bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of male and female sex hormones in cultured rat prostate
Authors: Mäkelä Sari I. , Santti Risto S. S. , Härkönen Pirkko L. , Suominen Jyrki J. O. , Martikainen Paula M.
Published: February 2007

The organ culture of the rat ventral prostate was chosen as a model to determine whether any of the estrogen effects in vivo on the prostate are direct and expressed at the hormone concentrations normally found in the male. During 2 weeks of culture, estradiol at the high concentration of 10−5 M blocked the androgenic activation of [3H]thymidine incorporation into DNA. The inhibition was localized in epithelium. Protein content of testosteronetreated explants and the accumulation of prostatein in the medium were considerably decreased, indicating inhibition of secretion. Antiandrogenic effects were not seen in morphology of estrogen‐treated explants. The lower concentrations (from 10−9 M to 10−6) of estradiol increased the volume density of epithelium from day 7 onwards. The height of epithelium was concomitantly increased. The volume density of epithelium as well as the percentage of acini with metaplastic changes were significantly increased. These epithelial changes were less pronounced in the presence of androgen, suggesting that physiological concentrations of androgen prevent the expression of estrogen action in the morphology of the prostate. A change in staining with peanut (PNA)‐ and wheat germ agglutinin (WGA)‐ lectins indicated defective secretory capacity in metaplastic epithelium. In spite of the increased protein content in the explants, no constant pattern of the changes in prostatein accumulation could be recorded. Although the concentrations of estrogen required to induce squamous metaplasia were still unphysiological, the occurrence of this abnormal differentiation of the prostatic epithelium suggests that the cooperative action of estrogen is involved in androgen‐dependent normal epithelial growth and possibly also in promoting growth of prostatic neoplasia.
Effect of cyproterone acetate in comparison to flutamide and megestrol acetate on the ventral prostate, seminal vesicle, and adrenal glands of adult male rats
Authors: El Etreby M. Fathy , Habenicht Ursula‐F. , Louton Thomas , Nishino Yukishige , Schröder Helmut G.
Published: February 2007

Cyproterone acetate (CPA) has a stronger inhibitory effect than megestrol acetate (MGA) and flutamide (FL) on the prostate and seminal vesicle of intact adult rats. Only in the clinically irrelevant regimen of castration and simultaneous androgen substitution is FL as a competitive androgen antagonist more potent than CPA and MGA. The latter inhibit complete involution of the ventral prostate but not of the seminal vesicle of castrated adult rats. This effect is very small in magnitude, cannot be increased by the use of higher doses, and is only reduced but not blocked by simultaneous treatment with high doses of FL. Further, CPA is unable to stimulate proliferation or restore the function of the involuted rat prostate. CPA and MGA inhibit adrenal weight in rats, thus indicating a glucocorticoidlike activity in this species. A critical review of all available data on the antiandrogenic, glucocorticoidlike, and possible paradoxical androgenlike activities of CPA in different animal experiments has no important bearing on the clinical effectiveness of CPA in the treatment of prostatic cancer.
Human PC‐3 prostate cell line DNA synthesis is suppressed by eicosatetraynoic acid, an in vitro inhibitor of arachidonic acid metabolism
Authors: Anderson K. M. , Wygodny J. B. , Ondrey F. , Harris J.
Published: February 2007

When human PC‐3 cells derived from a metastatic prostatic adenocarcinoma were incubated for 15 min to 4 h with the in vitro inhibitor of eicosanoid biosynthesis, eicosatetraynoic acid (ETYA) at 10–80 μM, DNA synthesis was suppressed. No reduction in cellular viability occurred, as judged by exclusion of trypan blue or unaltered release of 51Cr‐labeled proteins, and the inhibition was partially reversible. Indomethacin (to 12.5 μg/ml) did not inhibit DNA synthesis or alter the suppression of DNA synthesis by ETYA, suggesting a role for a lipoxygenase product in this effect. Addition of leukotriene B4 (LTB4) at 10−8 M did not reverse the inhibition of DNA synthesis produced by ETYA, nor did arachidonic acid (10−5–10−9 M) incubated with control cells mimic the effect of that agent. 3H‐arachidonic acid incubated with PC‐3 cells was rapidly incorporated into phospholipids and this labeling was differentially inhibited by ETYA. Positive modulation of PC‐3 cellular DNA synthesis by lipoxygenase products and inhibition of their synthesis by ETYA is one attractive hypothesis with which to account for these results. Other consequences of producing a selective deficiency of arachidonic acid in cellular membrane phospholipids and even the probable substitution of ETYA for arachidonic acid could also contribute to the inhibition of DNA synthesis by ETYA.
Androgen‐independent epithelial cells of the rat ventral prostate
Authors: Montpetit M. , Abrahams P. , Clark A. F. , Tenniswood M.
Published: February 2007

Androgen‐independent cell lines have been clonally selected from primary cultures of androgen‐dependent epithelial cells from the rat ventral prostate. These rapidly dividing epithelial‐like cells (RDE) have altered morphology and adherence characteristics. Unlike normal prostate epithelial cells, the RDE cell lines do not require androgens for cell division or cell survival. In the presence of physiological concentrations of testosterone, the isoelectric focusing patterns of prostatic acid phosphatases are abnormal in these RDE cells, and the prostate steroid‐binding protein genes are not expressed. The loss of androgen dependence is not due to the inability of RDE cells to metabolize testosterone to 5α‐dihydrotestosterone, the active androgen, since the RDE cell lines metabolize testosterone in a manner similar to normal androgen‐dependent epithelial cells. When RDE cells are grown on collagen matrices, the cells assume ductlike structures, similar to prostatic acini, although PSBP gene expression is not induced. When seeded into soft agar these cell lines form distinct foci, suggesting that they are potentially tumorigenic.
Three predominant proteins secreted by the human prostate gland
Authors: Lilja H. , Abrahamsson P.‐A.
Published: February 2007

Analyses of the proteins of azoospermic ejaculates from subjects with defective seminal vesicles demonstrated that three prostatic‐secreted proteins were predominant. Prostatic acid phosphatase (PAP), prostate‐specific antigen (PSA; or γ‐seminoprotein), and β‐microsemi‐noprotein (β‐MSP; or β‐inhibin), were identified as the three predominant proteins secreted by the normal human prostate gland. Immunohistochemical localization of these proteins, in the epithelium of normal prostatic acini and ducts, with the avidin‐biotin complex procedure demonstrated that each PAP‐immunoreactive cell was invariably immunoreactive both with PSA‐and β‐MSP‐monospecific antisera as well.
Tamoxifen in advanced prostate cancer: An ECOG pilot study
Authors: Horton John , Rosenbaum Charles , Cummings Frank J.
Published: February 2007

A group of 19 patients with advanced (Stage D) prostate cancer were treated with one of three dose levels of the anti‐estrogen tamoxifen, 10 mg (3 patients), 20 mg (8 patients), or 30 mg (8 patients) daily. Five patients had received no prior systemic therapy. The treatment was tolerated well, but no objective responses occurred.
A Case‐Control Study of Prostatic Cancer With Reference to Dietary Habits
Authors: Oishi Kenji , Okada Kenichiro , Yoshida Osamu , Yamabe Hirohiko , Ohno Yoshiyuki , Hayes Richard B. , Schroeder Fritz H.
Published: February 2007

A case‐control study of prostatic cancer which consisted of 100 patients with prostatic cancer, matched for hospital, age (±3 yr) and hospital admission date (±3 months) to patients with benign prostatic hyperplasia (BPH) and hospital controls, was conducted from 1981 to 1984. Low daily intake of beta‐carotene (RR = 2.13: 95% confidence interval, 1.20–3.77) and of vitamin A (RR = 1.94: 1.10–3.43), as compared to the intake of those substances by BPH controls, were factors significantly correlated with the development of prostatic cancer. Low daily intake of beta‐carotene (RR = 2.13: 1.20–3.77), as compared with hospital controls, were significantly correlated with prostatic cancer development. Infrequent intake of bread (RR = 2.40: 1.31–4.38), intended to represent a westernized diet, and of spinach (RR = 1.96: 1.01–7.73), a typical green and yellow vegetable, as compared to BPH controls and infrequent intake of spinach (RR = 4.55: 1.82–11.11) as compared to by hospital controls, were significant risk factors for prostatic cancer. Intake of carbohydrates, protein, fat, total calories, fibers, vitamin B and vitamin C were not correlated with the development of prostatic cancer.
Prediction of time to progression after orchiectomy by the nuclear androgen receptor content from multiple biopsy specimens in patients with advanced prostate cancer
Authors: van Aubel O. , Bolt‐de Vries J. , Blankenstein M. A. , Schröder F. H.
Published: February 2007

The nuclear androgen receptor (ARn) content of cancerous prostatic tissue has been investigated as a prognosticator for time to progression under endocrine therapy. In 1981 a prospective study was started to investigate whether the ARn content in biopsy specimens of patients with prostatic carcinoma predicts the duration of response following hormonal treatment. ARn was estimated by a microassay which involves extraction of nuclear pellets with a heparin‐containing buffer, exchange labeling of the nuclear extract with 3H‐R1881, and quantitation of the receptor with protamine sulphate precipitation. One hundred and fifteen patients with prostatic cancer entered this study; 47 patients had evidence of metastatic disease as proven by bone scan. Forty‐two patients were treated by orchiectomy; 37 of these patients are evaluable with a minimal follow‐up of 30 months. A relationship between the nuclear androgen receptor content and the time to progression following orchiectomy in these patients with metastatic disease of the prostate was not found. This could possibly be attributed to the heterogeneous nature of the prostatic tumor tissue with respect to the distribution of the ARn. We concluded that androgen receptor assay in needle biopsies, at least in this study, had no value for the prediction of the time to progression after orchiectomy.
Phosphotyrosine phosphatase activity of human and canine acid phosphatases of prostatic origin
Authors: Chevalier Simone , Landry Danielle , Chapdelaine Alcide
Published: February 2007

Human and canine prostatic specimens containing high levels of acid phosphatase (AP) activity were tested, at acid pH, for their ability to hydrolyze the major phosphoaminoacids present in phosphorylated proteins, phosphosertne (p‐ser), phosphothreonine (p‐thr), and phosphotyrosine (p‐tyr). The cleavage of a synthetic substrate, para‐nitrophenyl‐phosphate (p‐npp), was also measured as an indicator of AP activity; its inhibition by sodium‐L‐tartrate (T) was used as a criterion to identify prostatic acid phosphatase (PAP). It was found that: 1) the Km of p‐tyr and p‐npp were 2.0 mM and 0.41 mM, respectively, with similar Vmax values (0.078 and 0.087 μmoles of phosphate (Pi) liberated per minute per milligram of protein); 2) the ID50 were 0.25 mM and 0.50 mM with sodium otthovanadate (VO4) and T, respectively, using p‐npp as substrate—with p‐tyr as substrate, the values obtained were 0.016 mM and 0.11 mM, respectively; 3) activity toward p‐ser and p‐thr was minimal; 4) native PAP from dog seminal plasma, with a molecular weight of 90–100 kD, as determined by gel filtration on HPLC, hydrolyzed p‐tyr preferentially, and this phosphatase (Pase) activity was also strongly inhibited by both T and VO4; and 5) the AP present in human and canine prostatic tissue and cells, as well as in their secretions, also preferentially hydrolyzed phosphotyrosine, and it was inhibited by T and VO4. It is proposed that these p‐tyr Pases may be involved in the local regulation of prostatic growth.
Intraprostatic spermatozoa in the squirrel monkey
Authors: Nelson Glenn A. , Scimeca Joseph M. , Abee Christian A. , Gardner William A.
Published: February 2007

The recent observation of spermatozoa within the human prostate prompted this study to determine if spermatozoa were present in prostates of nonhuman primates. Six of 32 squirrel monkey prostates contained intraglandular spermatozoa. No associated pathologic lesions were found. Spermiophages were seen in one case. Although intraprostatic spermatozoa have been postulated to play a role in various prostatic diseases, a normal physiologic phenomenon cannot be excluded.
Heparin‐binding growth factor isolated from human prostatic extracts
Authors: Mydlo Jack H. , Bulbul Muhammad A. , Richon Victoria M. , Heston Warren D. W. , Fair William R.
Published: February 2007

Prostatic tissue extracts from patients with benign prostatic hyperplasia (BPH) and prostatic carcinoma were fractionated using heparin‐Sepharose chromatography. The mitogenic activity of eluted fractions on quiescent subconfluent Swiss Albino 3T3 fibroblasts was tested employing a tritiated‐thymidine‐incorporation assay. Two peaks of activity were consistently noted—one in the void volume and a second fraction which eluted with 1.3–1.6 M NaCl and contained the majority of the mitogenic activity. Both non‐heparin‐ and heparin‐binding fractions increased tritiated thymidine incorporation into a mouse osteoblast cell line (MC3T3), while only the heparin‐binding fractions stimulated a human umbilical vein endothelial cell line (HUV). No increased uptake of thymidine was seen using a human prostatic carcinoma cell line (PC‐3). Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) of lyophilized active fractions showed a persistent band at 17,500 daltons. The purified protein demonstrated angiogenic properties using the chick embryo chorioallantoic membrane (CAM) assay. Western blot analysis using antibodies specific to basic fibroblast growth factor (bFGF) or acidic FGF (aFGF) demonstrated that the former, but not the latter, bound to prostatic growth factor (PrGF), and inhibited its mitogenic activity as well. It appears that PrGF shares homology with basic fibroblast growth factors.
Effect of adrenalectomy, flutamide, and leuprolide on the growth of the dunning rat R‐3327 prostatic carcinoma
Authors: Kung Ted T. , Mingo Garfield G. , Siegel Marvin I. , Watnick Arthur S.
Published: February 2007

The R‐3327 prostatic tumor implanted in the male Copenhagen x Fischer F1 rat continues to grow because androgen is being supplied from an endogenous source. It follows that regimens which decrease the availability of androgen will retard the growth rate of the tumor. These experiments showed that castration, the antiandrogen flutamide, and the luteinizing hormone‐releasing hormone (LHRH) agonist leuprolide inhibited tumor growth. Adrenalectomy alone had no significant effect on tumor size and did not further retard the growth of the tumor in castrated rats. Further, under the conditions of this study, there was no significant difference in tumor growth rates between the groups of rats treated with either flutamide alone or flutamide combined with leuprolide. Total ablation of androgen may not be needed for maximal inhibition of tumor growth.
Differential expression of keratins in the basal and luminal compartments of rat prostatic epithelium during degeneration and regeneration
Authors: Verhagen Anja P. M. , Aalders Tilly W. , Ramaekers Frans C. S. , Debruyne Frans M. J. , Schalken Jack A.
Published: February 2007

The role of the different epithelial compartments during degeneration and regeneration of the rat prostate is examined on basis of intermediate filament protein (IFP) expression pattern. With the monoclonal antibodies RCK 103 and RGE 53, directed against specific keratins, it was possible to differentiate between the basal (RCK 103 +) and luminal (RGE 53 +) cells of the prostatic epithelium. After testosterone deprivation, by orchiectomy, an extensive and rapid cell loss was observed which appeared to affect mainly the luminal cells. In the process of prostate regeneration, induced by testosterone administration, using silastic implants, the luminal compartment rapidly regained its normal thickness. A heterogeneous population of morphologically luminal cells was observed showing keratin expression patterns intermediate between basal and luminal cells. These findings support the idea of a relationship between basal and luminal cells as being members of the same lineage of differentiation.
Activation of a Ca2+−Mg2+‐dependent endonuclease as an early event in castration‐induced prostatic cell death
Authors: Kyprianou Natasha , English Hugh F. , Isaacs John T.
Published: February 2007

Previous studies have demonstrated that castration‐induced androgen withdrawal results in the fragmentation of prostatic DNA into nucleosomal oligomers, and this process comprises an early event in the activation of programed cell death in the rat ventral prostate. This DNA fragmentation could be due to changes in the chromatin conformation increasing its sensitivity to preexisting nucleases and/or to increases in the activity of the nucleases themselves. However, comparative kinetic analysis of in vitro DNA fragmentation induced by exogenous nucleases did not reveal any differences in the sensitivity of prostatic chromatin between intact and castrated rats. In contrast to these negative findings, using [3H] DNA as an exogenous substrate, it was shown that within the first day following castration there was a twofold increase in a Ca2+‐Mg2+‐dependent nuclease activity without a concomitant increase in other nuclear nucleases. This Ca2+‐M2+‐dependent nuclease activation occurred coincidental with the initial increase in nuclear DNA fragmentation following castration and preceded the enhanced appearance of morphological changes characteristic of dying cells (i.e., apoptosis), as well as the major increase in prostatic DNA loss. These results suggest that castration‐induced androgen deprivation leads to a sequential activation of a Ca2+‐Mg2+‐dependent nuclease leading to the fragmentation of the genome into discrete nucleosomal‐sized fragments of DNA, subsequently followed by the fragmentation of the nucleus itself (i.e., apoptosis) and eventually with the complete digestion of the nucleosomal oligomers into component nucleotides (i.e., DNA loss).

Since the castration‐induced nuclease is dependent upon calcium ions for maximal activity, a potential role of intracellular calcium in the early events activating prostatic cell death was investigated. Acute disturbances in intracellular calcium homeostasis within the ventral prostate by means of a potent calcium influx blocker, nifedipine, simultaneous with castration, resulted in a significant delay in the biochemical and morphological changes associated with prostatic cell death (i.e., prostatic weight loss, prostatic DNA loss, and DNA fragmentation). These results point to a potential role of intracellular calcium levels in the mechanism of activation of castration‐induced death of the androgen‐dependent epithelial cells in the ventral prostate.
Calcium channel antagonists delay regression of androgen‐dependent tissues and suppress gene activity associated with cell death
Authors: Connor John , Sawczuk Ihor S. , Benson Mitchell C. , Tomashefsky Philip , O'Toole Kathleen M. , Olsson Carl A. , Buttyan Ralph
Published: February 2007

Androgen deprivation subsequent to castration of an adult male rat results in the regression of sexual accessory tissues. Regression of these tissues involves the massive death of androgen‐dependent cells. Using the rat ventral prostate gland as a model to study androgen‐programed cell death, we have characterized a series of molecular events that accompany its regression. This analysis has shown that there was a sequential induction of specific gene transcripts in the ventral prostate gland following castration. The first event in this cascade was an abrupt induction of transcripts encoding c‐fos. Since c‐fos expression has been linked to perturbations in intracellular Ca2+ levels, we investigated whether membrane‐mediated Ca2+ flux might be an early physiological step involved in the death of prostatic cells. To test this, rats were treated simultaneously upon castration with either verapamil or nifedipine, two different calcium channel antagonist drugs. Compared to the ventral prostate glands of untreated castrated rats, the glands of the calcium channel antagonist‐treated rats showed a significant delay in all parameters associated with regression (loss of wet weight and DNA content and delay in histological changes associated with prostatic regression). The seminal vesicle glands of treated rats also showed signs of delayed regression. Furthermore, calcium channel antagonists suppressed the induction of transcripts encoding both c‐fos and testosterone‐repressed prostate message‐2 (TRPM‐2), a gene expressed exclusively by dying cells, during the first 62 hr following castration. These findings further support a role for calcium ion influx in the pathway leading to hormonally programed prostate cell death, and suggest the intriguing possibility that modulation of this activity can alter the process by which cells die.
Prognostic value of serum hormone concentrations in prostatic cancer
Authors: Eriksson Ambjörn , Carlström Kjell
Published: February 2007

Seventy‐eight patients with cytologically and/or histologically confirmed prostatic cancer were randomly allocated to orchidectomy (ORX, n = 37) or combined intramuscular and oral estrogen treatment (ESTR, n = 41). Serum levels of testosterone (T), 17α‐ hydroxyprogesterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, total estrone (tEl;sum of unconjugated and conjugated estrone, ≥85% estrone sulfate), cortisol, luteinizing hormone, follicle‐stimulating hormone, prolactin, growth hormone, sex hormone‐binding globulin (SHBG), and albumin were determined prior to treatment and 12, 24, and 36 months after initiation of treatment.

Fifty patients responded to treatment or had stable disease, and 28 did not respond (12 in the ORX and 16 in the ESTR group). There was no association between pretreatment hormone or protein levels and outcome of the treatment, neither in the total material nor within either of the two treatment subgroups. Significantly higher pretreatment levels of cortisol and prolactin and significantly lower levels of T, tEl, and albumin and a significantly lower T/SHBG‐ratio (index on biologically active T) were found in patients with metastatic disease, compared with the patients without metastases. There was no association between testicular or adrenal androgens, SHBG, T/SHBG, and albumin values during treatment and the clinical outcome.

The differences found between metastatic and nonmetastatic disease probably simply reflect the more stressful and catabolic condition and generally poorer health in patients with disseminated malignant disease. Furthermore, the study does not lend any support to the hypothesis that indicates an important role of adrenal “rest androgen” in prostatic cancer tumor growth.
Effect of a 4‐methyl‐4‐aza steroid on androgen metabolism by rat ventral prostate epithelial and stromal cell cultures: Selective inhibition of 5α‐reductase activity
Authors: Orlowski John , Clark Albert F.
Published: February 2007

The effect of a potent steroid metabolic inhibitor, 17β‐N,N‐diethylcarbamoyl‐4‐methyl‐4‐ aza‐5α‐androstan‐3‐one (DMAA), on androgen metabolism was investigated in primary monolayer cultures of rat ventral prostate epithelial and stromal cells. Using testosterone (T) as substrate, 5α‐reductase (5α‐R) activity in both cell types was inhibited by greater than 98% at an inhibitor concentration of 1000 nM. The concentrations required to produce a 50% inhibition (IC50) were 7.4 and 9.0 nM for epithelial and stromal cells, respectively. To examine the specificity of this compound, its effect on other steroid‐metabolic enzymes was examined. DMAA at a concentration of 1,000 nM had no effect on 3α‐hydroxysteroid oxidase (3α‐HSORox), 3‐ketosteroid reductase (3α‐HSORred), and 6/7‐hydroxylase (6/7‐HSH) activities in both cell types; 17β‐hydroxysteroid oxidase (17β‐HSORox) activity, located primarily in epithelial cells, also was not influenced by DMAA. In contrast, epithelial 3β‐hydroxysteroid oxidase (3β‐HSORox) and 3‐ketosteroid reductase (3β‐ HSORred) activities were inhibited by 65% (P < .001) and 58% (P > .05), respectively, albeit the latter result was not statistically significant. Stromal 3β‐HSORox and 3β‐ HSORred activities were negligible; hence the effect of the inhibitor on these enzymes could not be assessed. In conclusion, DMAA is a relatively selective and potent inhibitor of 5α‐R activity in primary cultures of rat ventral prostate epithelial and stromal cells and should be a useful compound for antagonizing androgen‐mediated actions in the prostate and other androgen target tissues.
The periurethral zone of the prostate of the cynomolgus monkey is the most sensitive prostate part for an estrogenic stimulus
Authors: Habenicht Ursula‐F. , Etreby M. Fathy El
Published: February 2007

In man, benign prostatic hyperplasia (BPH) develops in the so‐called transition zone of the periurethral region of the prostate. Assuming that estrogens have a specific effect in this context, it would be expected that the periurethral glands are the most sensitive prostate part for an estrogenic stimulus. Morphological and imunocytochemical studies of serial sections of the prostate of castrated male adult cynomolgus monkeys treated with 17β‐estradiol for a period of three months revealed stromal proliferation, hyperplasia, and hypertrophy of the keratin‐positive basal cells and squamous epithelial metaplasia. These estrogen‐induced effects were most marked or found exclusively in the dorsal periurethral glands–a finding that is inconsistent with pertinent animal studies conducted thus far on this subject, and which further bears out the suitability of the cynomolgus monkey as a model for investigating BPH.
Effect of treatment on the expression of estramustine‐binding protein (EMBP) in prostatic cancer patients: An immunohistochemical study
Authors: Flüchter Stephan H. , Nelde Hans J. , Björk Per , Müntzing Jonas , Bichler Karl‐Horst
Published: February 2007

Estramustine‐binding protein (EMBP) was determined immunohistochemically in prostatic cancer (PC) specimens taken from patients before and after therapy. The EMBP staining intensity was correlated with the tumor malignancy grade in untreated PCs. The effect of various treatments (i.e., androgen‐withdrawal therapy, treatment with estramustine phosphate or radiation) on the expression of EMBP was also investigated.

Although a rabbit polyclonal antiserum raised against rat EMBP was used all through the study, all untreated PCs (n = 53) examined so far displayed a positive immunoreaction. The staining intensity was higher in moderately and poorly differentiated than in well‐differentiated tumors. Furthermore, two types of staining patterns were observed, that is, a diffuse type in about 70% and a focal in the remaining cases, which might reflect the multifocal appearance of PCs. The prognostic significance of these staining patterns is discussed.

Irrespective of the treatment used, EMBP staining was reduced to lower or undetectable levels in PCs where cytological as well as clinical regression were indicated after 6–30 months of therapy. In nonresponders or patients with refractory disease, however, EMBP expression reappeared and returned to pretreatment levels. In a short‐term follow‐up, the diminuation of EMBP was evident as early as 10 days after androgen‐withdrawal therapy and persisted as long as the patient responded to therapy. When estramustine phosphate was given as secondary treatment to hormone refractory PCs, EMBP decreased to undetectable levels in 3/4 of the specimens, suggesting response to therapy.

In conclusion, a decreased EMBP staining was well correlated with favorable cytological regression as well as with clinical regression, whereas unchanged staining intensity was indicative of clinical progression and a poor cytological regression grade. The high levels of EMBP in moderately and poorly differentiated tumors as well as in relapsing PCs, despite continued androgen withdrawal, strongly support a regulation of EMBP that is not under androgenic control. Based on the present findings, we suggest the use of EMBP as a therapy marker. Provided that immunohistochemical measurements can be performed on fine‐needle aspirates, EMBP analysis may be a direct and early means to distinguish between responding patients and nonresponders.
Hormonal effects of an orally active 4‐azasteroid inhibitor of 5α‐reductase in humans
Authors: Vermeulen A. , Giagulli V. A. , De Schepper P. , Buntinx A. , Stoner E.
Published: February 2007

The objective of this study was to estimate the minimum in vivo effective oral dose and duration of action of the competitive 5α‐reductase inhibitor MK‐906, a 4‐azasteroid, in humans. Plasma dihydrotestosterone (DHT), 5α‐androstane‐3α, 17β‐diol (AD), and its glucuronide (ADG), as well as urinary androsterone (A) and 5α‐pregnane‐3α, 11β, 17α, 21‐tetrol‐20‐one (aH4F) were determined in 54 healthy young men before and up to 7 days after a single morning dose of the compound. Twenty‐four hours after a single 5‐to 40‐mg dose (n = 24), plasma DHT levels decreased by a mean of ± 65%, with slow recovery of DHT levels. Seven days later, DHT remained decreased by ± 15%. Plasma AD levels decreased to a similar degree, whereas ADG levels decreased by about 75%, indicating inhibition of target tissue 5α‐reductase. Testosterone levels did not show any significant variations. The A as well as aH4F excretion in the 24‐hour urine test following drug administration decreased by 65%, indicating inhibition of the hepatic 5α‐reductase. After a single dose of 1.5 or 0.5 mg, DHT levels decreased by 50% 24 hours after administration, returning to normal within 5–7 days; at this dose, urinary A and aH4F excretion decreased by 50%. A single dose of 0.2 mg appeared to be slightly active as a 5α‐reductase inhibitor, but no statistically significant effect on DHT levels was observed after administration of a single 0.04‐mg dose. It is concluded that MK‐906 is a highly effective 5α‐reductase inhibitor in vivo. The effect on plasma DHT lasts for several days after administration of a single oral dose. The data suggest that both hepatic and extrasplanchnic 5α‐reductases are inhibited.
Regional distribution of opioidergic nerves in human and canine prostates
Authors: Aumüller Gerhard , Jungblut Thomas , Malek Bashar , Konrad Sabine , Weihe Eberhard
Published: February 2007

The regional distribution of opioidergic nerves in the juvenile and adult human prostate and in the adult canine prostate has been studied immunohistochemically using well‐characterized polyclonal antisera against multiple opioid peptides. Nerves displaying immuno‐reactivity (ir) for the proenkephalin (PRO‐ENK) derivatives met‐enkephalin (ME), leuenkephalin (LE), octapeptide, and heptapeptide (ordered in decreasing frequency) were present in the dorsolateral stroma of human prostate. In canine prostate, the situation was similar, but the number of opioid‐ir nerve fibers was lower than in human prostate. In both species, staining for the prodynorphin (PRO‐DYN) derivatives dynorphin A and α‐neoendorphin or staining for the pro‐opiomelanocortin (POMC)‐derived β‐endorphin was not visualized. In addition to their presence in nerve fibers, PRO‐ENK‐ir opioids (octapeptide) occurred in intrinsic ganglionic cells situated in the capsule. Octapeptide but not LE‐ir fibers supplied stromal blood vessels. The periurethral region and tissue adjacent to the ejaculatory ducts appeared to be devoid of opioid‐ir innervation. We conclude that endogenous opioids apparently exclusively derived from PRO‐ENK may fulfill important comessenger functions in the fine regulation of prostatic stromal tonus and of local vascular perfusion.
Prostatic growth effects of rat urogenital sinus and human prostatic tissue in the rat
Authors: Jarow Jonathan P. , Isaacs John T.
Published: February 2007

It is known that fetal urogenital sinus (UGS) implanted into one ventral lobe of an adult mouse prostate produces a significantly increased DNA content in that lobe. In our study, we attempted to determine whether that growth was of host or of graft tissue. UGS from fetal rats and ventral prostate from adult rats were implanted in various sites in syngeneic Fischer rats, alone or as a recombinant tissue complex. Human benign prostatic hyperplasia (BPH) tissue was implanted into the ventral prostate of adult, male, hooded nude rats to determine whether it stimulated prostatic growth. All UGS‐implanted in situ ventral lobes enlarged. Mean DNA content of UGS and ventral prostate implanted together in the flank was not different from the mean DNA content of UGS and ventral prostate implanted separately in the flank (P = 0.69). Mean DNA content of in situ control ventral lobe and of UGS grown singly in the flank was less than that of a UGS‐implanted in situ ventral lobe (P < 0.01). Thus overgrowth in the UGS‐implanted in situ ventral prostate was location‐dependent, but which tissue(s) enlarged remains unclear. Implanted human BPH tissue did not stimulate rat prostatic growth.
Androgen‐supported estrogen‐enhanced epithelial proliferation in the prostates of intact noble rats
Authors: Leav Irwin , Merk Frederick B. , Kwan Paul W.‐L. , Ho Shuk‐Mei
Published: February 2007

Using a stathmokinetic in vivo metaphase‐arrest technique, we studied cell proliferation and histological changes in the ventral (VP) and dorsolateral (DLP) prostate lobes of intact Noble (Nb) rats following a 16 week treatment with testosterone (T) or 5α‐dihydrotestosterone (DHT) administered separately or in combination with various estrogens. The combined treatment of rats with T and either estradiol‐17β, estradiol‐17α, or moxestrol induced florid dysplasia and markedly elevated the mitotic index (MI) in affected regions of the DLP. In contrast, joint DHT and estrogen treatment caused only mild proliferative lesions in this lobe. The separate administration of either androgens or estrogens suppressed epithelial proliferation in both the VP and DLP, but they differed in their histological effects on these tissues. Thus DHT or T alone maintained the morphological integrity of VP and DLP, whereas E2‐17β or moxestrol caused massive atrophy of both lobes. Although dysplastic foci were randomly scattered throughout the DLP, the most dramatic lesions occurred in periurethral ducts. With the exception of joint T and E2‐17α treatment, which induced proliferative alterations in the VP, dysplasia was always restricted to the DLP of all animals receiving both androgens and estrogens. Concomitant comparative stathmokinetic studies of the prostates of T‐treated castrates suggest that protracted androgen‐supported estrogen stimulation of the DLP is necessary to overcome factors that normally limit cell proliferation.
Prostatic carcinoma with melanosis
Authors: Furusato Masakuni , Matsumoto Izuru , Kato Hiroyuki , Takahashi Hiroyuki , Kawashima Yoshio , Wada Tetsuro , Suzuki Masafumi , Aizawa Shigeo
Published: February 2007

Melanosis in which melanin deposition is found in the epithelia and stroma or blue nevus of the prostate gland is an uncommon lesion, and the histogenesis is still unclear. To our knowledge, there have been only two case reports in which prostatic melanosis and prostatic adenocarcinoma were both present. This article reports a third case having this combination and discusses the existence of melanin pigment in the carcinoma cell with melanosis.
Prevention and treatment of experimental prostate cancer in lobund‐wistar rats. I. Effects of estradiol, dihydrotestosterone, and castration
Authors: Pollard Morris , Luckert Phyllis H. , Snyder David
Published: February 2007

The Lobund‐Wistar (L‐W) rat is unique in its susceptibility to spontaneous and induced metastasizing prostate adenocarcinomas (PAS). A single IV inoculation of methylnitrosourea (MNU) produced PAS in 20% of L‐W rats in 12 months. The combination of MNU plus two to seven slow‐release implants of testosterone propionate (TP) induced PAs in 50‐90% of rats respectively in an average of 11.5 months. The induction of PAs was prevented by early treatments of rats at risk with estradiol and less so with dihydrotestosterone (DHT). However, on a technical basis, the results were not significant. Treatments of MNU‐inoculated rats with estradiol, with DHT, or by castration, at intermediate points in the projected latency time of tumor development, reduced significantly the incidences of PA development. Rats in which overt PAS had already developed in response to 12 months of exposure to implants of TP did not respond to treatment by estradiol, DHT, or castration. Thus there are early stage(s) in induced prostate tumorigenesis in L‐W rats that are sensitive to modulating agents.
Secretion of epidermal growth factor and related polypeptides by the DU 145 human prostate cancer cell line
Authors: Connolly Jeanne M. , Rose David P.
Published: February 2007

Epidermal growth factor (EGF)‐like proteins may be important in regulating the growth of human prostate cancer cells and in the development of hormone independence. In the present study, we demonstrated that the DU 145 human prostate cancer cell line secretes EGF‐like polypeptides into serum‐free culture medium. The production of both authentic EGF and transforming growth factor‐α was demonstrated by specific radioimmunoassays. In addition to 6–7k monomers, immunoreactive higher molecular weight species were isolated by gel chromatography. The DU 145 cells also specifically bound human EGF, with both high‐ (Kd 1.8 × 10−10 M) and low‐ (Kd 1.1 × 10−9 M) affinity binding sites. Exogenous EGF stimulated 3H‐thymidine incorporation when cells were plated at low density in serum‐free culture medium, while at higher cell density neither cell division nor 3H‐thymidine incorporation was significantly altered. We postulate that DU 145 cells may be autologously stimulated by endogenously produced EGF and related polypeptides, which, under normal culture conditions, precludes any further effect of exogenous EGF.
Correlation between bone scans and serum levels of osteocalcin, prostate‐specific antigen, and prostatic acid phosphatase in monitoring patients with disseminated cancer of the prostate
Authors: Tarle Marko , Kovaćić Ksenija , Strelkov‐Alfirević Ana
Published: February 2007

Response of prostatic cancer bone metastases to therapy (androgen withdrawal and Estracyt) was studied in 43 patients by applying scintiscanning and radioimmunodetective measurement of serum osteocalcin (OC) values. The prostate‐specific antigen (PSA) and prostatic acid phosphatase (PAP) concentrations, as sensitive probes for the overall tumor spread, were used in parallel in a monitoring procedure. A significant rise in OC levels to values elevated from a pretreatment normal level has been found in patients with a partial osseous tumor remission, and this may be easily distinguished from normal and/or subnormal OC level in bony tumor progression (P < 0.01) and during stabilization in metastatic spread (P < 0.01). On these bases, differences between disease progression and the “no change” response category could not be statistically recognized (P > 0.05). A sharp increase in circulating OC level has been recorded 1 months after the beginning of the treatment leading to bone remodeling processes and precedes improvements in scintiscan appearance. Blood OC concentration seems also to be of utility 1) in distinguishing scintigraphic flare phenomenon from a slight bone scan progression and 2) when related to scans with regions of both disease improvement and worsening. Furthermore, serum OC concentration can frequently be measured through a noninvasive procedure, thus serving as a significant addition to bone scintigraphy.
Effects of castration and androgens upon prostatic proteoglycans in rats
Authors: Kofoed J. A. , Tumilasci O. R. , Curbelo H. M. , Fernandez Lemos M. , Arias N. H. , Houssay A. B.
Published: February 2007

In studies performed on male Wistar rats, castration induced atrophy of the prostate with a marked increase in the uronic acid content. The administration of testosterone propionate to castrated rats produced opposite effects. Fractionation of the glycosaminoglycans on cellulose microcolumns showed that the changes in uronic acid content in the dorsolateral lobes were due to variations in hyaluronic acid, chondroitin‐4‐sulfate, and dermatan sulfate, but in the ventral lobes, there were changes in all the chromatographic fractions. There were also changes in the physical properties of proteoglycans. In the ventral lobes, castration induced a wider distribution of molecular weight, increased density, and predominance of lateral chains of greater size. In the dorsolateral lobes, there was a decrease in molecular weight and density of proteoglycans and in the length of lateral chains. Opposite results were obtained when testosterone propionate was given to castrated rats. It is postulated that the effects of androgens upon prostatic growth would depend on an interrelationship between epithelium and stroma mediated by the proteoglycans.
Plasminogen activator activities in the ventral and dorsolateral prostatic lobes of aging fischer 344 rats
Authors: Wilson Michael J. , Ditmanson Janet V. , Sinha Akhouri A. , Estensen Richard D.
Published: February 2007

Plasminogen activator (PA) activities were measured in extracts of ventral and dorsolateral prostate lobes in Fischer 344 (F344) rats of different ages. Ventral prostates of 30‐month‐old animals demonstrated widespread epithelial atrophy, some foci of inflammation, in‐traglandular atypical hyperplasia and/or adenocarcinoma, and a marked increase in PA activities compared with younger animals. Both low‐ and high‐molecular‐weight forms of activator were found in zymograms and both forms of activator showed an increase at 30 months. However, the PA activity of the aged rats showed a greater resistance to amiloride inhibition, suggesting a greater relative increase in the tissue‐type activator activity than that of urokinase. These changes were not observed in the dorsolateral prostate. The lobe‐specific changes in activator activity appear related to dysplasia/neoplasia and not aging.
Quantitation of cytosolic and nuclear estrogen and progesterone receptor in benign, untreated, and treated malignant human prostatic tissue by radioligand binding and enzyme‐immunoassays
Authors: Mobbs B. G. , Johnson I. E. , Liu Y.
Published: February 2007

Estrogen receptor (ER) and progesterone receptor (PgR) were quantitated in benign and malignant human prostatic tissue by using radioligand binding assays (RBA) and enzyme‐immunoassays (EIA). Using a hydroxylapatite exchange method for ER, little or no nuclear ER (ERN) could be detected, but with the EIA both cytosolic (ERC) and ERN were detected in almost all specimens, although in meager concentrations. Tissue from patients with carcinoma had significantly higher ERC concentrations than tissue from patients with benign disease. Specimens from estrogen‐treated patients had significantly lower ERC:ERN ratios than those from untreated patients.

Progesterone receptor was detected in virtually all specimens by both methods, at concentrations higher than those of ER. Carcinoma tissue with a high malignant involvement contained significantly less PgR than benign tissue. Using either method, the highest concentrations of PgR were observed in tissue from carcinoma patients treated with estrogen. Overall, the data suggest that although human prostatic tissue contains only modest amounts of ER, this is active in that treatment with estrogen promotes association of this receptor with the nuclear fraction and increases PgR content.
Interactions of retinoic acid and androgens in human prostatic tissue
Authors: Jutley Jaswant K. , Reaney Sue , Kelleher Jerry , Whelan Peter
Published: February 2007

The effect of retinoic acid (RA) on testosterone metabolic pathway was investigated in hyperplastic and neoplastic human prostatic tissues, and also the effects of steroids on RA binding to its receptor. Steroids only had a minimal effect on the binding of RA by its receptor. The conversion of testosterone to DHT by 5α‐reductase was reduced in the presence of retinoic acid. The inhibition was probably due to competition with NADPH for enzyme binding sites. The degree of inhibition found with retinoic acid at a concentration of 10−4M was greater for hyperplastic (41%) than that for neoplastic tissue (24%). The inhibition of 5α‐reductase by retinoic acid was dose‐dependent. The activity of 5α‐reductase is significantly less in neoplastic compared with hyperplastic tissue.
Relationship of age to histologic grade in prostate cancer
Authors: Borek Deborah , Butcher David , Hassanein Khatab , Holmes Frederick
Published: February 2007

We studied 4,968 cases of prostatic carcinoma to determine if there is a relationship between tumor grade and patient age at diagnosis. Cases were stratified into arbitrary age groups and classified as either better differentiated (Grades I and II) or worse differentiated (Grades III and IV). The 4,596 graded cases were distributed by stage as follows: Local 3,451 (75%), Regional 509 (11%), and Distant 636 (14%). When patients in all stages were considered together, the percentage of men with better differentiated tumors dropped from 77.8% of patients under 60 to 67.5% of patients 80 or older (P<0.00001). This trend for older patients to have more poorly differentiated tumors was also seen in patients with localized disease (P>0.0005). The fact that occult, biologically inactive prostate cancer is common in older men has led some to extrapolate that clinically apparent disease follows a more benign course in the elderly. Our findings suggest that, on the contrary, elderly men with clinically apparent disease have worse differentiated tumors than their younger counterparts.
R 75251, a new inhibitor of steroid biosynthesis
Authors: Bruynseels J. , De Coster R. , Van Rooy P. , Wouters W. , Coene M.‐C. , Snoeck E. , Raeymaekers A. , Freyne E. , Sanz G. , Vanden Bussche G. , Vanden Bossche H. , Willemsens G. , Janssen P. A. J.
Published: February 2007

R 75251, a new imidazole derivative, inhibited the conversion of androgens to estrogens, of progestins to androstenedione and testosterone, and of 11‐deoxycorticosterone to corti‐costerone in human placenta microsomes, subcellular fraction of rat testis, bovine adreno‐cortical mitochondria, in cultured rat granulosa, testicular and adrenal cells, respectively. In vitro, no effect on cholesterol synthesis and cholesterol side‐chain cleavage was found at concentrations up to 10 μM. In rat granulosa cells, no effect on progesterone production was detected. In vitro, no effect on steroid radioligand binding was observed.

In male volunteers, a single dose of 300 mg of R 75251 significantly lowered plasma testosterone and estradiol for 24 hours and increased plasma concentration of 17α‐hydroxy‐progesterone and progesterone.

As compared with ketoconazole high dose (600 mg b.i.d), R 75251 (300 mg b.i.d) was at least as efficacious as inhibitor of testosterone synthesis when studied during ACTH stimulation. In contrast to ketoconazole, R 75251 did not significantly affect circulating adrenal androgen levels in male volunteers. Precursors of gluco‐ and mineralocorticoids such as 11‐deoxycortisol and 11‐deoxycorticosterone accumulated more than after ketoconazole administration.

The data show that the cytochrome P450‐dependent aromatase, 17‐hydroxylase/17,20‐lyase, and 11‐hydroxylase are the target enzymes for R 75251.