol diphosphate (DES-DP). The sensitivity of this assay system was 40 pg per tube, with a recovery of 98%. The cross reactivity of the anti-DES antibody with estradiol, testosterone, and ethynylestradiol was less than 0.01% of DES, and that with DES-DP was 0.7%. In patients with prostatic carcinoma, plasma DES concentration at 6 and 24 hr after was declined to 10.2% and 4.4% of the level at the termination of intravenous administration of DES-DP, respectively; however, the concentration in patients with renal dysfunction was higher than that in ones with normal renal function.

Chemohormonal therapy of metastatic prostate cancer. A pilot study.

Combined chemohormonal therapy of metastatic prostate cancer has not been previously evaluated in patients failing primary hormones (estrogens and/or orchiectomy). The combination of Adriamycin and high-dose diethylstilbestrol diphosphate (Stilphostrol) was studied in 19 heavily pretreated patients, to document toxicity and patient acceptability. Major toxicity was myelosuppression, cardiac failure and venous thrombosis. Clinical improvement was noted in 10/16 (63%) of evaluable patients. Patients with pre-existing cardiac disease or venous thrombosis are not suitable for this therapy.

Disseminated intravascular coagulation in carcinoma of prostate: role of estrogen therapy

Advanced carcinoma of the prostate may present as disseminated intravascular coagulation and its sequelae. It is postulated that the slow release of thromboplastic material from tumor cells eventually overcomes normal homeostatic mechanisms. High-dose intravenous diethylstilbestrol diphosphate successfully reversed this coagulopathy in 2 cases of metastatic carcinoma of the prostate.

Toxic Reaction to Methotrexate in a Patient Receiving Penicillin and Furosemide: A Possible Interaction

<h3>To the Editor.—</h3> We recently treated a patient who was receiving daily prednisone and weekly methotrexate sodium therapy for dermatomyositis without ill effect. After furosemide and penicillin V potassium were added for other reasons, a severe toxic reaction to methotrexate developed, complicated by staphylococcal sepsis. We believe this toxic reaction to methotrexate may have resulted from the inhibition of methotrexate renal secretion by furosemide and penicillin. If true, this hypothesis raises the more general issue of possible serious drug interactions between methotrexate and the larger class of weak organic acid drugs. <h3>Report of a Case.—</h3> A 47-year-old man had biopsy-proven dermatomyositis and metastatic prostatic adenocarcinoma of nine months' duration. In March 1981 his prostatic cancer had been controlled by diethylstilbestrol diphosphate. However, the dermatomyositis had responded only partially to oral prednisone, and intravenous (IV) methotrexate therapy was begun with dosages that increased weekly. By April 16, he was receiving 50

In Vivo Selection of Androgen-Insensitive Cells in R3327-G Rat Prostate Tumors: Diethylstilbestrol Diphosphate Treatment Versus Orchiectomy&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;

Tumors grown in diethylstilbestrol diphosphate (DES)-treated rats grew significantly more slowly than tumors grown in orchiectomized animals, and tumors grown in orchiectomized animals grew significantly more slowly than tumors grown in controls (intact male rats). When these tumors (phase I) were dispersed and reimplanted into DES-treated, orchiectomized, or control rats in all possible combinations (phase II), a partial selection of androgen-insensitive cells was observed in tumors grown in DES-treated animals. Tumors grown in DES-treated phase I animals responded significantly less to DES treatment or orchiectomy in phase II. In contrast, tumors from phase I orchiectomized animals showed the same responses to orchiectomy in phase II. Since the administration of exogenous testosterone propionate prevented the growth rate inhibitory effects of both DES treatment and orchiectomy, the added effect of DES seemed to be antiandrogenic.

Androgen, estrogen, and progesterone receptors in peripheral and central zones of human prostate with adenocarcinoma

For this study a prostate gland was obtained by retropubic total prostatectomy performed on a seventy-six-year-old patient at Gunma University Hospital. A surgical pathologist separated the gland into peripheral and central portions which were clearly divided by a fibrous stroma. Histopathologic examination of each layer revealed different patterns of adenocarcinoma. The cytosol was incubated with [ 3H]R1881, [ 3H]estradiol, or [ 3H]R5020 in the presence or absence of 100 fold excess unlabeled competing, R1881, diethylstilbestrol, or R5020, respectively. In addition, to measure only androgen receptor all androgen tubes contained 1 × 10 −5 M triamcinolone acetonide. Using glycerol density gradient technique, concentrations of androgen, estrogen, and progestogen receptor were measured on both tissues. Specific receptor concentrations were determined by computation of the suppressible binding from the 8S region of the gradients. The ratio of the androgen receptor to progestogen receptor in the central zone was 1.5 to 2.0 while the same ratio in the peripheral zone was 0.3 to 0.5. Estrogen receptor could not be detected in either portion of this gland, possibly because the patient had received large amounts of diethylstilbestrol diphosphate prior to operation. This is the first report of varying hormone receptor profiles in different anatomic zones of the human prostate.

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 di-ethylstilbestrol 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.