bluuebunny/crossref_metadata_2025 huggingface dataset:
High‐affinity L‐aspartate transporter in prostate epithelial cells that is regulated by testosterone
Authors: Lao Lixing , Franklin Renty B. , Costello L. C.
Published: February 2007

The prostate gland produces and secretes extraordinarily high levels of citrate. Studies with rat ventral prostate (VP) have demonstrated that aspartate can serve as a four‐carbon source of oxalacetate in the synthesis of citrate. To achieve this, prostate secretory epithelial cells must contain a transport system for the active uptake of aspartate from circulation. The present studies with VP epithelial cells confirm the existence of a Na+ ‐dependent high‐affinity L‐aspartate transporter. The transporter has an optimal pH ≈ 7.5 and is temperature dependent. It appears to be an anionic amino acid transporter capable of transporting L‐glutamate but not basic or neutral amino acids. The transporter is inhibited by ATPase inhibitors, thereby indicating its dependency on a Na+ gradient. The characteristics of the high‐affinity L‐aspartate transporter are consistent with its operation at the basilar membrane for the transport of circulating aspartate into the cell.

Castration (24 hr) resulted in a significant decrease‐ in the ability of VP epithelial cells to transport L‐aspartate. The administration of testosterone to castrated rats completely restored L‐aspartate transport. In addition, in vitro testosterone addition (10−8 M for 30 min) to isolated prostate epithelial cells markedly increased L‐aspartate transport. Both cycloheximide and actinomycin inhibited the testosterone effect. The studies reveal that testosterone is a regulator of this Na+ ‐dependent high‐affinity L‐aspartate transporter. The mechanism of this testosterone effect appears to involve both RNA and protein synthesis. We now have a model system to elucidate this novel effect of testosterone. © 1993 Wiley‐Liss, Inc.
Effects of danazol on DNA synthesis in rat prostate
Authors: Sakamoto Shinobu , Mori Takao , Sawaki Keiko , Sassa Shuji , Suzuki Satoe , Sugiura Yoshie , Kudo Hideki , Kasahara Noriyuki , Nagasawa Hiroshi
Published: February 2007

Effects of danazol, an isoxazol derivative of the synthetic steroid 17α‐ethinyltestosterone, on activities of thymidylate synthetase and thymidine kinase, which are the DNA‐synthesizing enzymes included in de novo and salvage pathways of pyrimidine metabolism, respectively, were investigated in rat prostate. Danazol markedly reduced plasma levels of luteinizing hormone and testosterone, and organ weight, both enzyme activities and bro‐modeoxyuridine‐immunoreactive cells which were regarded as the S‐phase cells in prostate. These results indicate that danazol shows a property as a potent antigonadotropin. © 1993 Wiley‐Liss, Inc.
Is there a role for transrectal microwave hyperthermia of the prostate in the treatment of abacterial prostatitis and prostatodynia?
Authors: Montorsi Francesco , Guazzoni Giorgio , Bergamaschi Franco , Galli Laura , Consonni Paolo , Matozzo Vincenzo , Barbieri Luigi , Rigatti Patrizio
Published: February 2007

Transrectal microwave hyperthermia of the prostate was administered to 54 patients with chronic abacterial prostatitis or prostatodynia, who failed to respond to several courses of conventional therapies. Hyperthermia was delivered in 60‐min long sessions with three randomly chosen regimens (1 session / week for 4 weeks; 1 session / week for 6 weeks; 2 sessions / week for 3 weeks). A prostatic temperature of 42.5 ± 0.5°C was maintained throughout the entire duration of each session. Patients were assessed pre‐ and postopera‐tively by scoring of subjective symptoms, uroflowmetry with flow nomograms, determination of residual urine volume, and transrectal ultrasonography of the prostate. At the long‐term follow‐up, the subjective symptom score was significantly improved in all patients. Fifty percent of the patients also reported an improvement of life quality, 47. reported their condition unchanged, and 3% reported deterioration, despite therapy. Urodynamic parameters improved but did not reach statistical significance. No major complications were encountered. Our preliminary data indicate that transrectal microwave hyperthermia of the prostate is a safe therapy that can be beneficial as a second line treatment in selected patients with recurring symptoms of abacterial prostatitis or prostatodynia, which do not respond to medical therapy. © 1993 Wilcy‐Liss. Inc.
Measurement of cellular proliferation in human prostate by AgNOR, PCNA, and SPF
Authors: Sakr Wael A. , Sarkar Fazlul H. , Sreepathi Prabhakar , Drozdowicz Scot , Crissman John D.
Published: February 2007

Tumor differentiation and proliferative activity are important predictors of biological behavior. While routine histological evaluation is fairly adequate to assess differentiation, tumor proliferative activity is difficult to measure. Silver staining for nucleolar organizer regions (AgNORs) is reported to be helpful for assessing tumor proliferation. We investigated the AgNOR counts in 20 formalin fixed, paraffin embedded human prostate tissues in three microscopic fields of 330X, using an image analysis system. A total of 200–700 nuclei were evaluated on histologically controlled areas of nonneoplastic prostate tissue, prostatic intraepithelial neoplasia (PIN), and invasive carcinoma. The values were compared to flow cytometrically obtained synthesis phase fractions (SPF) and immunohis‐tochemically semi‐quantitated, proliferative cell nuclear antigen (PCNA) patterns. AgNOR counts were also compared to tumor stage and Gleason's score.

The pattern of PCNA staining in formalin fixed specimens was widely variable, probably due to differences in preservation of antigen. The positive counts varied from 0 to 55%, with a mean value of 8.55 ± 15.9. The SPF values ranged from 5 to 13% with a mean value of 8.50 ± 2.37. Two of 20 tumors were aneuploid and 18 were of diploid range. The mean AgNOR values in nonneoplastic nuclei (1.836 ± 0.299), PIN (3.129 ± 0.295), and invasive tumor cell nuclei (4.737 ± 0.369) were highly significant (P < 0.0001) when paired differences were compared. AgNOR counts correlated significantly with tumor Gleason's score (P < 0.0145). However, the correlation coefficient for SPF and AgNOR values was not significant (P > 0.24), possibly because of the small number of samples examined. The highest AgNOR counts were found in the two aneuploid tumors. We conclude that AgNOR count may be a potential indicator of cellular proliferation, and possibly a marker of tumor differentiation. © 1993 Wiiey‐Liss, Inc.
Influence of transforming growth factor β1 and other growth factors on basic fibroblast growth factor level and proliferation of cultured human prostate‐derived fibroblasts
Authors: Story Michael T. , Hopp Kathleen A. , Meier Daniel A. , Begun Frank P. , Lawson Russell K.
Published: February 2007

Basic fibroblast growth factor (bFGF) has been identified in the human prostate. The level of bFGF has been reported to be elevated in benign prostatic hyperplasia (BPH), compared with normal prostate, suggesting that the growth factor may play a role in this disease of the prostate. Basic FGF is a mitogen for cultured human prostate‐derived fibroblasts (PF). PF also synthesize bFGF, suggesting that growth regulation of these cells may be under autocrine control. The current study was undertaken to identify factors that affect PF proliferation and bFGF expression. Transforming growth factor β1 (TGF‐β1) inhibited PF proliferation. The inhibition by TGF‐β1 was partially overcome by bFGF but not by epidermal growth factor (EGF), platelet‐derived growth factor (PDGF), insulin‐like growth factor type 1 (IGF‐1), or insulin. Incubation of PF with TGF‐β1 increased bFGF mRNA and immunoreactive bFGF levels in a dose‐ and time‐dependent fashion. None of the other growth factor studies affected bFGF levels. PF were also found to express TGF‐β1 mRNA, the level of which was increased two‐ to fivefold by TGF‐β1. These observations suggest that PF proliferation is controlled by the interaction of two different growth factors. It is possible that bFGF/TGF‐β imbalance in favor of cell proliferation promotes prostatic stromal hyperplasia. © 1993 Wiley‐Liss, inc.
Modified apical dissection for early continence after radical prostatectomy
Authors: Klein Eric A.
Published: February 2007

A prospective evaluation of urinary continence in 83 consecutive patients undergoing radical prostatectomy using a modified apical urethral dissection is described. Using this technique, complete continence has been achieved in 88%, with stress incontinence in 11% and total incontinence in 1%. Continence was achieved in less than 1 week to a maximum of 16 weeks, with 17% dry during the first week, 53% dry by 6 weeks, and 81% by 3 months. Median time to continence was 5 weeks. Median age of the continent patients was significantly lower than that of incontinent patients. Neither the number of neurovascular bundles resected, the need to reconstruct the vesical neck, nor the number of anastomotic sutures used affected the rate of continence. The described technique, which incorporates the fascia posterior to the urethra into the vesicourethral anastomosis, results in earlier continence after radical prostatectomy, and thereby lessens the morbidity of this procedure. © 1993 Wiley‐Liss, Inc.
Ultrasonic diagnosis of 3,2′‐dimethyl‐4‐aminobiphenyl induced tumors in the urogenital organs of F344 rats
Authors: Suzuki Takanori , Tamura Yoshimi , Takezawa Yutaka , Mashimo Tooru , Imai Kyoichi , Yuasa Hisako , Yamanaka Hidetoshi , Shirai Tomoyuki
Published: February 2007

The usefulness of transabdominal ultrasonography in the diagnosis of 3,2′‐dimethyl‐4‐aminobiphenyl‐ and testosterone propionate‐induced tumors of the urogenital organs was evaluated in F344 rats. Seven mass lesions (1 ventral prostate, 1 dorsolateral prostate, 3 seminal vesicles, and 1 kidney) in the urogenital organs could easily be diagnosed concerning size and localization by ultrasound. Histological examination revealed a lesion in the ventral prostate to be an abscess and the other tumors to be malignant. Three hydronephroses by tumor invasion to the ureter, and six tumors in organs other than the urogenital organs could be detected by ultrasound. The threshold of malignant tumor detection by ultrasound was 7 mm in actual length. The size of the mass lesion estimated by ultrasound correlated well with the direct measurement (r = 0.96). Transabdominal ultrasonography is useful for diagnosing the localization of experimental tumors and accurately measuring their size in the urogenital organs of rats. © 1993 Wiley‐Liss, Inc.
Insulin‐like growth factor I: Action and receptor characterization in human prostate cancer cell lines
Authors: Iwamura Masatsugu , Sluss Patrick M. , Casamento Jeffrey B. , Cockett Abraham T. K.
Published: February 2007

The role of insulin‐like growth factor I (IGF‐I) in the growth and development of prostate cancer was studied using established human prostate cancer cell lines. Under steroid and growth factor‐free culture conditions, IGF‐I significantly stimulated the androgen‐independent cell lines PC‐3 and DU‐145 to incorporate [3H]thymidine into DNA, while the androgen‐dependent cell line, LNCaP, was not affected. However, in the presence of dihydrotestosterone (DHT), DNA synthesis of LNCaP cells was stimulated by IGF‐1 in a dose‐dependent manner. None of the cell lines tested secreted an immunoreactive level of IGF‐I into their conditioned medium. Characterization of receptors by ligand binding assays revealed that all prostate cancer cell lines tested express specific binding sites for IGF‐I with similar dissociation constants (0.23–0.39 nM). Crosslinking studies supported the suggestion that 1251‐IGF‐I was bound to a receptor on these cells. The IGF‐I receptor concentrations of androgen‐independent cell lines were significantly higher than those of the androgen‐dependent cell line. Androgen appeared to affect neither the expression of IGF‐1 receptors nor the secretion of IGF‐I. The results suggest that IGF‐I may play an important role in stimulating the growth and progression of prostate cancer. © 1993 Wiley‐Liss, Inc.
Cigarette smoking: A review of possible associations with benign prostatic hyperplasia and prostate cancer
Authors: Matzkin Haim , Soloway Mark S.
Published: February 2007

There are conflicting data on the effect of cigarette smoking on serum levels of the various sex hormones. Some studies suggest that cigarette smoke produces an antiestrogenic effect. Smoking may also affect the metabolism of other sex steroids such as testosterone and adrenal hormones, and thereby influence the incidence of benign and malignant growth of the prostate.

Epidemiologic studies analyzing a possible association between cigarette smoking and prostate cancer are not conclusive, although some show a positive relationship. The etiology of BPH is undoubtedly multifactorial. Estrogens as well as androgens may be involved in the pathogenesis of BPH. There are several studies that indicate that cigarette smokers have a lower likelihood of requiring surgery for BPH.

Growth of the prostate may not correlate with serum levels of androgens and estrogens. The local hormonal milieu of the target cells in the prostate are probably more critical than the more easily measured serum levels. This review examines the literature dealing with cigarette smoking and both BPH and prostate cancer. If there is an effect, then elucidation of the mechanism by which smoking affects the growth of the prostate may improve our understanding of BPH and prostate cancer, and may suggest preventive strategies for high risk groups. © 1993 Wiley‐Liss, Inc.
Ultrastructural study of the ventral lobe of the prostate of rats submitted to experimental chronic alcoholism
Authors: Martinez F. E. , Garcia P. J. , Padovani C. R. , Cagnon V. H. A. , Martinez M.
Published: February 2007

The effects of chronic alcohol ingestion on the ventral lobe of the prostate were studied in rats (Rattus norvegicus). Ultrastructural observations on the epithelial cells of the ventral lobe of the prostate showed irregularly shaped nuclei with deep infoldings, dilated RER cisternae, and a small number of microvilli covering the cell surface. After 90 and 135 days of alcohol treatment, the epithelial cells showed signs of degeneration. © 1993 wiiey‐Liss, Inc.
Impact of benign prostatic hyperplasia on general well‐being of men
Authors: Tsang K. K. , Garraway W. M.
Published: February 2007

Little is known about the impact of benign prostatic hyperplasia (BPH) on the general well‐being of men with this condition. All men aged 40–79 years registered with a group general practice were enumerated. BPH was defined as enlargement of the prostate gland of equivalent weight >20 g in the presence of symptoms of urinary dysfunction and/or a urinary peak flow rate <15 ml/s, without evidence of malignancy. Four hundred and ten men (20% of those who participated) satisfied these criteria. The proportion of men with a negative feeling of well‐being was higher in men with BPH than in men who did not have BPH. The difference was consistent for all aspects of well‐being (anxiety, depression, self‐control, vitality, being worried or being bothered by illness). Men with BPH had a higher level of bothersomeness attributed to urinary symptoms, and more interference in selected daily living activities caused by urinary dysfunction. These were related to worry or concern over urinary function and prostate cancer, together with a higher level of embarrassment caused by urinary dysfunction, compared with men who did not have BPH. Patients' feelings of well‐being should be taken into account in the clinical management of BPH. © 1993 Wiley‐Liss, Inc.
An immunocytochemical analysis of TGFα expression in benign and malignant prostatic tumors
Authors: Harper M. E. , Goddard L. , Glynne‐Jones E. , Wilson D. W. , Price‐Thomas M. , Peeling W. B. , Griffiths K.
Published: February 2007

Transforming growth factor alpha (TGFα) expression was analyzed immunocytochemically on formalin‐fixed wax‐embedded sections obtained from 24 benign prostatic hyperplasia (BPH) specimens and 76 prostatic carcinoma tissues, 3 human prostatic tumor xenografts, normal kidney, and salivary gland. Low amounts of TGFα immunopositivity were encountered in the epithelium of BPH glandular tissues, whereas in the prostatic adenocarcinoma samples, a greater heterogeneity and intensity of TGFα immunostaining was observed. The most intense staining was exhibited by the least differentiated tumors, although a few of these were weakly stained. Statistical analysis of the relationship of histopathological grade of tumor with TGFα expression in the carcinomas showed a significant correlation of these parameters, 0.01 > P > 0.001. The expression of the proliferation markers Ki‐67 and PCNA was also analyzed in the carcinoma specimens, and the relationship of these to TGFα expression indicated that there was no significant correlation in this series of tumors between increased growth activity and TGFα expression (p ˜ 0.25 with both markers). The prostatic carcinoma xenografts TEN 12 and TEN 15 contained low levels of immunoreactive TGFα, which was uniformly distributed, whilst heterogeneous immunostaining was observed in the uroepithelial xenograft TEN 16. In the normal human kidney, TGFα was concentrated in the epithelium of the distal convoluted tubules (DCT) and the collecting tubules (CT), and lower amounts were identified in the proximal convoluted tubules (PCT). As in the prostatic carcinomas, the immunostaining was eliminated by prior absorption of the antibody with pure TGFα and not with human or mouse EGF. No crossreactivity of the TGFα antibody with salivary EGF was demonstrated. This study concludes that, in prostate carcinoma, the least differentiated tumors more often expressed greater amounts of immunoreactive TGFα; however, no relationship between TGFα expression and cellular proliferation markers was found. © 1993 Wiley‐Liss, Inc.
Effect of long‐term oral testosterone undecanoate treatment on prostate volume and serum prostate‐specific antigen concentration in eugonadal middle‐aged men
Authors: Holmäng Sten , Mårin Per , Lindstedt Göran , Hedelin Hans
Published: February 2007

Testosterone undecanoate (160 mg/day) or placebo was given orally in a double‐blind fashion for 8 months to 23 middle‐aged men without urinary tract symptoms. Testosterone was found to increase the mean prostate volume by 12% (P < .012). The treatment suppressed the serum concentrations of sex‐hormone‐binding globulin and follicle stimulating hormone. The observed decrease in the mean serum concentration of luteinizing hormone was not statistically significant. The serum concentrations of prostate‐specific antigen did not change as measured by two different well‐validated immunometric assays. No changes in micturition habits or urine flow charts were reported. © 1993 Wiley‐Liss, Inc.
Bacterial localization in antibiotic‐refractory chronic bacterial prostatitis
Authors: Nickel J. Curtis , Costerton J. William
Published: February 2007

Chronic bacterial prostatitis, that has become resistant to antibiotic therapy, remains a frustrating clinical entity for both clinicians and patients. Twenty men with a history of documented bacterial prostatitis, that had become resistant to appropriate antibiotic therapy, were studied in an attempt to determine where the bacteria had become localized, and possibly explain their survival in a relative bactericidal environment. The antibiotics were discontinued for 4 weeks, and cultures of the expressed prostatic secretions, tissue biopsies, histology, and ultrastructure were correlated. Twelve (60%) of the tissue biopsies cultured presumed pathogens. In six of the tissue‐positive cases, the expressed prostatic secretion was negative. Specific electron micrographs demonstrate exopolysaccharide coated micro‐colonies of bacteria firmly attached to the ductal and acinar walls. This mode of growth helps explain some of our difficulties in the diagnosis and treatment of chronic bacterial prostatitis. © 1993 Wiley‐Liss, Inc.
Effect of LHRH analog on the seminal vesicles evaluated by transrectal sonography
Authors: Terasaki Toyohiro , Kojima Munekado , Kamoi Kazumi , Naya Yoshio , Ohe Hiroshi , Watanabe Hiroki
Published: February 2007

The maximum horizontal area (MHA) of the seminal vesicles was measured in 20 prostatic cancer patients by means of transrectal sonography (TRS) after LHRH analog treatment. MHA of the seminal vesicles changed in parallel to the serum testosterone (T) level and decreased by 11–62%, compared with the baseline after LHRH analog treatment for 4 months. Two different patterns were observed for the change of MHA. In 9 cases, MHA of the seminal vesicles increased transiently and then decreased gradually, while in the other 11 cases, MHA decreased continuously from the beginning with no significant increase. Thus, the direct and dynamic response of the seminal vesicles to the change of serum T level was clarified. © 1993 Wiley‐Liss, Inc.
Expression of prostatic TRH‐like peptides differs between species and between malignant and nonmalignant tissues
Authors: Gkonos Peter J. , Kwok Chuen K. , Block Norman L. , Roos Bernard A.
Published: February 2007

Thyrotropin‐releasing hormone‐immunoreactive peptides (iTRH) were analyzed in normal rat and rabbit prostates and in human benign prostatic hyperplasia (BPH) and prostate cancer. Peptides were extracted from tissues, fractionated by anion and cation exchange chromatography, and analyzed by TRH radioimmunoassay. pGlu‐Glu‐Pro‐NH2 predominated in rabbit, but accounted for only 10–15% of iTRH in rat and human BPH. Uncharged peptides predominated in rat and human prostate. Authentic TRH (pGlu‐His‐Pro‐NH2) is not present in rabbit prostate, but may account for up to 25% of iTRH in rat and human prostate. iTRH was virtually absent in prostate cancer. These results demonstrate considerable heterogeneity in the expression of TRH‐like peptides in the prostates of various animal species, and suggest decreased expression of these peptides in prostate cancer. © 1993 Wiley‐Liss Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America

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Inhibition of growth of experimental prostate cancer in rats by LH‐RH analogs linked to cytotoxic radicals
Authors: Pinski Jacek , Schally Andrew V. , Yano Tetsu , Szepeshazi Karoly , Halmos Gabor , Groot Kate , Comaru‐Schally Ana Maria , Radulovic Sinisa , Nagy Attila
Published: February 2007

The effects of hybrid cytotoxic LH‐RH analogs, produced by linking anthraquinone or methotrexate to carrier LH‐RH agonist [D‐Lys6]LH‐RH, were evaluated in Copenhagen‐Fisher Fl rats bearing Dunning R‐3327H prostate adenocarcinoma. The two cytotoxic LH‐RH analogs T‐98 [(D‐Lys6)LH‐RH coupled to glutaryl‐2‐(hydroxymethyl)anthraquinone (G‐HMAQ)], and AJ‐04 [(D‐Lys6)LH‐RH linked to methotrexate (MTX)], carrier [D‐Lys6]LH‐RH, or the free cytotoxic compounds MTX and G‐HMAQ were administered from Alzet Osmotic minipumps for 7–8 weeks. The cytotoxic LH‐RH analogs caused somewhat greater tumor growth inhibition than the carrier peptide, while anthraquinone or methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary‐gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in tumors treated with AJ‐04, T‐98, [D‐Lys6]LH‐RH, or by castration than in those of controls. Serum hormone levels were lowered by both carrier peptide and cytotoxic analogs, LH being substantially depressed, and testosterone not detectable. These results and other findings indicate that LH‐RH analogs containing cytotoxic radicals anthraquinone or methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic LH‐RH analogs to tumors such as prostate cancer, which have receptors for LH‐RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted chemotherapy, might be of practical therapeutic importance for the management of advanced prostate cancers, which eventually relapse after palliative hormonal therapy. © 1993 Wiley‐Liss, Inc.
Effect of culture conditions on androgen sensitivity of the human prostatic cancer cell line LNCaP
Authors: Langeler Erna G. , Van Uffelen Connie J. C. , Blankenstein Marinus A. , Van Steenbrugge Gert Jan , Mulder Eppo
Published: February 2007

Several effects of androgens on LNCaP‐FGC prostate tumor cells showed a biphasic pattern. Stimulation of growth and inhibition of secretion of prostatic acid phosphatase (PAP) was observed at low androgen concentrations (below 1 nM of the synthetic androgen R1881), and inhibition of growth and stimulation of PAP secretion was observed at higher concentrations. In contrast, prostate specific antigen (PSA) secretion did not show this biphasic response pattern. Comparable effects were found for two sublines of the LNCaP‐FGC cells: an early (passage 20, androgen‐dependent) and relatively late (passage 70, androgen‐sensitive) passage of the cells. Culturing of both sublines in the presence of a high concentration of androgens (10 nM R1881) resulted initially in a decrease in growth rate, but the cells started to proliferate within 3 weeks. These cells became less sensitive to androgens, lost their biphasic response pattern, and showed reduced androgen receptor levels. Three weeks after removal of the excess of androgens, the passage 70 cells regained a biphasic growth response to androgens. Culture in medium without steroids but with EGF resulted in a decrease of both androgen sensitivity and androgen receptor level.

In conclusion, rapid changes of the androgen sensitivity and receptor level of the LNCaP cells occurred under the influence of culture conditions. These changes were partly reversible and, therefore, were most likely due to adaptation of the cells. © 1993 Wiley‐Liss, Inc.
Comparison of the pathologic features and DNA ploidy value of prostate cancers detectable by sonography and by palpation
Authors: Ohori Makoto , Wheeler Thomas M. , Greene Damian R. , Scardino Peter T.
Published: February 2007

Ultrasonography of the prostate detects some cancers that are not palpable, but the pathologic features of such cancers have not been well described. Since screening trials consistently find sonography more sensitive (though less specific) than digital rectal examination, nonpalpable cancers that are visible as hypoechoic lesions on ultrasound have been postulated to be early cancers of limited malignant potential and may not require aggressive treatment.

To test this hypothesis, we determined the pathologic features and DNA ploidy value of prostate cancers in 63 radical prostatectomy specimens taken from patients with clinical stage T1 (n = 28) and T2 (n = 35) prostate cancer. In 40 patients (63%), the cancer appeared hypoechoic on ultrasound. The median volume of these cancers was 4.19 cm3 (range 0.45–19.22); 80% exhibited extra‐capsular extension (ECE); 30% had seminal vesicle invasion (SVI); and 95% were nondiploid by nuclear image analysis (CAS 200 system). In patients with isoechoic cancer, tumor volume was significantly less (median 0.38 cm3) and ECE and SVI occurred less frequently (13% and 0%, respectively). Only seven (30%) had nondiploid tumors. In 35 patients, the tumor was palpable, and the pathologic features and DNA ploidy values (94% nondiploid) of these cancers were similar to those of the tumors that were visible on ultrasound. In seven patients, the cancer was visible by ultrasound but not palpable by digital rectal examination. Median tumor volume was 1.72 cm3 (range 0.45–18.98); four patients (57%) had ECE; one (14%) had SVI, and six (86%) had nondiploid cancers.

We conclude that most cancers that appear hypoechoic on ultrasound are clinically important and exhibit aggressive pathologic features. Palpable cancers and sonographically visible cancers are similar and should be staged and treated similarly. © 1993 Wiley‐Liss, Inc.
Multivariate analysis of plasma hormones in patients with metastatic prostate cancer receiving combined LHRH‐analog and antiandrogen therapy
Authors: Fiet Jean , Doré Jean‐Christophe , Le Gǒ Alice , Ojasoo Tiiu , Raynaud Jean‐Pierre
Published: February 2007

The following hormones, the plasma protein SHBG, and the tumor markers prostatic acid phosphatase (PAP) and prostate‐specific antigen (PSA) were assayed at 18 time‐points over 1 month during a double‐blind randomized study in 36 stage D2 cancer patients receiving either “buserelin + placebo” or “buserelin + nilutamide (Anandron)”: LH, FSH, estradiol, testosterone, dihydrotestosterone, androstenedione, 5‐androstene‐3,17β‐diol, dehydroepiandrosterone and its sulfate, cortisol, 17α‐hydroxyprogesterone, pregnenolone, 17α‐hydroxypregnenolone, and 3α‐androstanediol glucuronide. Multivariate analysis of the treatment values (over 10,000 assays) by two complementary methods, correspondence factorial analysis (CFA) and the minimum spanning tree (MST) method, identified those variables within the pathways of androgen metabolism that were correlated over time and, in a comparison of the two treatment groups, identified the enzyme targets of nilutamide action in humans. Whereas nilutamide tended to decrease androstenedione slightly, it affected no other variables including cortisol, except for pregnenolone, 17α‐OH‐pregnenolone, and 17α‐OH‐progesterone, which were increased. These increases are indicative of weak inhibition of C17,20 lyase by nilutamide, but, according to the multivariate analysis, are insufficient to account for the more marked and rapid fall in PAP and PSA noted on addition of nilutamide to buserelin that must therefore be explained by another mechanism such as androgen receptor blockade by nilutamide. © 1993 Wiley‐Liss. Inc.
Characterization of a soluble LHRH‐degrading activity in the rat ventral prostate
Authors: Maggi Roberto , Dondi Donatella , Limonta Patrizia , Pimpinelli Federica , Montagnani Marina , Moretti Roberta M. , Motta Marcella
Published: February 2007

Recent evidence supports the hypothesis of a direct action of LHRH at the level of the prostate. Since peptidases able to degrade the hormone are present in several LHRH target structures, it was deemed of interest to investigate whether the prostate of adult normal male rats might possess LHRH degrading activities (LHRH‐DA). Through the use of RP‐HPLC, it has been observed that LHRH‐DA is present in the soluble fraction of the rat ventral prostate homogenate, and is able to hydrolyze synthetic LHRH and to generate fragments 1–3 and 1–5 of the decapeptide. The degradation of [pGlu‐3H]LHRH is inhibited by LHRH itself, and affected by several LHRH agonists and antagonists with different kinetics and potencies. TRH, the enkephalin analog [D‐Ala2‐D‐Leu5]enkephalin and rat prolactin do not inhibit the degradation of [pGlu‐3H]LHRH by the soluble fraction of prostate homogenate; on the contrary, this is inhibited by graded doses of somatostatin. The prostatic LHRH‐DA is also inhibited, in a dose dependent manner, by bacitracin, serine protease inhibitors (diisopropylfluorophosphate and phenylmethansulfonylfluoride), the metal chelating agent EDTA, HgCl2, and dithiothreitol. No inhibitory effect on [pGlu‐3H]LHRH hydrolysis was observed after incubation of the prostatic extract in the presence of captopril. The prostatic LHRH‐DA seems to be different from that present in other tissues of the rat (e.g., hypothalamus, pituitary, gonads), and to be decreased by castration performed 3 weeks before. These results suggest that (1) an LHRH‐DA is found in the soluble fraction of rat prostate homogenate; (2) this enzymatic activity exhibits the characteristics of a metallo‐ and thioldependent neutral endopeptidase; (3) it appears to be different from similar hydrolytic activities found in other tissues; and (4) it is influenced by the hormonal milieu, since castration causes a significant decrease of its activity. © 1993 Wiley‐Liss, Inc.
Nuclear casein kinase 2 (CK‐2) activity in human normal, benign hyperplastic, and cancerous prostate
Authors: Yenice Sedef , Davis Alan T. , Goueli Said A. , Akdas Atif , Limas Catherine , Ahmed Khalil
Published: February 2007

In previous work, we had observed that chromatin‐associated nonhistone protein phosphorylation, catalyzed by intrinsic protein kinase reaction in chromatin preparations from human benign prostatic hyperplasia (BPH) prostate samples was markedly elevated, compared with the normal prostate chromatin samples [Rayan et al: Cancer Res 45:2277‐2282, 19851]. The properties of this protein kinase reaction were suggestive of the involvement of casein kinase(s). By employing the specific synthetic substrate for casein kinase 2 (CK‐2) for assays in cellular fractions, we have shown that this protein kinase is present in human prostate chromatin. Its activity is increased in BPH chromatin by about 25‐fold, as compared with its activity in the normal prostate chromatin. This suggests that CK‐2 is a possible mediator of the enhanced phosphorylation of chromosomal proteins in BPH chromatin. By comparison, CK‐2 activity in chromatin preparations from prostatic carcinoma samples was markedly less elevated than that of the BPH chromatin. Immunohistochemical analysis of the enzyme in human frozen sections of prostate tissue samples showed that the enzyme immunostaining was diffuse in the cytoplasm, but more intense in the nucleus, especially in the nucleoli. In general, the staining corresponded with the en‐zymic data. However, sections from prostatic carcinoma samples appeared to show differential staining, depending on the Gleason's grade of the sample. The samples with higher Gleason's grade showed less intense immunostain in the nucleus, compared with samples of lower Gleason's grade. Further, regions of sections in samples with higher Gleason's grade did not show any immunostaining. These differences in the characteristics of CK‐2 expression in prostatic carcinoma samples may be potentially significant, but need to be evaluated further for their significance to the pathobiology of prostatic neoplasia. © 1994 Wiley‐Liss, Inc.
Age‐related changes of the prostate gland in the senescence‐accelerated mouse
Authors: Sugimura Yoshiki , Sakurai Masaki , Hayashi Norio , Yamashita Atsushi , Kawamura Juichi
Published: February 2007

Aging is of utmost importance in the pathogenesis of the prostate gland (i.e., benign prostate hyperplasia or prostatic carcinoma). The object of this study was to examine the morphological and histological changes of the aging prostate of the so‐called senescence‐accelerated mouse (SAM). Ventral and dorsolateral lobes of prostate glands of SAM were microdissected into two‐dimensional ductal arrays. Gross morphology, ductal branching patterns, and histology were examined in these microdissected specimens. Wet weight and numbers of ductal tips in ventral and dorsolateral prostate glands in senescence accelerated‐prone (SA‐P) mice were significantly smaller than those of senescence accelerated‐resistant (SA‐R) mice, although the changes of patterns of gross ductal morphology were virtually identical in these groups. High incidence of stromal hyperplasia with fibrosis and inflammation was observed in the dorsal lobe of the aged SA‐P mouse. Atypical glandular epithelial cells and cribriform glandular deformity were observed in the dorsal and lateral lobe of aged SA‐P mice. Marked heterogeneity in age‐related pathological changes was observed between prostatic lobes. These data suggest that the aging process occurs heterogeneously within the prostate gland, and that SA‐P mice may be an important model for the study of age‐related changes in the prostate gland. © 1994 Wiley‐Liss, Inc.
The proliferative function of basal cells in the normal and hyperplastic human prostate
Authors: Bonkhoff Helmut , Stein Ute , Remberger Klaus
Published: February 2007

To obtain more insight into the proliferative function of basal and secretory cell types in human prostate, we studied the immunoprofile of three well‐characterized proliferation‐associated antigens (Ki‐67, PCNA, MIB 1) in normal and hyperplastic prostate tissue. Distinction between labeled basal and secretory cell types was made by simultaneous demonstration of the proliferation‐associated antigens and basal cell‐specific cytokeratins in identical sections. In normal and hyperplastic acini, approximately 70% of labeled cells were of the basal cell phenotype. These data clearly suggest that the proliferative compartment of the normal and hyperplastic epithelium is located in the basal cell layer. Compared to normal and hyperplastic conditions, severe proliferative abnormalities were detected in high‐grade prostate intraepithelial neoplasias (PIN), as documented by the extension of the proliferative compartment up to the luminal border. Conversely, approximately 70% of proliferating cells detected in atypical hyperplasias that progressed in invasive carcinomas were localized in the remaining basal cell layer.

These findings may indicate the proliferative role of basal cells in the epithelial renewal, and the development of hyperplastic and neoplastic disorders in the human prostate. © 1994 Wiley‐Liss, Inc.
Effect of early exposure of flutamide on subsequent growth of transplantable rat prostatic tumor (dunning R‐3327)
Authors: Lee Sue Zen , Sato Naohide , Suzuki Hiroyoshi , Watabe Yoshio , Masai Motoyuki , Shimazaki Jun
Published: February 2007

Rat transplantable prostatic tumors (Dunning R‐3327) were treated with flutamide before tumors grew palpable, in order to examine the effect of short term treatment of antiandrogen for prostatic cancer in latent period on the growth after appearance of tumor. Flutamide delayed an appearance of the tumor nodule and retarded the growth rate in proportion as treatment began earlier. Flutamide also reduced final tumor volume. Flutamide‐treated tumors histologically consisted of small or dilated glandular structure with an increase in stromal area, but androgen receptors were preserved. Flutamide‐treated tumor showed slow growth with androgen sensitivity when transplanted to intact rats, showing prolonged influences of antiandrogen on tumor growth. There was no significant difference between flutamide‐treated and control groups in weight of accessory sex organs and serum androgen or estrogen levels. In conclusion, flutamide treatment may retard an appearance of prostatic cancer concomitant in benign prostatic hyperplasia. © 1994 Wiley‐Liss, Inc.
Expression of bone morphogenetic protein messenger RNAs by normal rat and human prostate and prostate cancer cells
Authors: Harris Stephen E. , Harris Marie A. , Mahy Patrick , Feng Jian Q. , Mundy Gregory R. , Wozney John
Published: February 2007

Human prostate cancer cells are known to produce several growth regulatory factors, including transforming growth factor β (TGFβ) and heparin‐binding fibroblast growth factors (FGFs), which may play as‐yet‐undefined roles in prostate gland morphogenesis, as well as in prostate cancer cell behavior. Recently, a family of proteins in the extended TGFβ family, the bone morphogenetic proteins (BMPs), has been identified which stimulates bone formation in vivo, and in which, the proteins are likely involved in a variety of morphogenetic processes during embryogenesis. These powerful morphogenetic factors are capable of redirecting muscle mesenchyme cells to differentiate along the lines of bone tissue. We examined a number of well‐characterized rat and human prostate cancer cell lines for the expression of BMP 2, 3, 4, and 6 messenger RNA. Poly(A + )‐RNA was isolated from normal human and rat ventral prostate, from the rat prostate adenocarcinoma PAIII tumor and cultured cells derived from it, and from human prostate cancer cell lines PC‐3, LNCaP, and DU‐145. BMP mRNA levels were measured using BMP 2, 3, 4 and Vgr‐1 (BMP 6) cDNA probes. Both normal and neoplastic prostate tissue expressed these BMP mRNAs, although the level of expression varied from tumor to tumor. Normal human prostate expressed BMP 4 mRNA predominantly, as did the human prostate cancers PC‐3 and DU‐145. PC‐3 also expressed BMP 2 mRNA and BMP 3 mRNA in large amounts. Normal rat ventral prostate expressed all these BMP mRNAs, but the rat prostate adenocarcinoma PAIII expressed predominantly BMP 3 mRNA. The reason that different BMPs are expressed in varying amounts by these normal and neoplastic cells is unknown. However, if these BMPs are expressed in biologically active form, they could be responsible for important effects on normal prostate growth and morphogenesis, on neoplastic prostate cell behavior, and could even contribute to the capacity of prostatic cancer cells to stimulate new bone formation at metastatic tumor sites in bone. © 1994 Wiley‐Liss, Inc.
Detection of prostatic‐inhibin‐like peptide in the cytoplasm of LNCaP cells, a human prostatic adenocarcinoma cell line
Authors: Hurkadli Kalpana S. , Sheth Anil R. , Lokeshwar Balakrishna , Block Norman L.
Published: February 2007

Prostatic inhibin peptide (PIP) is a 94‐amino acid peptide involved in various cellular functions. The concentration of this peptide changes with prostatic pathophysiology suggesting a role in various disease conditions; present study was undertaken to investigate the presence of this peptide in two human prostatic cell lines: LNCaP and PC3 cells. The LNCaP cells showed an intense intracellular fluorescence pattern after staining with rabbit‐anti‐PIP antiserum and FITC conjugated goat antirabbit‐IgG, while the PC3 cells did not exhibit any fluorescence. There was no alteration in the concentration of PIP in LNCaP cells with or without supplementation of steroids in culture medium. Immunoblot analysis indicates similarities between PIP from LNCaP cells and that from the human seminal plasma. Thus, present study demonstrates the presence of PIP in a human prostatic cell line, i.e., LNCaP cells. Its intracellular concentration is androgen independent, and has a close similarity with PIP isolated from the human seminal plasma. © 1994 Wiley‐Liss, Inc.
N‐(4‐hydroxyphenyl) retinamide induces cell cycle specific growth inhibition in PC3 cells
Authors: Igawa Mikio , Tanabe Tetsuyuki , Chodak Gerald W. , Rukstalis Daniel B.
Published: February 2007

The synthetic retinoid N‐(4‐hydroxyphenyl) retinamide (4‐HPR) has been demonstrated to inhibit the development of primary and metastatic neoplasms in several animal models. In order to investigate the effect of 4‐HPR on human prostate adenocarcinoma, we designed a series of in vitro experiments with the PC3 cell line to evaluate effects on proliferation, cell cycle kinetics, and c‐myc mRNA expression. 4‐HPR demonstrated cytoxicity only at the supraphysiologic concentration of 10.0 μM. However, asynchronously growing cells exposed to 1 μM 4‐HPR demonstrated a 51% reduction in proliferation rate, associated with an accumulation of cells in the G0/G1 phase of the cell cycle. PC3 cells synchronized with serum deprivation or aphidicoline exhibited significant decreases in DNA synthesis when treated with 1 μM 4‐HPR. Additionally, these cells were found to accumulate in G0/G1 and S phase. Northern blots indicated a significant decrease in c‐myc mRNA expression in asynchronously growing cells with continuous administration of 1 μM 4‐HPR for 6 days. These data suggest that 4‐HPR can inhibit growth of PC3 cells as a consequence of a block in cell cycle transition from G1 to S phase at a concentration of 1 μM, and that this inhibition is associated with a suppression of c‐myc gene expression. © 1994 Wiley‐Liss, Inc.
DNA analysis by flow cytometry of paraffin embedded core biopsies of the prostate
Authors: Warzynski Michael J. , Soechtig C. Eugene , Goldsmith Larry C. , Maatman Thomas J. , Carothers George G.
Published: February 2007

The majority of literature concerning DNA analysis of prostate cancer involves testing formalin‐fixed prostatectomy tissue, fresh or formalin‐fixed transurethral resections of the prostate (TURP), or fresh core biopsies. We were interested if flow cytometry could analyze the DNA of formalin‐fixed, paraffin‐embedded, core biopsies separated into normal versus malignant segments.

Of the 50 potentially available samples for analysis representing 11 controls of normal core tissue and 39 core biopsies from the 11 patients, one patient had no normal tissue, one core had no malignancy, and three cores had no tissue visibly remaining in the paraffin blocks for analysis. Therefore, of 45 actual samples available for processing, sometimes representing segments as small as 0.2 cm, separate segments containing malignant glands or normal glands were excised from the blocks, and processed separately by the Hedley technique. Forty‐four of the 45 available samples produced interpretable DNA histograms as defined by discernible G0/G1 peaks, a calculable cell cycle analysis, and the qualitative appearance of a “smooth” histogram appearance, reflecting sufficient nuclei were analyzed. This is the first report to our knowledge where flow cytometry has successfully been used to analyze paraffin blocks of core biopsies which were, in addition, separated into malignant versus normal enriched segments. © 1994 Wiley‐Liss, Inc.
Characterization of high‐affinity receptors for bombesin/gastrin releasing peptide on the human prostate cancer cell lines PC‐3 and DU‐145: Internalization of receptor bound 125I‐(Tyr4) bombesin by tumor cells
Authors: Reile Herta , Armatis Patricia E. , Schally Andrew V.
Published: February 2007

Specific receptors for bombesin/gastrin releasing peptide (GRP) on the androgen‐independent human prostate cancer cell lines PC‐3 and DU‐145 were characterized. No specific binding of 125I‐[Tyr4]‐bombesin to the androgen‐dependent human prostate cancer cell line LNCaP was detectable. The binding of 125I‐[Tyr4]‐bombesin to PC‐3 and DU‐145 cells was found to be time‐ and temperature‐dependent, saturable, and reversible. Scatchard analysis revealed a single class of binding sites with high affinity (Kd 9.8 × 10−11 M for PC‐3, and 9.1 × 10‐11 M for DU‐145 cells at 25°C) and with a binding capacity of 44,000 binding sites/cell and 19,000 binding sites/cell, respectively. Bound 125I‐[Tyr4]‐bombesin was rapidly internalized by PC‐3 cells. The nonhydrolyzable GTP analog GTP‐gamma‐S caused a dose‐dependent inhibition of 125I‐[Tyr4]‐bombesin binding to PC‐3 and DU‐145 cells, indicating that a G‐protein (guanine nucleotide‐binding protein) couples the bombesin receptor to intracellular effector systems. Bombesin and GRP(14‐27) inhibited the binding of 125I‐[Tyr4]‐bombesin to both cell lines in a dose‐dependent manner with inhibition constants (Ki of 0.5 nM and 0.4 nM, respectively. Both cell lines express the bombesin/GRP preferring bombesin receptor subtype, since, in displacement studies, neuromedin B was more than 200 times less potent than bombesin and GRP(14‐27) in inhibiting the binding of 125I‐[Tyr4]‐bombesin. Two synthetic bombesin/GRP antagonists, RC‐3095 and RC‐3110, powerfully inhibited the specific binding of 125I‐[Tyr4]‐bombesin with Ki 0.92 nM and 0.26 nM on PC‐3 cells, and 3.3 nM and 0.89 nM on DU‐145 cells, respectively. These findings indicate that the PC‐3 and DU‐145 human prostate cancer cell lines possess specific high‐affinity receptors for bombesin/GRP, and are suitable models for the evaluation of the antineoplastic activity of new bombesin/GRP antagonists in the treatment of androgen‐independent prostate cancer. © 1994 Wiley‐Liss, Inc.