bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostatein C3‐mRNA: A sensitive marker of androgen‐responsiveness in prostate explant cultures
Authors: Shao T. C. , Kong A. , Young C. , Chu W. H. , Tindall D. J. , Cunningham Glenn R.
Published: February 2007

Prostatein is an androgen‐dependent protein which is secreted by the rat ventral prostate. To determine if prostatein or its mRNA were responsive to androgen in vitro, prostate explants were cultured in media containing 0 or 25 nM dihydrotestosterone (DHT), estradiol (E2), or cortisol (F). Prostatein concentrations in medium were measured by radioimmunoassay at 2 and 4 days and in homogenates at 4 days. They were not changed significantly by any of these steroids. The concentration of the mRNA for the C3‐subunit of prostatein was determined by dot hybridization at 0, 2, 4, 6, and 8 days. It was decreased significantly by 2 days when compared with explants cultured in the presence of DHT and significant differences persisted through 8 days.

In conclusion, quantitation of the mRNA for the C3‐subunit of prostatein in short‐term cultures of ventral prostate explants appears to be more sensitive to changes in androgen concentration than does measurement of prostatein, per se. Prostatein C3‐mRNA may be a useful marker for in vitro studies of androgen agonists and antagonists.
Effects of androgen and antiandrogen treatment on canine prostatic arginine esterase
Authors: Juniewicz P. E. , Barbolt T. A. , Egy M. A. , Frenette G. , Dube J. Y. , Tremblay R. R.
Published: February 2007

A series of experiments were conducted to investigate the regulation of the primary secretory protein of the canine prostate, arginine esterase, by androgens and/or new antiandrogens under development. In the first experiment, castration decreased (P<0.05) prostatic arginine esterase levels relative to intact controls (0.26±0.1 and 17.0±0.1 μmole/min/mg protein, respectively). Treatment of castrate dogs with either 5, 10, or 20 silastic capsules (8 cm length) containing the androgen 5α‐androstane‐3α, 17β‐diol (3α‐diol) plus 1 capsule containing estradiol‐17β (E2) or the i.m. injection of 25 mg 3α‐diol and 0.25 mg E2 for 12 weeks resulted in a dose‐dependent increase (P<0.05) in prostatic arginine esterase activity (6.8±1.7, 19.0±3.6, 21.3±0.9, and 14.2±0.7 μmole/min/mg protein, respectively). In the second experiment, steroid treatment (10 3α‐diol plus 1 E2 silastic capsules) of castrate dogs for 12 weeks resulted in prostatic arginine esterase activity of 17.8±2.3 μmole/min/mg. Co‐administration of the steroidal androgen receptor antagonist Win 49,596 (WIN) at doses of 0.625, 2.5, 10, or 40 mg/kg/day p.o., dose‐dependently inhibited (P<0.05) prostatic arginine esterase activity (14.9±1.1, 14.3±1.3, 3.4±1.9, and 0.21±0.1 μmole/min/mg, respectively) to levels similar to that observed in castrate controls (0.14±0.03 μmole/min/mg). Administration of the nonsteroidal androgen receptor antagonist flutamide at 10 mg/kg/day p.o. to steroid‐induced dogs also inhibited (P<0.05) arginine esterase activity (0.07±0.02 μmole/min/mg). In the last experiment, treatment of intact dogs with WIN at 0.625, 2.5, 10, and 40 mg/kg/day for 16 weeks dose‐dependently reduced (P<0.05) arginine esterase levels (17.0±1.0, 16.3±1.5, 10.2±1.2, and 3.9±2.5 μmole/min/mg, respectively) compared to intact controls (14.4±1.2 μmole/min/mg). Histomorphologic and ultrastructural evaluation of prostates from dogs indicated that antiandrogen treatment resulted in glandular epithelial atrophy as well as a reduction in the number of secretory granules. The results of these experiments support that canine prostatic arginine esterase activity is under androgenic control, can be inhibited by antiandrogen treatment and may serve as a functional marker of the androgenic state of the prostate. Whether the effects of androgen and antiandrogens on prostatic arginine esterase is direct or indirect due to a general inhibitory effect on secretory epithelial cell function requires additional study. Furthermore, subject to further evaluation, the steroidal androgen receptor antagonist, Win 49,596, may be useful in the treatment of androgen‐dependent disorders of the prostate.
Experimental prostatitis in nonhuman primates: II. Ascending acute prostatitis
Authors: Neal Durwood E. , Dilworth J. Patrick , Kaack M. Bernice , Didier Peter , Roberts James A.
Published: February 2007

Bacterial prostatitis is a common cause of urinary tract infection in males, but little is known of its pathophysiology. To study this, we developed a nonhuman primate model using a wild‐type clinical isolate of Escherichia coli. Primates have a prostatic anatomy that is similar to humans, which makes them ideal as an animal model of this disease. The monkeys had a urethral inoculation of this organism and were then followed with urine, blood, and semen cultures, white blood counts, and renal scans. They were sacrificed at from 10 days to 4 weeks, and their genitourinary tracts histologically examined. The prostatitis paralleled that reported in humans, and we conclude that the infection occurs by the ascending route. The organisms causing the infection in man do so in our primate model, and the histologic change is also the same. Thus, the primate model holds promise for studies to help us understand this disease.
A comparison of Zoladex® and DES in the treatment of advanced prostate cancer: Results of a randomized, multicenter trial
Authors: Citrin Dennis L. , Resnick Martin I. , Guinan Patrick , Al‐Bussam Nazar , Scott Mark , Gau Timothy C. , Kennealey Gerard T.
Published: February 2007

This open, prospective study was conducted to compare ZOLADEX® (goserelin acetate implant) and diethylstilbestrol (DES) in the treatment of stage D2 prostate cancer. Sixtyseven patients were allocated to receive 3.6 mg of ZOLADEX® every 28 days by subcutaneous injection (n=48) or 3 mg of DES daily by oral administration (n=19). Median serum levels of testosterone were reduced to castrate levels (<50 ng/dl) within one month of therapy in each group and remained so for up to 120 weeks. According to modified criteria of the National Prostatic Cancer Project, 88% of patients in the ZOLADEX® group and 84% in the DES group were objective responders. Time to treatment failure and survival were not significantly different between groups, yet the confidence limits for the hazard ratios were wide. ZOLADEX® was better tolerated than DES. We conclude that ZOLADEX® is an alternative to DES in patients with stage D2 prostate cancer.
Steroid receptor profile in human prostate cancer metastases as compared with primary prostatic carcinoma
Authors: Ekman Peter , Brolin Jan
Published: February 2007

The steroid receptor profile in seven prostate cancer metastases was compared with the profile in seven primary prostate cancers. The secondaries were all lymph node metastases, obtained during pelvic lymphadenectomy, preceeding radical prostatectomy or irradiation. Cytosol androgen receptor content was higher in metastases, whereas the nuclear androgen receptor content was only one‐fourth that in primary cancer. Cytosol progesterone as well as estrogen receptor contents were markedly lower in metastases compared with primary cancer. The steroid receptor profile differed very little between primary cancer and normal tissue. Primary prostatic carcinoma is usually obtained at early stages of the disease, whereas metastases represent a dedfferentiated, more aggressive cell population. This may explain the low amounts of progesterone, estrogen, and nuclear androgen receptor levels. The total androgen receptor content was similar in metastatic and primary disease, however, with a shift towards a cytosolic predominance in metastases. Possibly androgen receptors in metastatic disease are “deactivated.”
Estramustine binding protein (EMBP) in rat R3327 dunning tumors: Partial characterization and effect of hormonal withdrawal, hormonal replacement, and cytotoxic treatment on its expression
Authors: Björk Per , Isaacs John T. , Hartley‐Asp Beryl
Published: February 2007

Expression of estramustine‐binding protein (EMBP) was determined in eight variants of the Dunning R3327 rat prostate adenocarcinoma. This secretory protein was previously isolated from the normal rat prostate and binds estramustine and estromustine, the metabolites exerting anti‐mitotic and anti‐proliferative activity of the anticancer agent estramustine phosphate (EstracytR). EMBP was found in relatively high amounts only in the androgenresponsive G and H tumors from intact hosts, whereas low (AT‐1, HI‐F) or nondetectable levels (HI‐S, AT‐3, MAT‐LyLu, MAT‐Lu) were obtained in the androgen‐independent tumors. Castration decreased EMBP expression in both G and H tumors, as did estradiol and estramustine when given separately to intact rats. Supplementation of castrates with exogenous androgen stimulated EMBP expression above the pre‐castration level and was further enhanced when combined with estradiol and in particular estramustine. Partial physicochemical characterization of EMBP in G and H tumors was performed by using ligand‐based and immunoblotting techniques. [3H]Estromustine was bound to cytosols and salt extracts from tumors with the same affinity and displayed similar surface‐charge distribution, sedimentation behavior, and subunit composition as found for ventral and dorsolateral prostatic tissue from tumor‐bearing rats. This study indicates that the synthesis of EMBP is under androgenic control and that its expression may be correlated to androgen responsiveness, metastatic potential, and androgen receptor content but not to growth rate and morphology of the tumors. EMBP may therefore provide a mechanism for concentration of cytotoxic activity at the target site in EMBP‐positive tumors and help in the evaluation of antitumor effects obtained when administering estramustine.
Histological changes in dunning prostate tumors and testes of rats treated with LH‐RH antagonist SB‐75
Authors: Szepeshazi Karoly , Korkut Edib , Szende Bela , Lapis Karoly , Schally Andrew V.
Published: February 2007

Rats bearing Dunning R‐3327 hormone‐dependent prostate tumors were treated with LH‐RH antagonist SB‐75 in the form of microcapsules for sustained delivery administered every 3 weeks and which released 24, 48, 72 μg/day respectively. The effects were compared with those of microcapsules of the agonist D‐Trp‐6‐LH‐RH releasing 25 μg/day. Both types of LH‐RH analogs significantly inhibited tumor growth over a period of treatment lasting 8 weeks. The effect of SB‐75 was dose‐dependent. The total inhibition of spermatogenesis, as well as atrophic signs in the prostate and seminal vesicles, demonstrated a marked suppression of the pituitary‐gonadal system by these analogs.

The histological signs of tumor regression were analyzed. The vascular content of tumors did not change after the treatments, but an increased amount of connective tissue was found in the treated tumors, especially after administration of SB‐75. Both the agonist and the antagonist caused a moderate decrease of the number of mitotic cells and a marked increase of apoptosis in the tumors. The apoptotic index, i.e. the percentage of tumorous glands showing signs of apoptosis, reached 40–50% in treated groups, compared to only 15% in controls. An apoptotic index of 60% was noted in a separate group of rats treated with 200 μg SB‐75/animal/day for 3 days. The signs of enhanced apoptosis disappeared 1 week after the short‐term treatment. The induction of apoptosis by LH‐RH analogs seemed to be of greater importance in tumor growth inhibition than their antimitotic effect. These results extend our previous observations on the efficacy of LH‐RH antagonists in inhibition of various cancers. This histopathologic evaluation clearly supports our contention that modern antagonists of LH‐RH, free of edematogenic effects, inhibit the growth of Dunning prostate tumors. Because of the immediate inhibitory effects, the use of LH‐RH antagonists might lead to an improvement in the clinical response in patients with prostate cancer.
In vivo assay for conversion of testosterone to dihydrotestosterone by rat prostatic steroid 5α‐reductase and comparison of two inhibitors
Authors: Toomey Richard E. , Goode Robin L. , Petrow Vladimir , Neubauer Blake L.
Published: February 2007

An in vivo assay for steroid 5α‐reductase in rat ventral prostate has been developed and used to compare the inhibitory activity of N,N‐diethyl‐4–methyl‐3–oxo‐4–aza‐5 a‐andro‐stane‐17 β‐carboxamide (4–MA) and 6–methylene‐4–pregnene‐3,20–dione (LY207320). Immature rats (70–80 g) received test compounds 30 min prior to s.c. injection of [3H]‐T. The rats were sacrificed 30 min later and the ventral prostates were analyzed for [3H]‐T metabolites. Intraprostatic [3H]‐T and [3H]‐DHT reached peak levels within 5 min after injection of [3H]‐T and declined to about 25% of peak levels after 2 hr. 4–MA was a very potent inhibitor of [3H]‐DHT formation with an estimated IC50 of 0.2 mg/kg. LY207320, an inhibitor of 5α‐reductase in vitro, was weakly active in vivo and did not achieve greater than 45% inhibition at high doses (> 200 mg/kg, s.c.). Tissue uptake of [3H]‐T was also inhibited by LY207320, which may contribute to its inhibitory activity on accessory sex organ growth in the rat.
Distribution of langerhans cells and HLA class II molecules in prostatic carcinomas of different histopathological grade
Authors: Bigotti Giulio , Coli Antonella , Castagnola Diana
Published: February 2007

We have investigated Langerhans cell (LC) distribution in 38 prostatic carcinomas, of various degrees of differentiation, by immunohistochemistry with a polyclonal anti‐S‐100 serum, furthermore evaluating the expression of HLA class II‐DR by neoplastic cells using a monoclonal antibody (MoAb) that reacts with a monomorphic determinant in formalin‐fixed paraffin‐embedded tissue. Antiserum to S‐100 protein identified LCs mostly in carcinomas ranging from grade 1 to grade 2, while LCs were inconspicuous in grade 4 and virtually absent in grade 5 cancers. Moreover, sections stained with the anti ‐HLA‐DR MoAb displayed an immunoreactivity, both cytoplasmic and apical, especially confined to neoplastic glands of low grade (1–2) carcinomas. Although we did not find a direct correlation between the two parameters under investigation and lymphoid infiltrate, we were able to document an increased number of HLA class II‐positive interstitial cells in low‐grade carcinomas, corresponding mostly to macrophages.

Our results indicate that LC number is inversely correlated to the histopathological grade and directly to the expression of HLA class II‐DR molecules by tumor cells; we believe that this might be important in understanding the more favorable biological behavior of low‐grade prostate carcinomas as opposed to the higher grades, since LCs and HLA class II molecules may provide a means of eliciting the immune response, both LCs and epithelial cells expressing HLA class II molecules being capable of direct antigen presentation to immune cells. In this context macrophages might play a primary role in controlling tumor progression. To the best of our knowledge this is the first time that an attempt is made to correlate LCs and HLA class II expression to histopathological grading of prostatic carcinomas. We would also suggest that the presence of LCs and HLA class II molecules, either singly or in combination, in carcinoma of the prostate represents a good prognostic indicator, being constantly associated with the clinically less aggressive low‐grade tumors. The evaluation of these two parameters might prove useful in the assessment of intermediate grades where no valid histologic criteria have been found to predict the clinical course of the disease.
Relation of endocrine‐paracrine cells to cell proliferation in normal, hyperplastic, and neoplastic human prostate
Authors: Bonkhoff Helmut , Wernert Nicolas , Dhom Georg , Remberger Klaus
Published: February 2007

The relative distribution pattern of the pan‐endocrine marker Chromogranin A (Chr A) and the proliferation‐associated Ki‐67 antigen was investigated in 20 prospectively sampled prostatectomy specimens. In cryostat sections, the Chr A immunoreactivity showed evidence of endocrine differentiation in all 15 prostatic adenocarcinomas. Nine tumors displayed a weak, 5 a moderate, and 1 adenocarcinoma a strong endocrine differentiation. These findings highlight the importance of endocrine differentiation in prostate malignancy that histologically resembles ordinary adenocarcinomas.

The simultaneous demonstration of Ki‐67 and Chr A revealed that in normal, hyperplastic, and neoplastic prostate tissue Chr A‐positive cells were preferentially situated in proximity to Ki‐67‐labeled cells. This relative distribution pattern of both markers may indicate that endocrine cells are involved in controlling cell proliferation through a paracrine hormonal mechanism. However, an obvious correlation was not found between the degree of endocrine differentiation and proliferative activity in prostatic adenocarcinomas. Furthermore, a coexpression of Ki‐67 and Chr A in the same (tumor) cells was not observed suggesting that the endocrine phenotype is only expressed in the G0 phase of the cell cycle as well as in normal, hyperplastic, and neoplastic conditions.
Morphological and functional similarities between cultured prostatic stromal cells and testicular peritubular myoid cells
Authors: Swinnen Kristien , Deboel Ludo , Cailleau Jean , Heyns Walter , Verhoeven Guido
Published: February 2007

A number of androgen effects on epithelial cells may be mediated by androgen‐regulated paracrine factors produced by underlying mesenchymal cells. In previous studies we demonstrated that prostatic stromal cells and testicular peritubular cells, derived from immature rats, produce mediators of androgen action with identical effects on Sertoli cells. In the present paper we further compared the morphological and functional characteristics of both mesenchymal cell types. Cultured prostatic stromal cells and testicular peritubular cells look identical under phase‐contrast microscopy, share the ability to form tubular structures and „balls”︁ when cocultured with Sertoli cells, and contain proteins immunoreactive with an antiserum against α‐smooth muscle isoactin. Two‐dimensional gel electrophoresis shows that the pattern of proteins produced by both cell types is nearly identical. Conditioned media from stromal and peritubular cells contain a factor that stimulates transferrin and cGMP production in Sertoli cells. The behavior of the active principle in the media from both cell types is comparable. On reverse‐phase HPLC the elution profile of this factor is comparable for media from both cell types. In conclusion, these data point to a striking similarity in the morphological and functional characteristics of mesenchymal cells cultured from the prostate and testis.
Prostate plasma membrane receptor: A hypothesis
Authors: Farnsworth Wells E.
Published: February 2007

Based on 50 years of emerging knowledge about and changing views of prostate biochemistry and physiology and especially on the belief that there is an underlying mechanism of androgen control, the hypothesis is developed and tested that the rates of proliferation, biosynthesis, metabolism, and secretion are modulated through the hormone‐sensitive Na,K‐ATPase of the plasma membrane. These preliminary experiments, constituting a novel synthesis of technologies from endocrinology, intermediary metabolism, and membrane transport, attempt to explain the extraordinary production and secretion of citrate and how this may be coupled to sustaining prostate cell number and function. Attention is focused on learning where androgen is bound and how it interacts with the Na,K‐ATPase. Both the dissimilar properties of epithelial and stromal cells in the separate regions of the acinus and the changing environment of growth factors in which these cells are bathed help account for their unlike reactivities during development and ongoing mature function. Little wonder that one hormone can have so many effects!
Effects of extracellular matrix components and dihydrotestosterone on the structure and function of human prostate cancer cells
Authors: Murphy Brian C. , Pienta Kenneth J. , Coffey Donald S.
Published: February 2007

The extracellular matrix (ECM) has been shown to play a major role in cell structure and function. Several studies have demonstrated that the ECM can alter cell morphology and effect DNA synthesis and gene expression. The ECM also interacts with growth hormones which have been shown to be located in or near the ECM where they are believed to effect cell structure and function. In the nontransformed cell, these ECM and hormone‐mediated effects appear to be tightly regulated and this is believed to be accomplished through cell receptor‐tissue matrix interactions. We, therefore, undertook a study to determine the effects of a variety of ECM components and the androgenic hormone dihydrotestosterone (DHT) on the structure and function of the human prostate cancer cell line, LNCaP. The effects of individual matrix components in the presence and absence of 1 nM DHT on the static and dynamic morphology, growth rate, and PSA production of the LNCaP cell line were studied. We determined that the ECM and DHT interact in complex ways to effect cell structure and function. DHT produced alterations in cytoplasmic structure that increased cell size and decreased the nuclear area/cytoplasmic area ratio. Dynamic cell structure as measured by cell motility was very sensitive to the ECM components and the presence of DHT. PSA and growth could be regulated by substratum and DHT and there was an inverse relationship between PSA production and growth rate. These data exemplify the complex interactions which occur between prostate cancer cells, ECM components, and exogenous DHT that are reflected in cell structure and function.
Distribution of estradiol‐17β hydroxysteroid oxidoreductase in the urogenital tract of control and neonatally estrogenized male mice: Immunohistochemical, enzymehistochemical, and biochemical study
Authors: Pylkkänen L. , Santti R. , Mäentausta O. , Vihko R.
Published: February 2007

The present study was conducted to investigate the regional distribution of the enzymes catalyzing the interconversion of the hydroxyl and carbonyl groups at C‐17 of the estrogen molecule within the male urogenital tract of adult mouse and to test the hypothesis, whether regional differences in the distribution are critical for estrogen responses.

The highest ratios of NADPH‐dependent 3H‐estrogen reduction to oxidation at C‐17 of cell‐free homogenates were obtained from coagulating gland and seminal vesicle as well as from the prostatic and lower intrapelvic urethra, which are considered the most estrogensensitive parts of the male urogenital tract. Both NADP‐ and NAD‐dependent oxidation of 3H‐17β‐estradiol were low or nondetectable at these sites. The epithelium of the lower and prostatic urethra as well as the periurethral collecting ducts were stained with the antibody prepared against human placental 17β‐hydroxysteroid oxidoreductase.

The NAD‐dependent 3H‐estradiol‐17β oxidase activity was highest in the bladder epithelium, and the activity declined sharply in the urinary tract from the bladder downward. The lowest detectable activities were found in vas deferens and prostate (combined ventral and dorsolateral lobes). The uneven distribution of estradiol‐17β oxidase activity may provide additional explanation for the regional differences of estrogen responses.

The NADPH‐dependent 17β‐reduction of estrone and the immunohistochemical staining of the human placental estradiol‐17β oxidoreductase antigenicity were not significantly altered after neonatal estrogenization. These findings do not lend any support to the idea that the increased estrogen sensitivity observed after neonatal estrogenization is associated with changes in 17β‐oxidoreduction. However, the possibility remains that there are specific sites (e.g., epithelium of prostatic urethra and collecting ducts) in which the changes in 17β‐oxidoreduction of estrogen does play a role in the regulation of estrogen action.
The relative efficacy of terazosin versus terazosin and flutamide for the treatment of symptomatic BPH
Authors: Lepor Herbert , Machi Grace
Published: February 2007

Pharmacotherapy for the treatment of BPH is currently being targeted to relax prostate smooth muscle (alpha blockade) and decrease prostate volume (androgen suppression). The objective of the present study was to determine the relative efficacy of terazosin vs. terazosin and flutamide (combination therapy) for the treatment of symptomatic BPH. Twenty‐nine males with symptomatic BPH were enrolled into this 6‐month open label study. The entry criteria included peak urinary flow rate between 4–15 ml/sec, a total Boyarsky symptom score greater than 7, and postvoid residual less than 300 ml. The daily dosage of terazosin was titrated to 5 mg over a 2‐week interval. A 750 mg daily dosage of flutamide was added following 1 month of terazosin monotherapy. The dosages were lowered if significant adverse events developed. Efficacy assessments were performed at 1 month (terazosin alone), 6 months (combination therapy), or at the time of early withdrawal from the study. The efficacy of combination therapy was evaluable in 24 patients receiving combination therapy. At one month, the mean peak urinary flow rate and mean total Boyarsky symptom score improved 38% and 56% relative to baseline, respectively. The present study confirmed the previously observed efficacy and safety of terazosin for BPH. The addition of flutamide did not result in statistically significant improvements in the peak urinary flow rate or total Boyarsky symptom score. The adverse events related to flutamide resulted in 16 dose reductions and 14 premature withdrawals. The role of combination therapy will require a randomized placebo controlled study sufficiently powerful to identify clinically and statistically significant improvements in objective outcome parameters relative to the monotherapies.
Temperature mapping in the canine prostate during transurethrally‐applied local microwave hyperthermia
Authors: Roehrborn Claus G. , Krongrad Arnon , McConnell John D.
Published: February 2007

Although the therapeutic effects of heat on tumors have been known for more than a century, only recently has hyperthermia been applied in the treatment of various solid tumors in a scientific fashion. In preliminary clinical trials, heat applied by transurethrally or transrectally placed microwave antennas has been used in the treatment of benign prostatic hyperplasia (BPH) with some success. However, basic information about prostatic temperature distribution and the cellular effects of hyperthermia is lacking. In an attempt to establish the safety of local hyperthermia of the prostate and the precise temperature distribution within the gland, we performed temperature mapping studies in canine prostates. Eight mongrel dogs were anesthetized, and a 16 Fr catheter with three helical coil microwave antennas was placed in the bladder through a perineal urethrostomy. Laparotomy was performed and the bladder opened. The antennas were placed under direct control in the prostatic urethra. Linear array and single point thermometers (Clini‐Therm TS1200 thermometry system) were placed (1) within the catheter alongside the antennas, (2) alongside the Foley catheter in the urethra, and (3) longitudinally and radially in the prostate for mapping of tissue temperature. Heating was performed with a 915‐MHz ISM frequency Z‐80 microprocessor controlled microwave power generator (Prostek 3000, Clini‐Therm Corporation, Dallas, TX) using 2–9 watts per channel (6–27 watts total) for 30 min to 1 hr.

Baseline body temperatures varied between the individual dogs from 37° to 38°C, but temperature distribution within the prostate was even prior to heating. With relatively low power (6 watts total), temperatures of ˜45°C were reached within the catheter. Therapeutic temperatures of ˜43°C were achieved in the periurethral prostate. Intraurethral temperatures were in general 1–2°C lower than within the catheter. The radial temperature dropoff in the prostate was sharp and about 1°C per 3‐mm distance from the catheter. This would limit the area of effectiveness to a periurethral zone of 1 cm in diameter in this model. No unsafe temperature peaks were noted either intraurethrally or between the prostate and the rectum during steady‐state conditions. Histologic studies demonstrated an intact rectal wall and varying degrees of prostatic inflammation and/or necrosis despite uniform treatment regimens administered. These studies demonstrate the short‐term safety of microwave hyperthermia in the canine prostate. Further studies will be necessary to determine the clinical efficacy and toxicity in men with BPH.
Effects of 6‐methylene progesterone on growth, morphology, and blood flow of the dunning R3327 prostatic adenocarcinoma
Authors: Damber J.‐E. , Bergh A. , Daehlin L. , Petrow V. , Landström M.
Published: February 2007

Copenhagen x Fisher F1 rats were implanted with the androgen‐dependent Dunning R3327 prostatic adenocarcinoma. When the tumors had median volumes of ca 470 mm3, the rats were castrated and/or treated with 6‐methylene‐4‐pregnene‐3,20‐dione (6MP) in different doses. Tumor growth inhibition occurred in all castrated and treated groups, with decrease in volume of the epithelial compartment in the intact group. Tumor volumes at the highest dose level of 6MP equalled those observed in the castrate group. Plasma levels of testosterone were within the normal range. The administration of 6MP surprisingly induced an increment of tumor blood flow in the castrate group. Also in castrated and testosterone‐supplemented animals, 6MP induced a reduction of prostatic tumor growth. Through the castration‐like effect on tumor growth, the use of 6MP may represent an attractive alternative to castration for treatment of androgen‐responsive prostate cancer.
Estrogen treatment of dunning tumors in castrated rats: Qualitative and quantitative morphology
Authors: Landström M. , Bergh A. , Thornell L.‐E. , Virtanen I. , Damber J.‐E.
Published: February 2007

Adult male rats bearing the Dunning R3327 prostatic carcinoma were randomized to the following treatments: intact controls, castration, and castration + estrogen. After a study period for 6 weeks the rats were killed and the tumors were analyzed morphometrically to determine the amount of epithelium, stroma, and connective tissue fibers in the tumors, and the nuclear size of large stromal cells. Cryostat sections were analyzed with immunohistochemistry using a panel of antibodies against cytokeratins, desmin, vimentin, fibronectin and collagens.

Addition of estrogen to castration resulted in an inhibition of tumor growth. The expression of cytokeratin 14 (a marker for basal myoepithelial cells) was reduced, but the expression of cytokeratin 18 (a marker for the luminal epithelial cells) was unaffected by estrogen. The amounts of collagen I, III and fibronectin (plasma and cellular types) were increased in the stroma, and the nuclear size of large stromal cells was also increased by estrogen. It is concluded that castration + estrogen treatment has effects in the epithelium and stroma of Dunning tumors that are qualitatively and quantitatively different from the effects of castration alone.
Prognostic significance of antigenic heterogeneity, gleason grade, and ploidy of lymph node metastases in patients with prostate cancer
Authors: Bazinet Michel , Hamdy Seif M. , R. Bégin Louis , Stephenson Robert A. , Fair William R.
Published: February 2007

We retrospectively evaluated 51 prostate cancer patients found to have pelvic lymph node metastases at the time of pelvic lymphadenectomy and 125I implantation. All of them were followed until death or for a minimum of 70 months. Rabbit polyclonal anti‐PSA, anti‐PAP, anti‐PSP‐94, and mouse TURP‐27 monoclonal antibodies were used in immunohis‐tochemical evaluation of the metastatic lesions. In addition, Gleason grade and ploidy were assessed and correlated.

No tumor with a Gleason grade of less than 7 could be found in the metastatic lymph nodes. Time to progression (P = 0.003), disease‐specific survival (P = 0.009), and overall survival (P = 0.003) were significantly shorter in patients whose tumors had a primary Gleason pattern of 5 (grade 9 or 10).

In the PSA study, patients whose tumors were reactive in more than 75% of cancer cells experienced significantly longer survival than those with less than 75% of cancer cells expressing PSA (P = 0.0006 log rank test). The means of overall survival ± SEM were 71.5 ± 5.0 and 34.9 ± 5.4 months, respectively. Similar correlations were found with disease‐specific survival and time to progression. Patterns of PAP expression and TURP‐27 reactivity were not prognostically useful, whereas PSP‐94 expression may add some additional information.

These data suggest that evaluation of tissue PSA heterogeneity in lymph node metastases may offer additional prognostic information on prostate cancer patients. Better prediction of individual prognosis may be possible with the combined use of Gleason grade, flow cytometry, and PSA expression.
Induction of proliferative lesions of ventral prostate, seminal vesicle, and other accessory sex glands in rats by N‐methyl‐N‐nitrosourea: Effect of castration, pretreatment with cyproterone acetate and testosterone propionate, and rat strain
Authors: Bosland Maarten C. , Prinsen Menk K. , Kroes Robert , Rivenson Abraham , Silverman Jerrold , Fiala Emmerich , Williams Gary M. , Weisburger John H.
Published: February 2007

Wistar (Cpb:WU), F344 or Sprague‐Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N‐methyl‐N‐nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague‐Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophichyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague‐Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU‐induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA +TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU‐induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.
The development of vascular supply of normal rat prostate during the sexual maturation: An angiographic study
Authors: Scolnik M. , Abramovici A. , Servadio C. , Tykochinsky G.
Published: February 2007

Vascular distribution of small blood vessels and capillaries using India ink angiography was studied in normal rat prostate from puberty up to full sexual maturation. The study included both macroscopic observation of the lobular vascular irrigation and the histological assessment of the periacinar capillary network. The topographical distribution of the main prostate branches was found to be different among the rat prostate lobes. The ventral lobe seems to be better irrigated than the dorsal one. The former being supplied by two parallel vascular systems, one irrigating the median two‐thirds of the ventral lobe, whereas the remaining external one‐third was found to be conjointly irrigated from the pericapsular branches of the fat pads. The blood vessels of the dorsal and lateral lobes emerged radially from a periurethral circle, with the dorsal branches ending blindly in the connective tissue of the pelvic cavity, whereas the lateral prostate was also conjointly irrigated by a dual vascularization from the pericapsular fat pad and the periurethral circle branch. The histological study revealed quantitative differences between the periacinar capillaries of both ventral and dorsal lobes. The capillary density was found to be age dependent and directly proportional to the acinar size. Small acini were less well irrigated by capillaries than were the larger ones.

The number of capillaries per acinar area increased progressively toward the maturation (day 90); thereafter, their number remained constant. Both prostate lobes showed identical patterns. The heterogeneous vascular networks among the rat prostatic lobes might offer an additional clue for their distinctive morphophysiological characteristics, which most probably play a role in various pathogenetic processes.
Cellular differentiation in prostatic explant cultures: Assessed by electron microscopy and X‐ray microanalysis
Authors: Halgunset Jostein , Tvedt KåRe E. , Kopstad Gunnar
Published: February 2007

A method developed for X‐ray microanalysis (XRMA) of cell monolayers cultured on Formvar film has been shown to be well suited for the study of explant cultures of human prostate. Adherence and epithelial cell outgrowth occur as readily on the formvar as on ordinary tissue culture plastic, giving rise to cultures with the same morphological characteristics. Conventional transmission electron microscopy revealed intracytoplasmic granules with the appearance of secretory vesicles. XRMA of electron‐dense intracytoplasmic granules in freeze‐dried cryosections showed significant local sequestration of calcium, but not of magnesium or zinc, elements that have previously been shown to colocalize with calcium in secretory granules in vivo. It is concluded that some aspects of the secretory phenotype are supported in this in vitro model. The factors regulating the expression of a differentiated phenotype in prostatic epithelium await further elucidation. XRMA may be useful in assessing the effects on secretory differentiation induced by variations in the Culture conditions.
The prognostic value of histological grading and mean nuclear volume in human prostatic cancer
Authors: Nielsen Karsten , Berild Grete H. , Bruun Eywin , Jøsrgensen Per , Weis Nina
Published: February 2007

Fifty‐eight consecutive patients diagnosed with prostatic cancer at transurethral resection in the period 1979‐1983 were classified using histological grade according to Shelley, and using an unbiased estimate of mean nuclear volume. We find that both histological grade and mean nuclear volume appear to be significantly associated with survival. In eight of nine patients still alive after 89‐130 months mean nuclear volume at diagnosis was in normal range and the histological grade showed a highly differentiated cancer in eight of the nine cases. These findings suggest highly differentiated cancer and normal range of mean nuclear volume may be important for long‐term survival. In patients with advanced disease requiring endocrine treatment both histological grading and mean nuclear volume estimates failed to show any prognostic properties with regards to time to progression and time of survival. In patients not subjected to endocrine treatment histologic grade, but not mean nuclear volume, was found to be significantly associated with survival. Subtle changes in disease progression may be diagnosed early by repeated biopsies due to the accuracy and high reproducibility of mean nuclear volume measurements; however, a single estimate of mean nuclear volume has not been shown to offer advantage over histological grade with respect to prognostic properties. α 1992 Wiley‐Liss, inc.
Hormonal regulation of prostate‐specific antigen (PSA) glycoprotein in the human prostatic adenocarcinoma cell line, LNCaP
Authors: Montgomery Benjamin T. , Young Charles Y.‐F. , Bilhartz David L. , Andrews Paul E. , Thompson Nels F. , Tindall Donald J. , Prescott James L
Published: February 2007

Prostate‐specific antigen (PSA) has emerged as the most useful marker for management of patients with prostate cancer. The regulation of this glycoprotein in vivo has important clinical implications. Indirect evidence indicates that the PSA glycoprotein might be regulated by androgens, and previous studies in this laboratory have demonstrated that PSA mRNA is upregulated by androgens. The current work reports a detailed study of PSA glycoprotein expression as influenced by steroid hormones in a human prostatic adenocarcinoma cell line, LNCaP. First, we have examined the steroid binding specificity of the androgen receptor in this cell line. In comparison with wild‐type rat androgen receptor in prostate, the receptor in LNCaP cells has altered affinity for a number of steroids or analogs such as progesterone (R5020), antiprogesterone (RU486), two antiandrogens (cyperoterone acetate and hydroxyflutamide), and an androgen metabolite (epitestosterone). However, its affinity for androgens (mibolerone, dihydrotestosterone, and testosterone) is not changed. The receptor does not bind to the synthetic glucocorticoids (triaminolone acetonide and dexamethasone) nor to a synthetic estrogen DES (diethylstilbestrol). The change of the steroid binding specificity of the receptor is correlated with a single mutation (A → G at nucleotide #876 relative to the initiation codon) of the steroid binding domain of the receptor. The mutation and alteration of steroid‐binding specificity of the androgen receptor is also correlated with PSA glycoprotein expression affected by different ligands tested. We have demonstrated that the PSA glycoprotein is upregulated by androgens and is affected by neither epidermal growth factor nor basic fibroblast growth factor. Moreover, PSA glycoprotein could be induced by R5020, estradiol, and epitestosterone; but neither glucocorticoids nor DES had any effect on PSA induction. Interestingly, although the antiandrogen, cyperotone acetate, had the ability to induce PSA, both RU486 and hydroxyflutamide could block androgen and progesterone induction of PSA glycoprotein. Therefore, we conclude that the PSA glycoprotein expression is influenced predominantly by androgens via its receptor, and the mutation of the receptor can affect the expression of this cellular gene by the steroids other than androgens.
Presence of calcitonin‐like immunoreactivity (iCT) in human prostate gland: Evidence for iCT secretion by cultured prostate cells
Authors: Shah Girish V. , Noble Mark J. , Austenfeld Mark , Weigel John , Deftos L. J. , Mebust Winston K.
Published: February 2007

Immunoreactive calcitonin (iCT) has been detected in human prostate tissue extracts as well as seminal plasma. The present studies were undertaken to examine whether iSCT (immunoreactive salmon CT‐like human peptide) co‐exists with iHCT (thyroid CT‐like substance) in human prostate tissue extracts, and whether these substances are secreted by primary prostate cells in culture. Since the local secretion of these substances seems to increase in some neoplasms, a second objective of the study was to examine whether basal secretion of iCTs from primary prostate cells is increased in carcinoma. The present results have shown that both iHCT and iSCT were present in prostate tissue extracts. The mean iHCT levels in extracts of benign hyperplastic prostates (BPH) were 0.59 ng/g prostate, and these were significantly lower than iHCT concentrations in prostatic carcinoma (PC) (2.53 ng/g). No significant differences in their iSCT contents were observed. However, the results from culture of over 90 individual prostate tissue specimens from BPH or PC indicate that primary prostate cells secreted detectable quantities of iSCT and the basal release of this material from PC prostate cultures was almost four‐fold higher than that from BPH prostate cultures.

These results suggest that a CT‐like immunoreactive material is secreted by primary prostate cells in culture, and the basal secretion of this material is significantly higher in PC cells as compared to BPH cells. Endogenous secretion of prostatic CT, and the elevation of its expression in PC suggest that it may serve as a regulatory factor in the pathophysiology of the prostate gland.
Comparison of finasteride (proscar®), a 5α reductase inhibitor, and various commercial plant extracts in in vitro and in vivo 5α reductase inhibition
Authors: Rhodes Linda , Primka Raymond L. , Berman Charles , Vergult Gerard , Gabriel Munir , Pierre‐Malice Marie , Gibelin Bruno
Published: February 2007

Human prostate was used as a source of 5α reductase. Compounds were incubated with an enzyme preparation and [3H]testosterone. [3H]‐dihydrotestosterone production was measured to calculate 5ã reductase activity. IC50 values (ng/ml) were finasteride = 1; Permixon = 5,600; Talso = 7,000; Strogen Forte = 31,000; Prostagutt = 40,000; and Tadenan = 63,000. Bazoton and Harzol had no activity at concentrations up to 500,000 ng/ml. In castrate rats stimulated with testosterone (T) or dihydrotestosterone (DHT), finasteride, but not Permixon or Bazoton, inhibited T stimulated prostate growth, while none of the three compounds inhibited DHT stimulated growth. These results demonstrate that finasteride inhibits 5α reductase, while Permixon and Bazoton have neither anti‐androgen nor 5α reductase inhibitory activity. In addition, in a 7 day human clinical trial, finasteride, but not Permixon or placebo, decreased serum DHT in men, further confirming the lack of 5α reductase inhibition by Permixon. Finasteride and the plant extracts listed above do not inhibit the binding of DHT to the rat prostatic androgen receptor (concentrations to 100 μg/ml). Based on these results, it is unlikely that these plant extracts would shrink the prostate by inhibiting androgen action or 5α reductase. © 1993 Wiley‐Liss, Inc.