bluuebunny/crossref_metadata_2025 huggingface dataset:
Concepts of citrate production and secretion by prostate: 2. Hormonal relationships in normal and neoplastic prostate
Authors: Costello Leslie C. , Franklin Renty B.
Published: February 2007

A unique and major function of prostate secretory epithelial cells is to synthesize, accumulate, and secrete extraordinarily high levels of citrate. This function is regulated by testosterone and by prolactin. Concepts of the mechanisms of hormonal regulation are presented. The relationship of testosterone and prolactin to the origin and homologies of different prostate cell lines is described. The metabolic differentiation of citrate and noncitrate producing prostate secretory epithelial cells is discussed. Concepts of the pathogenesis of prostatic neoplasms are presented based on hormonal, metabolic, and homologous relationships associated with citrate production. Characterization of normal and neoplastic secretory epithelial cells by their citrate function is emphasized. The urgency and necessity for research relating to all aspects of prostate citrate production in normal and pathological prostate are emphasized.
Immunohistochemical prostatic acid phosphatase level as a prognostic factor of prostatic carcinoma
Authors: Sakai Hideki , Shiraishi Kazutaka , Minami Yuzo , Yushita Yoshiaki , Kanetake Hiroshi , Saito Yutaka
Published: February 2007

To determine whether prostatic acid phosphatase (PAP) immunoreactivity in prostatic adenocarcinoma is a reliable prognostic factor, the PAP immunohistochemical distribution has been examined in 78 prostatic carcinoma cases. The intensity of PAP immunostaining was graded from 0 to 2, and the scores of the primary and the secondary staining patterns were added to assess the extent of the PAP expression in needle biopsy specimens.

As a result, a higher cancer‐specific survival rate was observed in patients showing a greater PAP immunostaining (P<0.01). Further, a multivariate analysis was made of possible prognostic factors (age, stage, Gleason score, serum PAP, PAP‐immunostaining score, and the initial treatment) to estimate the extent of their impact on cancer‐specific survival.

Results have confirmed that the difference in PAP immunoreactivity is an excellent, independent prognostic factor for prostatic carcinoma.
Morphometric and stereological analysis of the effects of 17β‐estradiol on the glandular epithelium of the castrated guinea pig lateral prostate
Authors: Tam C. C. , Wong Y. C. , White F. H. , Fowler J. P.
Published: February 2007

Upon administration of pharmacological doses of estradiol to castrated guinea pigs, the secretory cells of the lateral prostate underwent hypertrophy which resulted from significant increases in nuclear and cytoplasmic volume. There were quantitative increases in the small highly electron‐dense granules and multivesicular bodies when compared with the castrated control. The dramatic increase in the number of highly electron‐dense granules probably occurred at the expense of the low electron‐dense granules. The average size of the condensing granules and mitochondria decreased significantly after estradiol administration. However, significant increase in the number of mitochondria was detected when compared with the castrated control. Ultrastructural data revealed no significant changes in the absolute dimensions of granular endoplasmic reticulum or of the Golgi complex, suggesting that estradiol exerted no significant stimulatory effects on these organelles. Pharmacological doses of estrogen appear to regulate the expression of secretory granules and multivesicular bodies in the lateral prostate of castrated guinea pigs.
Effect of calcium and calcium antagonists on 45Ca influx and cellular growth of human prostatic tumor cells
Authors: Batra Satish , Popper Lars D. , Hartley‐Asp Beryl
Published: February 2007

Calcium and calmodulin play significant roles in DNA synthesis and cell proliferation. In this work the effects of verapamil, trifluoperazine, and tamoxifen on 45Ca uptake and cell growth in human prostatic tumor cells (DU 145) and human fibroblast cells (1 BR) were studied. Although the maximum proliferation was achieved at a concentration of around 2 mM CaCl2 in both DU 145 and 1 BR, growth of DU 145 cells was considerably greater than 1 BR at all calcium concentrations (0.1–4 mM). Calcium uptake experiments, using 45Ca, revealed that the unstimulated 45Ca uptake in 1 BR fibroblasts was 4–5 times higher than in DU 145 cancer cells. Depolarization with high extracellular K caused a 2–3‐fold increase in 45Ca influx in 1 BR but only 25–55% increase in DU 145 cells. Verapamil caused a significant inhibition of cell growth with an IC50 value of 55 μM. Verapamil paradoxically increased 45Ca uptake in both unstimulated and K‐stimulated DU 145 cells. Whereas unstimulated 45Ca uptake could be blocked by very low concentrations of lathanum (10 μM), much higher concentrations (1–10 mM) were required to completely block uptake in K‐depolarized cells. Both trifluoperazine and tamoxifen also inhibited cell proliferation with an IC50 concentration of approximately 5 μM. These drugs, had, however, no effect on 45Ca uptake either in unstimulated or depolarized cells. The results suggest that voltagegated calcium channels exist in both DU 145 cancer cells and fibroblasts. However, verapamil, in contrast to 1 BR, failed to block these channels in DU 145 cells. The mechanism of antiproliferative action of verapamil may be related to the observed, although paradoxical, increase in cellular calcium. The effect of trifluoperazine and tamoxifen does not involve changes in transmembrane calcium movements but could be mediated by their inhibition of calmodulin‐mediated reactions within the cell.
Effect of glycine on retroperitoneal and intraperitoneal organs in the rat model
Authors: Maatman Thomas J. , Musselman Paul , Kwak Y. S. , Resnick Martin I.
Published: February 2007

Twenty Sprague Dawley rats were administered various doses of 1.5% amino acetic acid (glycine), lactated Ringer's, and water, both intravenously and retroperitoneally, in an attempt to recreate the post‐transurethral resection syndrome in a rat model. The kidneys, liver, and pancreas were harvested 6 hours after exposure and examined pathologically. Water and lactated Ringer's had no histologic effect on these organs. Glycine was found to have a toxic effect on the kidneys and liver and this effect was dose related. Based on these results, it is postulated that glycine toxicity may play a significant role as a causative factor in producing the post‐transurethral resection syndrome.
Argyrophilic nucleolar organizer regions in benign hyperplastic and cancerous human prostates
Authors: Masai Motoyuki , Abe Kouichi , Akimoto Susumu , Shimazaki Jun , Yatani Ryuichi
Published: February 2007

Argyrophilic nucleolar organizer regions (AgNORs) were examined histologically in cells of benign hyperplastic and cancerous human prostates. Individual dots of AgNORs inside nucleus that were stained as separate granules or as parts of clusters were counted as one, and the average number of dots per cell was obtained by counting 100 nuclei. The number in epithelial cells was similar to that in stromal cells of hyperplastic prostates. In cancerous prostates, the number was larger than in hyperplastic prostates and increased along with upgrading. The number in incidental cancers was smaller than in clinical cancers as compared with cells of the same Gleason pattern. Number correlated with T factor, but not with N and M factors. Response to treatment and cause‐specific survival in stage D2 patients receiving endocrine therapy did not correlate with number, although a relationship between Gleason pattern and survival was shown in these patients. It was concluded that AgNORs might not be an indicator to predict prognosis after endocrine therapy, since a number of AgNORs did not influence response to the therapy.
Prostate specific antigen and prostatitis I. Effect of prostatitis on serum psa in the human and nonhuman primate
Authors: Neal Durwood E. , Moon Timothy D. , Clejan Sanda , Sarma Deba
Published: February 2007

Prostate specific antigen (PSA) has become a mainstay in the diagnosis and management of patients with prostate cancer. We have found, as have others, that it may be elevated in patients with prostatic inflammation. Ten patients had clinical evidence of prostatitis and elevated PSA levels. Six of these had persistently elevated levels after antibiotic treatment. After transrectal ultrasonography and biopsy, two had findings of adenocarcinoma, and the rest had a pathologic diagnosis of acute or chronic prostatitis. We studied this process in an experimental model of prostatitis using a nonhuman primate. We infected six cynomolgus monkeys and followed their PSA levels until resolution of the infection. The PSA peaked between 5 and 7 days after inoculation and gradually returned to baseline in 8 weeks. The dramatically elevated serum PSA levels in bacterial prostatitis can cause confusion in the diagnosis of prostatic carcinoma.
Prostate specific antigen and prostatitis II. PSA production and release kinetics in vitro
Authors: Moon Timothy D. , Neal Durwood E. , Clejan Sanda
Published: February 2007

Elevations in serum prostate specific antigen (PSA) levels in patients with prostatitis are well known, but the pathophysiologic mechanisms involved with this phenomenon are poorly understood. We have recently evaluated the effect of prostatitis on PSA levels in primates. This data demonstrated a rapid rise in PSA, which subsequently fell along the biological decay curve. This suggested a release of sequestered PSA. We evaluated the effect of infection upon PSA production for the prostatic adenocarcinoma cell line LNCaP. The cell line was determined to produce 9.6 ± 2.7 fg/cell/hr PSA with essentially linear kinetics. No effect was seen with dead bacteria, bacterial supernatant or complement upon the PSA production. Live E. coli had no effect for 4–8 hours at which time the cells sloughed and PSA production ceased. No release of stored PSA was seen. These data do not elucidate the reasons for increased serum PSA levels found with acute bacterial prostatitis, but indicate that it is not a storage phenomenon.
Evaluation of a new tumor marker for localized prostate cancer
Authors: Culkin Daniel J. , Gelder Frank B. , Vick Stephen R. , Parra Brett L. , Mata John A. , Venable Dennis D. , Zitman Roger A.
Published: February 2007

Adenocarcinoma associated antigen (ACAA) is a large molecular weight protein that is normally found in low serum levels. Recent data have revealed elevations in patients with adenocarcinomas, including prostate cancer. To evaluate the relationship of ACAA levels with prostate cancer, we measured the cytosol content in malignant and nonmalignant prostate tissue and compared these results to those of the standard markers, prostatic acid phosphatase (PAP) and prostatic specific antigen (PSA). Enzyme solid phase immunoassay was used to quantitate PSA and ACAA levels, and the enzymatic method was used to measure PAP. Wedge resection from the right and left posterior lobes of 50 fresh radical retropubic prostatectomy specimens were used for cytosol analysis. All foci of cancer within each prostate gland were carefully mapped by a single pathologist. When all malignant wedges (N = 74) were compared to all the benign wedges (N = 21), only the PSA levels showed significant elevation (p < 0.02). However, when benign and malignant tissue from the same prostate were available for comparison, both PSA (N = 17) and ACAA (N = 16) showed significant elevations in the cytosol of the malignant tissue (p < 0.002 and p < 0.03, respectively). Although not statistically significant, the cytosol PAP did show a consistent trend to be greater in malignant tissue. It appears that there is an association of increased cytosol ACAA and PSA with prostate cancer.
Studies on the proliferation, secretory activities, and epidermal growth factor receptor expression in benign prostatic hyperplasia explant cultures
Authors: Jones E. Glynne , Harper M. E.
Published: February 2007

Short term explant cultures of benign prostatic hyperplasia (BPH) tissues were studied immunohistochemically to characterise both the morphological changes within the explant tissue and the cellular origin of the epithelial cell outgrowth. Altered patterns of expression of cytokeratins, prostate specific antigen (PSA) prostatic acid phosphatase (PAP), and epidermal growth factor (EGF) receptor were observed. After sloughing of the secretory epithelium in the majority of the acini repopulation and outgrowth of a monolayer was accomplished by cells which were strongly positive for stratifying keratin and EGF receptor and negative for PAP and PSA, indicative of a basal cell phenotype. The peak of proliferation in the acini, as assessed by Ki‐67 immunohistochemistry, occurred after 2–4 days in culture. Preliminary studies on BPH tissue xenografts in nude mice indicated that better preservation of normal morphology, secretory activity, and antigen expression could be achieved.
Relationship of proliferating cell nuclear antigen (PCNA) in prostatic carcinomas to various clinical parameters
Authors: Harper M. E. , Glynne‐Jones E. , Goddard L. , Wilson D. W. , Griffiths K. , Conn I. G. , Matenhelia S. S. , Peeling W. B.
Published: February 2007

Proliferating cell nuclear antigen (PCNA) expression was determined immunohistochemically, using a monoclonal antibody PC10, in 102 prostatic carcinoma samples and in prostate tissue from 21 patients with benign prostatic hyperplasis (BPH). The percentage of cells with stained nuclei ranged from 1% to 58% in the carcinoma specimens and 0% to 10% in the BPH specimens. A semiquantitative scoring system was devised for the degree of PCNA positivity observed in the tumors. Statistical analysis of the PCNA score in relation to the histological grade of the tumors gave a significant positive or negative correlation between these parametersP<0.001. No significant correlation between PCNA score was, however, seen with metastatic status, T category (TMN classification) of the primary tumor, or the patient's age at diagnosis.

In 65 prostatic cancer patients of known survival, those individuals whose tumors had a PCNA score of ± (< 10% of nuclei stained) were compared with those patients whose tumors were either 1+, 2+, or 3+ (>10% of nuclei stained). Life table analysis of the two groups indicated that the patients with the lower PCNA score survived significantly longer than those with the higher PCNA scores,P<0.04.

Comparison of the Ki‐67 expression in frozen sections with the PCNA expression in wax‐embedded tissue of 86 prostatic carcinomas was also undertaken. A significant correlation between these two parameters was found,P<0.001, although the growth fraction estimated by Ki‐67 expression was generally lower than that given by the PCNA scoring system. 1992 Wiley‐Liss, Inc.
Immunohistochemistry and biochemistry in detection of androgen, progesterone, and estrogen receptors in benign and malignant human prostatic tissue
Authors: Brolin Jan , Ekman Peter , Skoog Lambert
Published: February 2007

The relative distribution of androgen (AR), progesterone (PR), and estrogen receptors (ER) was localized and estimated in human prostate tissue by immunohistochemistry in five normal tissue samples, in eight benign hyperplastic (BPH) samples, in nine primary cancers, and in seven prostate cancer metastases. Moreover, three prostatic cancer cell lines (LNCaP, DU 145, and PC 3) were analyzed. A comparison between the results obtained by radioligand binding assays and immunohistochemistry was performed for the AR and PR.

Using immunohistochemistry, the AR was exclusively detected in the nuclei of both benign and malignant prostatic epithelial cells. The highest proportion of AR‐positive cells was found in BPH and in prostate cancer metastases as compared with normal prostatic tissue. In a majority of the cases, the PR was only present in the nuclei of stromal cells. Benign hyperplastic prostates contained higher proportions of PR‐positive cells as compared with primary carcinoma. PR was sparse in epithelial cells. ER‐positive stromal cell nuclei were only detected in carcinomatous prostates. A few ER‐positive epithelial cell nuclei were found in one sample each of a BPH and normal prostate.

All cells from the androgen‐dependent, LNCaP, cell line and a majority of the cells from the androgen‐independent, DU 145, cell line were AR‐positive. In contrast, the cells from the androgen‐independent, PC 3, cell line were all AR‐negative. All three cell lines were PR‐ and ER‐negative.

The radioligand binding technique detected the AR in extracts from both the cytosol and the nucleus. Again BPH contained higher amounts of AR as compared with normal prostatic tissue. The LNCaP cells contained high amounts of cytosolic AR while cells from the DU 145 and PC 3 cell lines lacked detectable AR as estimated by biochemical techniques. There seemed to be a discrepancy between biochemically measured and immunohistochemically estimated receptor content.
The relationship between cardiovascular complications of estrogen therapy and fibrinolysis in patients with prostatic cancer
Authors: Hasui Yoshihiro , Nishi Shohei , Kitada Shinichiro , Osada Yukio , Sumiyoshi Akinobu , Marutsuka Kousuke
Published: February 2007

To determine the relationship between cardiovascular complications of estrogen therapy and fibrinolysis, fibrinolysis parameters plasminogen, urokinase‐type plasminogen activator (u‐PA), tissue‐type plasminogen activator (t‐PA), and plasminogen activator inhibitor‐1 (PAI‐1), were assessed in 12 prostatic cancer patients before and 6 weeks after the onset of estrogen therapy. The levels of plasminogen, u‐PA, and PAI‐1 in the patients treated with the estrogen therapy were significantly higher than those in the patients before the therapy. The t‐PA level in the patients during the therapy was significantly lower than that before the treatment. Cardiovascular complications were found in two patients (16.7%) during estrogen therapy. In the two patients, marked elevation of PAI‐1 and decreased level of t‐PA were observed during the therapy. These results indicate that cardiovascular complications of estrogen therapy in patients with prostatic cancer may be related to hypofibrinolysis resulting from changes of PAI and t‐PA.
Isolation and characterization of transforming growth factor beta response variants from human prostatic tumor cell lines
Authors: Watts Rebecca G. , Ware Joy L.
Published: February 2007

In this study we examined the relation between the response to transforming growth factor beta (TGFβ1) in vitro and the growth in vivo of 1‐LN‐PC3‐1A (1‐LN) human prostatic carcinoma cells. 1‐LN cells resistant to the growth‐inhibitory effects of TGFβ1, were isolated after exposure to 2 ng/ml TGFβ1, in an anchorage‐independent growth assay. Cloning of TGFβ1,‐resistant and ‐sensitive populations produced 2 clones (R2‐6 and 1‐LN clone 4), which maintained relatively stable resistance or sensitivity, respectively, in the absence of TGFβ1, for up to 12 passages. Colony formation by the R2‐6 cells in the presence of TGFβ1, was 2‐10 times greater than that of 1‐LN clone 4, depending upon the TGFβ1, concentration. Injection of 1 × 105 R2‐6 cells into athymic nude mice produced tumors with a significantly shorter latency interval as compared with 1‐LN clone 4 tumors (P < 0.0001). Western immunoblotting showed that higher levels of latent TGFβ1, protein were secreted into the culture medium by 1‐LN clone 4 cells. Acidified conditioned media from both clones inhibited mink lung epithelial cell DNA synthesis. Neutralizing monoclonal antibody to TGFβ1, but not TGFβ2 abrogated this inhibitory effect. Comparison of the different sensitive and resistant clones showed that in vitro sensitivity to TGFβ1, and in vivo tumor latency interval were not invariably correlated. Thus, the TGFβ1, response phenotype in vitro was not always predictive of growth delay in vivo.
The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle
Authors: Shapiro Ellen , Hartanto Victor , Lepor Herbert
Published: February 2007

The objective of the present study was to determine whether the smooth muscle content of the prostate adenoma is related to the clinical response to terazosin, a long‐acting selective alpha, blocker. Multiple random biopsies of the prostate were obtained from 26 male subjects with symptomatic benign prostatic hyperplasia (BPH) prior to initiating therapy with terazosin. Double immunoenzymatic staining and computer‐assisted quantitative color image analysis were utilized to quantify the area density of smooth muscle, connective tissue, glandular epithelium, and glandular lumen. The clinical response to alpha blockade was based upon changes in peak urinary flow rate and the Boyarsky symptom score. A significant direct relationship was observed between the percent area density of smooth muscle and the percent change in peak urinary flow rate. A statistically significant correlation between the percent area density of smooth muscle and the percent change in Boyarsky symptom score was not observed. The percent area density of prostate smooth muscle in the subjects exhibiting a favorable clinical response was 38% greater than the nonre‐sponders (P = 0.068). The clinical response to alpha blockade in BPH is related to the area density of prostate smooth muscle.
Immunohistochemical evidence of the existence and localization of aromatase in human prostatic tissues
Authors: Matzkin Haim , Soloway Mark S.
Published: February 2007

Estrogens may be involved in normal growth of the prostate and the development of benign prostatic hyperplasia (BPH). The location of estrogen production is still unclear, and there has never been a direct evidence for the existence of the aromatase system, which converts androgens to estrogens, in the prostate. Using an avidin‐biotin technique with a polyclonal anti‐human placental aromatase, we demonstrated the existence of aromatase in normal prostates of young men and BPH tissue from elderly men. The staining is more pronounced in the stroma. However, positive stains were also seen in the glandular epithelium. While evidence of the existence of an enzyme system does not equal demonstration of its activity in a specific tissue site, our findings suggest that local estrogen production in the stroma and/or epithelium of the prostate may play a role in the maintenance of normal growth and development Of BPH.
DNA sequence of the androgen receptor in prostatic tumor cell lines and tissue specimens assessed by means of the polymerase chain reaction
Authors: Culig Zoran , Klocker Helmut , Eberle Johannes , Kaspar Felizia , Hobisch Alfred , Cronauer Marcus V. , Bartsch Georg
Published: February 2007

Essentially all prostatic carcinomas relapse to an androgen‐independent stage during androgen ablation therapy. The underlying genetic changes are still unclear. Such changes are suspected to affect the androgen‐signalling pathway as well as growth promoting and inhibiting factors. This study was undertaken to test for structural changes of the androgen receptor in prostatic tumor cell lines and primary tumors. Complementary DNA (cDNA) fragments of the androgen receptor (AR) were isolated from the cell lines LNCaP, PC‐3, and DU 145, ten tissue specimens obtained by radical prostatectomy, and five fine‐needle biopsies by means of the polymerase chain reaction (PCR) technique. Fragments encoding the hormone‐and DNA‐binding domains were analyzed by DNA sequencing. The PCR technique is highly sensitive and especially recommended for the analysis of small tissue samples, such as those obtained by fine‐needle aspiration.

No alterations were detected in the tissue specimens and the five fine‐needle aspirates. In the three tumor cell lines that represent late stages of prostatic tumor, different findings were obtained. The androgen‐independent DU 145 cells did not express androgen receptors, whereas the PC‐3 cells, which are also androgen‐independent, expressed very low levels of normal AR. In contrast to this, the androgen‐dependent LNCaP cells expressed high levels of structurally abnormal androgen receptors. These results suggest that androgen receptor mutations are probably uncommon molecular events in the early stages of prostatic cancer. Qualitative and quantitative changes, however, seem to occur in advanced prostatic cancer. © 1993 Wiley‐Liss, Inc.
The effect of finasteride on prostate‐specific antigen in men with benign prostatic hyperplasia
Authors: Guess H. A. , Heyse J. F. , Gormley G. J.
Published: February 2007

Finasteride is a specific 5‐α‐reductase inhibitor that has been shown to reduce prostate size and decrease serum levels of prostate specific antigen (PSA). Among men who received finasteride (5 mg/day) for 12 months in North American clinical trials and in whom prostate cancer was not diagnosed the median percentage change in PSA was −50% (5–95% range: −81% to + 20%). At baseline 72% had PSA ⩽ 4.0 ng/ml and 93% had PSA ⩽ 10.0 ng/ml. After 12 months on finasteride, 75% had PSA ⩽ 2.0 ng/ml and 95% had PSA ⩽ 5.0 ng/ml. Thus, the proportion of BPH patients with PSA levels of 2.0 ng/ml and 5.0 ng/ml after 12 months of treatment was comparable to the proportion with pretreatment PSA levels of 4.0 ng/ml and 10.0 ng/ml. Among the 10 men in these trials subsequently diagnosed with prostate cancer while on long‐term finasteride therapy (5 mg/day), the median percentage change in PSA was −26% (range: −48% to + 12%). Limited experience with finasteride in men with prostate cancer suggests that the reduction in PSA of malignant origin appears to be no greater than the percentage reduction in PSA of benign origin. These effects on PSA have not been shown to confer any therapeutic benefit. Physicians using finasteride should be aware of its effect on PSA levels. © 1993 Wiley‐Liss, Inc.
Growth of an androgen‐sensitive human prostate cancer cell line, LNCaP, in nude mice
Authors: Lim David J. , Liu Xiang‐Lin , Sutkowski Debra M. , Braun Eva J. , Lee Chung , Kozlowski James M.
Published: February 2007

This study was undertaken to establish an androgen‐sensitive model of human prostatic carcinoma in nude mice. The androgen‐sensitive prostatic carcinoma cell line, LNCaP, was suspended in reconstituted basement membrane (Matrigel) and injected subcutaneously into nude mice. The LNCaP cell line was chosen for the study, because the cell line is androgen‐sensitive and secretes prostate specific antigen (PSA) into culture media. Following injection of 1 × 106 LNCaP cells with 0.25 ml of Matrigel, 88. of mice exhibited palpable tumor burdens after 12 weeks of observation. In addition, significant levels of PSA were observed in the serum of LNCaP‐bearing mice. Bilateral orchiectomy of mice resulted in tumor regression and stabilization of serum PSA levels, compared to testis‐intact controls. A significant correlation of PSA to tumor volume and weight was observed. The castrate level of testosterone was confirmed by radioimmunoassay and was similar to testosterone levels in female nude mice. Matrigel allows for a conducive environment to propagate LNCaP cells in nude mice. Furthermore, the growth can be manipulated by castration, leading to involution of tumor and stabilization of serum PSA level. This in vivo model of hormone‐sensitive human prostate cancer cell line will serve as a model for the study of prostate tumor biology and treatment. © 1993 Wiley‐Liss, Inc.
Detection of human papillomavirus (HPV) DNA in human prostatic tissues by polymerase chain reaction (PCR)
Authors: Sarkar Fazlul H. , Sakr Wael A. , Li Yi‐Wei , Sreepathi Prabhakar , Crissman John D.
Published: February 2007

Human papillomavirus (HPV) infections are strongly linked to the pathogenesis of uterine cervical neoplasms, and have been implicated in other cancers of the female genital tract. In contrast, the association of HPV with the cancers of the male urogenital tract is less evident, except in anal and penile cancers. However, recent studies reporting the prevalence of HPV infections in human prostate cancers (60–100% HPV 16 positive vs. no infection of HPV) have raised controversies regarding the prevalence of HPV in benign and neoplastic human prostate.

We investigated the prevalence of HPV infections in prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinomas in 23 surgically resected prostates. Polymerase chain reaction (PCR) was used to amplify HPV 6b/11, 16 and 18 specific DNA sequences, using type specific HPV primers selected from the transforming gene E6‐E7. The areas of PIN and cancer in 6 p.m H&E stained tissue sections were identified, and respective areas of PIN and cancer were isolated from the adjacent serial sections and used for DNA amplification and HPV detection (Fig. 1). Our results demonstrated the presence of HPV 16 in three carcinomas (13%), using type specific primers in PCR amplified samples. We were not able to demonstrate the presence of other HPV types (HPV 6b/11 or HPV 18) in any of the samples using specific primers. Two of these prostates showed relatively strong positive signals by dot blot analysis, when hybridized with a 32P‐labeled HPV 16 type specific oligonucleotide probe. One more sample showed weak positivity, when hybridized with a 32P‐labeled HPV 16 type specific oligonucleotide probe. Subsequently, we have confirmed these results by Southern hybridization of the samples transferred to nylon membrane after agarose gel electrophoresis and detected by HPV 16 type specific oligonucleotide probe, using chemiluminescent assay. We, therefore, conclude that HPV infections of the prostate in general are not as common as has been previously claimed by other investigators. © 1993 Wiley‐Liss, Inc.
Finasteride (MK‐906) in the treatment of benign prostatic hyperplasia
Authors:   The Finasteride Study Group
Published: February 2007

The effects of finasteride, a potent 5α‐reductase inhibitor, were assessed in 750 patients with benign prostatic hyperplasia (BPH) in a multicenter, double‐blind, placebo‐controlled study. Patients were randomized to finasteride, 1 or 5 mg, or placebo, daily for 12 months. The following changes were seen with finasteride 5 mg after 12 months: (1) Serum dihydrotestosterone decreased by 62% compared to no change with placebo (P < 0.001); (2) serum prostate‐specific antigen (PSA) decreased by 46% compared to no change with placebo (P < 0.001); (3) prostate volume was reduced by 22% compared to a 5% decrease with placebo (P < 0.001); (4) maximum urinary flow rate increased by 1.7 ml/sec compared to a 0.4 ml/sec increase with placebo (P < 0.025); (5) total urinary symptom scores decreased by 3.3 points compared to a 2.0 point decrease with placebo (P = 0.005), and (6) obstructive symptom scores decreased by 2.1 points compared to a 1.4 point decrease with placebo (P = 0.017). The effects of finasteride 1 mg were similar to 5 mg, except in urinary symptoms, where no significant differences between 1 mg and placebo were seen. Patients treated with 5 mg finasteride demonstrated significantly greater improvements in urological status (assessed by the investigator) and the troublesome symptom score, compared to placebo. Treatment with finasteride was well tolerated. We conclude that finasteride is an effective medical therapy for a significant proportion of patients with BPH. © 1993 Wiley‐Liss, Inc.
Genistein and biochanin A inhibit the growth of human prostate cancer cells but not epidermal growth factor receptor tyrosine autophosphorylation
Authors: Peterson Greg , Barnes Stephen
Published: February 2007

The effect of the isoflavones, genistein, daidzein, and biochanin A on the growth of the LNCaP and DU‐145 human prostate cancer cell lines has been examined. Genistein and biochanin A, but not daidzein, inhibit both serum and EGF‐stimulated growth of LNCaP and DU‐145 cells (IC50 values from 8.0 to 27 μg/ml for serum and 4.3 to 15 μg/ml for EGF), but have no significant effect of the EGF receptor tyrosine autophosphorylation. In contrast, tyrphostin 25, a specific EGF receptor tyrosine kinase inhibitor, inhibits EGF‐stimulated growth and EGF receptor tyrosine autophosphorylation in these whole cells, but does not inhibit serum‐stimulated growth. These data suggest that the mechanism of action of genistein and biochanin A does not depend on inhibition of EGF receptor tyrosine autophosphorylation, but on a more distal event in the EGF receptor‐mediated signal transduction cascade. © 1993 Wiley‐Liss, Inc.
A common set of nuclear matrix proteins in prostate cancer cells
Authors: Pienta Kenneth J. , Lehr Jeffrey E.
Published: February 2007

The nuclear matrix is the RNA‐protein network which forms the skeleton of the nucleus, and participates in DNA organization as well as in multiple cellular functions. Nuclear matrix proteins have been demonstrated to be tissue and cell type specific, as well as to reflect the state of cell differentiation and/or transformation. Previously, common nuclear matrix proteins were demonstrated between the rat prostate and the Dunning rat prostate adenocarcinoma cell lines. This study demonstrates that nuclear matrices derived from Dunning rat and human prostate cancer cell lines, as well as human tumors, share several common proteins. These common proteins suggest that alterations which occur in the nuclear matrix with prostate cell transformation may share a common basis. © 1993 Wiley‐Liss, Inc.
Vitamin A regulates proliferation and differentiation of human prostatic epithelial cells
Authors: Peehl Donna M. , Wong Stephen T. , Stamey Thomas A.
Published: February 2007

The response of cultured human prostatic epithelial cells to vitamin A was measured by clonal growth assay in serum‐free medium. Retinoic acid at 3 nM or higher inhibited the proliferation of cell strains derived from normal, benign hyperplastic and malignant tissues, while lower levels (0.03 nM) were stimulatory. Reduced proliferation induced by retinoic acid was accompanied by a marked change in morphology, as intercellular adhesion decreased. In conjunction, the expression of keratins 8 and 18, associated with the differentiated luminal phenotype of prostatic epithelia, was increased. In post‐confluent cultures, retinoic acid prevented the appearance of keratin 1, which accompanied the development of a squamous phenotype by cells maintained under these conditions. The findings of this study indicate a role for vitamin A as a modulator of the growth and differentiation of prostatic epithelial cells. © 1993 Wiley‐Liss, Inc.
Castration‐induced changes in morphology, androgen levels, and proliferative activity of human prostate cancer tissue grown in athymic nude mice
Authors: Van Weerden W. M. , Van Kreuningen A. , Elissen N. M. J. , Vermeij M. , De Jong F. H. , Van Steenbrugge G. J. , Schröder F. H.
Published: February 2007

The transplantable human prostate tumor lines PC‐82 and PC‐EW regress after androgen depletion. The castration‐induced decline in tumor volume was faster in the PC‐EW tumor (half‐life 6 days) than in the PC‐82 tumor (half‐life 18 days), despite similar castrate androgen levels of less than 3 pmollg tissue. Androgen ablation of the PC‐82 tumor induced a wave of apoptosis, whereas in the PC‐EW tumor, necrotic cell death was predominantly observed. The proliferative activity (BrdU index) of PC‐82 and PC‐EW tumor tissue declined from 3% to less than 1% after castration. After androgen depletion, some proliferative activity remained, the major part of which was localized in the (murine) stromal compartment of the tumors. In contrast to the PC‐EW tumors, regrowth of androgen‐ablated PC‐82 tumors was rapidly induced by androgen resubstitution. The differences in response of these tumor models to androgen depletion and repletion appear to be related to the putative involvement of different cell death pathways. The role of the stroma in these processes is unclear. © 1993 Wiley‐Liss, Inc.
Presence of 11 β‐hydroxysteroid dehydrogenase enzyme in the human prostate tumor cell line LNCaP
Authors: Nath Nagendra , Lakshmi Vijaya , Rosenthal Julian C.
Published: February 2007

11 β‐Hydroxysteroid dehydrogenase (11β‐HSD) is the enzyme that catalyzes the reversible oxidation of the biologically active steroid cortisol and corticosterone to their inactive metabolites cortisone and dehydrocorticosterone. We report its presence in significant levels in the human prostate carcinoma cell line LNCaP cultured in medium RPMI‐1640 with 10% fetal calf serum (FCS). The 11‐dehydrogenase activity of 11β‐HSD is present, while the 11‐reductase activity is undetectable in these tumor cells under the present culture conditions. The enzyme activity is found to be linear with time of incubation, and is proportional to plated cell density. The enzymatic activity can be determined in cultures maintained for longer times. Carbenoxolone, the potential inhibitor of the 11β‐HSD, inhibits 95% of the dehydrogenase activity of the tumor cells when used in nM concentration. The presence of this enzyme in tumor cell line indicates that 11β‐HSD plays an important role in maintaining the active glucocorticoid levels in the prostate. © 1993 Wiley‐Liss, Inc.
Effect of epidermal growth factor on prostate cancer cell line PC3 growth and invasion
Authors: Jarrard David F. , Blitz Barry F. , Smith Robert C. , Patai Barbara L. , Rukstalis Daniel B.
Published: February 2007

Elevated levels of epidermal growth factor (EGF) and epidermal growth factor receptor (EGF‐R) have been demonstrated in prostate cancer cell lines and clinical specimens suggesting a role for polypeptide growth factors in prostate tumor cell growth and invasion. To more clearly define the role of EGF in prostate cancer invasion, we undertook a series of studies utilizing the PC3 prostate cancer cell line, an aggressive, hormone‐independent cell line derived from a metastatic lesion. No statistical differences were noted in the growth of PC3 cells under serum‐free conditions when EGF (10−10 M‐10−8 M) or monoclonal anti‐EGF‐R antibody (10−11 M‐10−8 M) were added. Utilizing the Boyden chamber microinvasion assay, EGF supplemented cells demonstrated a statistically significant augmentation in invasion (P < 0.05) when compared to control cells at each time point in the study. With increasing length of exposure to EGF, the number of concentrations that produced significant invasion increased: day 1 (10−8 M), day 3 (10−9, 10−9 M), and day 5 (10−7, 10−8, 10−10 M). Northern blot analysis of EGF supplemented cells revealed an increase in expression of urokinase plasminogen activator (uPA) RNA, a serine protease involved in the regulation of pericellular proteolysis and membrane degradation. Protein analysis confirmed these findings. Statistically significant inhibition of invasion by anti‐uPA antibodies was demonstrated for EGF‐stimulated and PC3 control cells. Our results demonstrate that certain concentrations of EGF augment invasion in the PC3 cell line. This enhancement of invasion occurs in part by an overproduction of uPA, an extracellular protease. These findings suggest that the autocrine production of EGF may potentiate tumor cell invasion. © 1994 Wiley‐Liss, Inc.
Developmental estrogenization and prostatic neoplasia
Authors: Santti Risto , Mäkelä Sari , Pylkkänen Liisa , Newbold Retha R. , McLachlan John A.
Published: February 2007

The association of estrogens with benign prostatic hyperplasia and prostatic cancer has been widely studied, but no conclusive evidence exists for a role of estrogens in prostatic disease. This paper reviews the literature and describes studies which have sought to show a correlation of estrogens and alterations in the prostates of humans and experimental animal models. Using the developmentally estrogenized mouse model, we propose an alternative role for estrogens as a predisposing factor for prostatic diseases: estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to hyperplasia or neoplasia. Thus, the critical time for estrogen action would be during the development of the prostatic tissue. We further suggest that estrogen‐sensitive cells may remain in the prostate and be more responsive to estrogens later in life or less responsive to the normal controlling mechanisms of prostatic growth. © 1994 Wiley‐Liss, Inc.
In vitro radiation sensitivity of the lncap prostatic tumor cell line
Authors: Leith John T.
Published: February 2007

Because there is extremely limited information on the intrinsic radiosensitivity of human prostatic cancer cells, we have investigated the in vitro radiation response of exponentially growing LNCaP cells. Due to the very poor colony‐forming potential of the LNCaP cells, radiation survival was investigated using the dose‐dependent (0‐6 Gy) changes seen after X‐irradiation in the shapes of regrowth curves. Survival was described using both the single‐hit, multitarget (SHMT) equation and the linear‐quadratic (LQ) equation. The values and 95% confidence limits of the extrapolation number (n), quasi‐threshold dose (Dq), and mean lethal dose (Do) in SHMT terminology were respectively: 0.9 (0.7‐1.0), 0.0 Gy, and 1.39 (0.11) Gy. The LQ alpha and beta parameters were respectively 6.80 (1.13) and ‐0.53 (2.89). The X‐ray dose response of the LNCaP line is, therefore, purely exponential. The mean survival at the clinically relevant dose of 2 Gy (S2) was 51.2% for the LNCaP line. Comparison of the S2 value for the LNCaP line with previous investigations with other human prostatic cancer cell lines (DU145 and PC‐3) indicates a mean S2 value of 47.6%, which suggests that human prostate cancer cells might lie toward the resistant side of the spectrum for various classes of human neoplasms. © 1994 Wiey‐Liss, Inc.
Effects of 4‐MAPC, a 5α‐reductase inhibitor, and cyproterone acetate on regrowth of the rat ventral prostate
Authors: Shao Tsang C. , Kong Ann , Cunningham Glenn R.
Published: February 2007

Inhibitors of 5α‐reductase activity cause less involution of the rat ventral prostate (VP) than does castration. Studies were conducted in adult Sprague Dawley rats to evaluate the effects of a potent 5α‐reductase inhibitor, 4‐MAPC, and the antiandrogen, cyproterone acetate (CA), on DNA synthesis and apoptosis. In experiment 1, VP weight fell 33%, 53%, and 83%, and DNA per ventral prostate was reduced 24%, 46%, and 71%, by 4‐MAPC, CA, and castration, respectively. In experiment 2, adult rats were castrated, and the VP involuted for 7 days prior to 3 daily injections of testosterone propionate (TP; 1 mg/kg/d) ± 10 mg/kg/d of 4‐MAPC or CA. 3H‐thymidine incorporation into VP DNA was increased in castrated animals treated with TP, and 4‐MAPC and CA reduced uptake. In experiment 3, animals were treated for 14 days with the same protocol as that used in experiment 2. VP weight was increased in all animals treated with TP when compared with castration, and was reduced by both 4‐MAPC and CA. DNA in rats treated with TP was similar to that in intact animals. DNA was not reduced by 4‐MAPC, but was reduced by CA. The mRNA for TRPM‐2, a marker of apoptosis, was increased only in untreated castrated rats. It appears that CA has a greater inhibitory effect than 4‐MAPC on DNA synthesis. A major reason why castration reduces DNA more than either 4‐MAPC or CA is that neither of these agents was able to increase programmed cell death to the degree seen with castration. © 1994 Wiley‐Liss, Inc.
Interleukin‐2 transfected prostate cancer cells generate a local antitumor effect in vivo
Authors: Moody D. Branch , Robinson John C. , Ewing Charles M. , Lazenby Audrey J. , Isaacs William B.
Published: February 2007

In an effort to stimulate host‐mediated antitumor response against prostate cancer in an animal model, highly malignant Dunning MAT‐LyLu rat prostate carcinoma cells were transfected with the interleukin‐2 (IL‐2) cDNA, resulting in their ability to secrete large amounts of biologically active IL‐2. Although parental cells form lethal tumors when injected subcutaneously into syngeneic hosts at doses of ≥5,000, injections of IL‐2 secreting cells initially formed tumors and regressed completely in each of over 200 animals at all doses tested (104‐8 × 107 cells). Mixtures of parental and IL‐2 transfected cells were similarly rejected, demonstrating the non‐cell autonomous nature of the response. Histological analysis of regressing tumors revealed a vigorous, predominantly lymphocytic and macrophage infiltrate at day 2 and marked tumor necrosis by day 6. Immunohistochemical staining of infiltrating lymphocytes at this latter time point demonstrated numerous T cells bearing either CD4 or CD8 surface markers, suggesting these cells as possibly mediating the tumor rejection. The ability of athymic mice to reject the IL‐2 secreting tumor cells, however, suggests a non‐T‐cell‐mediated mechanism. Although splenic natural killer (NK) activity is increased following injection of IL2 secreting tumor cells, this activity appears to be unnecessary for tumor elimination since syngeneic animals injected with asialo‐GM1 antiserum to decrease NK activity also rejected IL‐2 transfected cells, albeit slightly less effectively than untreated animals. Immunization of animals with subcutaneous injections of IL‐2 transfected cells protected animals against a subsequent challenge of 104 wild‐type cells 1 to 2 weeks later in 19 of 51 cases; however, immunization did not confer protection against larger doses of parental tumor. These studies indicate that high local concentrations of IL‐2 stimulate the elimination of large local burdens of prostate cancer in this model system, and this elimination results in a weak, but detectable systemic immune response against wild‐type prostate cancer cells. © 1994 Wiley‐Liss, Inc.
Metastatic prostate cancer pulmonary nodules: Beneficial effects of combination therapy and subsequent withdrawal of flutamide
Authors: Cusan Leonello , Gomez José‐Luis , Dupont Andé , Diamond Pierre , Lemay Martin , Labrie Fernand , Moore Sean
Published: February 2007

A case is presented of a middle‐aged man suffering from stage D2 prostate cancer with pulmonary metastases who responded favorably, first, to endocrine combination therapy with the antiandrogen flutamide and an LHRH agonist for 5.5 years, and, second, to the subsequent withdrawal of Flutamide at the time of the progression of the disease. This case has several exceptional features: absence of bone metastases, pulmonary metastatic nodules characterized as focal neuroendocrine differentiation, and a positive response to antiandrogen withdrawal upon relapse of metastases after initial positive response. The concept of escape to androgen blockade and development of androgenic hypersensitivity is discussed. © 1994 Wiley‐Liss, Inc.