estramustine and Prostatic-Hyperplasia

To determine whether the inhibition of estrogen-related effect in the prostate would be of value in the management of benign prostate hyperplasia (BPH), we examined the effect of TZA-2209, a new steroidal aromatase inhibitor, on the prostate in three of six castrated beagles that received 75 mg/week androstenedione. The three other animals served as controls. Sequential measurements of prostate volume by transrectal ultrasonography showed that the volume in TZA-treated dogs was significantly decreased compared with that in the controls. Prostatic aromatase activity was suppressed by TZA administration. Histopathologically, the stromal component was increased and glands were atrophied by androstenedione treatment. TZA administration increased the volume of the glands. Immunohistochemical detection of estramustine-binding protein showed more positive staining of the protein in the glands that were increased in volume by TZA administration. We concluded that the aromatase inhibitor effectively antagonized the estrogen-related stromal changes, however, this action was accompanied by stimulation of the glandular component due to the accumulation of androgens, the substrate of the aromatase. In the light of these findings, we suggest the simultaneous treatment for the androgen-glandular component route in the prostate is necessary for the effective management of BPH.

Topics: Androstenedione; Animals; Aromatase Inhibitors; Carrier Proteins; Castration; Dogs; Estramustine; Immunoenzyme Techniques; Male; Organ Size; Prostate; Prostatic Hyperplasia; Prostatic Secretory Proteins; Stromal Cells; Testolactone

For the purpose of elucidating whether the biological characteristics of estramustine-binding protein (EMBP) are different in benign prostatic hypertrophy (BPH) and prostatic carcinoma (PC) and also to determine the clinical value of EMBP in the tissue, the EMBP concentration in 19 patients with BPH and 26 with untreated PC was measured by means of radioimmunoassay (RIA) using an antibody raised against EMBP obtained from the rat ventral prostate and compared simultaneously with the dihydrotestosterone (DHT) level in the same tissue. The level of serum prostate-specific antigen (PSA) was also measured in these patients. The EMBP concentration was significantly correlated with the tissue DHT level in BPH and well-differentiated PC (r = 0.745, p < 0.0001), whereas it did not correlate in moderately and poorly differentiated PC (r = -0.159, p = 0.542). By comparing well-differentiated PC with moderately and poorly differentiated PC, the EMBP concentration was significantly lower in the former than in the latter two conditions (p < 0.005) in spite of the highest tissue DHT level in well-differentiated PC. The ratio of the EMBP concentration to the DHT level in moderately and poorly differentiated PC was significantly higher when compared with that observed in either BPH or well-differentiated PC (p < 0.005, respectively). However, the level of serum PSA did not reflect the histological differentiation of PC. These results suggest that: (i) the correlation of the EMBP concentration to the DHT level changed with the progression of the histological grade, and (ii) the ratio of the EMBP concentration to the DHT level in the tissue is clinically valuable in elucidating the biological potential of individual tumors.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Carrier Proteins; Dihydrotestosterone; Estramustine; Humans; Male; Middle Aged; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Radioimmunoassay

The expression of estramustine-binding protein (EMBP) was studied immunohistochemically in whole-mount prostate sections. Specimens were taken from the prostates of 15 patients who had undergone total prostatectomy due to localized (TOd-T2 NO MO) prostatic cancer (PC). Almost all the examined whole-mount sections displayed areas with prostatic intraepithelial neoplasia (PIN). PIN is regarded as the main precursor of invasive PC. High- and low-grade PIN expressed EMBP. The average positively stained areas accounted for averages of 69.2% and 48.7%, respectively. High-grade PIN contained the highest EMBP levels of all the investigated (benign and malignant) epithelia, followed by moderately differentiated PC. With regard to areas with PC, the highest levels of EMBP expression (61.3%) were observed in moderately differentiated PC; poorly differentiated PC came second. Of all the examined epithelia, EMBP levels were lowest in well-differentiated PC (25.8%). Normal prostatic epithelia and hyperplasia were characterized by low EMBP expression, although somewhat higher than well-differentiated PC. A moderate expression (45%) was observed in the seminal vesicles. According to these results, EMBP was expressed mainly in the diseased peripheral zone (PZ), where PIN and prostatic cancer have their highest prevalence.

Topics: Aged; Carrier Proteins; Epithelium; Estramustine; Humans; Immunoenzyme Techniques; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Seminal Vesicles

Estramustine, an estradiol-17 beta and nornitrogen mustard complex, is used in the treatment of advanced prostatic carcinoma. A specific estramustine binding protein (EMBP) is important for its cytotoxic action, and the presence of EMBP has previously been demonstrated in rat and human prostatic cancer tissue. Significant levels of EMBP were detected by radioimmunoassay in human brain-tumor tissue. The EMBP concentrations (expressed as ng/mg protein) in 16 astrocytomas (mean 2.6 ng/mg, range 0.5 to 6.2 ng/mg) and seven meningiomas (mean 5.1 ng/mg, range 0.3 to 9.3 ng/mg) were significantly higher than that found in four samples of epileptic brain (mean 0.7 ng/mg, range 0.5 to 1 ng/mg) and 18 samples of normal brain (mean 0.5 ng/mg, range 0.2 to 1.0 ng/mg). The uptake, metabolism, and antiproliferative effects of the prostatic anticancer agent estramustine have been previously demonstrated in cultured glioma cells. The presence of EMBP may suggest a selective binding and effectiveness in human brain-tumor tissue.

Topics: Astrocytoma; Brain; Brain Neoplasms; Carrier Proteins; Epilepsy; Estramustine; Female; Glioma; Humans; Male; Meningeal Neoplasms; Meningioma; Prostatic Hyperplasia; Prostatic Secretory Proteins; Radioimmunoassay; Reference Values

An immunohistochemical technique for determination of "estramustine-binding protein" (EMBP) in rat prostate is described. The localization and staining intensity of this protein were correlated to prostatic morphological structures in intact animals and at different time intervals after androgen deprivation by castration. EMBP was found almost exclusively in epithelial cells, while the fibromuscular stroma seemed to be negative. Intracellularly, immunostaining was confined to the cytoplasm, but was absent in nuclei. In intact rats, acinar lumina demonstrated heavy immunostaining, indicating secretion of EMBP. Orchiectomy caused a diminution of EMBP expression as well as secretion, suggesting that EMBP synthesis is under androgenic regulation. Human benign hyperplastic and cancerous prostatic specimens were also examined. All human specimens examined so far exhibited positive epithelial staining although of varying intensity. Therefore, this immunohistochemical technique may be used for studying the correlation of EMBP with tumor malignancy grade and for clinical investigations of how various treatments affect EMBP expression in prostatic carcinomas.

Topics: Animals; Carrier Proteins; Cross Reactions; Estramustine; Humans; Immunoenzyme Techniques; Immunohistochemistry; Male; Nitrogen Mustard Compounds; Orchiectomy; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Rats; Rats, Inbred Strains; Species Specificity

Estramustine binding protein (EMBP) was purified from the ventral prostate of the rat using DEAE-cellulose chromatography, concanavalin-A affinity chromatography and DEAE-sepharose chromatography. At the final step of the purification, two different peaks (Peaks A and B) of A280 nm were obtained. Peak A had a high binding activity to [3H] estramustine. On the other hand, Peak B had a low binding activity. On the analysis of polyacrylamide gel electrophoresis, Peak A gave two protein bands, whereas Peak B gave a single band. The molecular weight of the markedly stained band of Peak A was approximately 27,000, whereas that of Peak B was 18,000, as estimated by analysis of Fargusson's plot. The antibody against Peak B was used for establishing a radioimmunoassay (RIA) of EMBP. The sensitivity of this assay system was sufficient to measure of 1 ng of EMBP. The dilution curve of rat prostatic cytosol was paralleled with the standard curve. As a result obtained from this RIA, the mean concentration of immunoreactive EMBP was 8.01 ng/mg cytosol protein in human benign hyperplastic prostate (BPH) and 4.28 ng/mg protein in human prostatic carcinoma (PC), respectively. These results here obtained indicate that human prostate has an immunoreactive protein to the purified EMBP obtained from the ventral lobe of rat prostate.

Topics: Animals; Carrier Proteins; Chromatography; Electrophoresis, Polyacrylamide Gel; Estramustine; Humans; Male; Molecular Weight; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Prostatic Secretory Proteins; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values

The assay of hormone receptors in neoplastic tissues recognizes their sensitivity or autonomy with regard to the hormonal action. The hormone dependency of the activity of neoplastic tissues can be employed to select the cases having the highest probability to be benefited by the treatment with anti-hormones, castration or hypophysectomy, as in breast and prostatic cancers. Examining the case for prostatic cancer, the authors indicate that there is a good correlation between the predictive assay and the clinical evolution of the treated prostatic carcinoma employing the determination of cell receptors for 5-alpha-dihydrotestosterone (DHT) by exchange at 15 degrees C with the synthetic steroid methyltrienolone. The electrophoretic determination of binding of DHT to cell receptor a 4 degree C is a much less efficacious procedure.

Topics: Diethylstilbestrol; Electrophoresis, Agar Gel; Estramustine; Estrenes; Humans; Male; Metribolone; Orchiectomy; Prognosis; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen; Receptors, Estradiol

23 patients with prostatic cancer were treated with (Estracyt) estramustine phosphate disodium, (Hexron) hexestrol, and (Honvah) diethylstilbestrol 4, 4-diphosphoric ester. 16 cases were given 560-840 mg of Estracyt, 6 cases 30 mg of Hexron, and 1 case 200 mg of Honvan orally daily. Fasting serum lipids and lipoproteins fractions were measured before and during this treatment with these drugs. The results were as follows. 1) In the 1-2 months of Estracyt administration a decrease of (TC) total cholesterol and extreme increase of (TG) triglycerides were confirmed. 2) In those 5 cases where 840 mg of Estracyt/day was given, almost no difference was observed in their TC, (NEFA) free fatty acids, or (PL) phospholipid values. 3) Cardiovascular complications although not serious, were found in 2 cases of the group receiving Estracyt. With these 2 cases, their beta+pre-beta/alpha lipoprotein fraction ratio decline was either very gradual or rather turned to increase markedly despite the extreme rise of their TG values. 4) The serum lipid values in the group receiving Hexron did not show any obvious changes in TG. These values did not change much in the first 5-6 months but an increase was seen between 7-9 months. Lipoprotein fractions were similar to those in the Estracyt group. 5) With those receiving Honvan, TG values began to rise 2-4 weeks following administration. In view of the above results, the coronary risk factors which are a consequence of Estracyt, Honvan, or Hexron ingestion for treatment of prostatic cancer must be taken very seriously and must be closely monitored. (Authors' modified)

Topics: Aged; Diethylstilbestrol; Estramustine; Hexestrol; Humans; Lipids; Lipoproteins; Male; Middle Aged; Nitrogen Mustard Compounds; Prostatic Hyperplasia; Prostatic Neoplasms

Topics: Animals; Carrier Proteins; Cytosol; Estramustine; Humans; Male; Nitrogen Mustard Compounds; Prostate; Prostatic Hyperplasia; Prostatic Secretory Proteins; Protein Binding; Rats

Topics: Estramustine; Humans; Male; Progestins; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen; Receptors, Estrogen; Receptors, Steroid

Specific cytoplasmic androgen and estrogen binding has been measured in human benign prostatic hypertrophy and carcinomatous tissue. In vitro support for the binding of estramustine phosphate (Estracyt) to both estradiol- and dihydrotestosterone-binding sites is presented, which in part could explain the clinical effect of estramustine phosphate when pure estrogenic compunds are not effective.

Topics: Androgens; Binding Sites; Cytoplasm; Estradiol; Estramustine; Estrogens; Humans; Male; Nitrogen Mustard Compounds; Prostatic Hyperplasia; Prostatic Neoplasms