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PubMed2001

Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium.

Prostate cancer (PCa) is an androgen dependent disease that can be treated by androgen ablation therapy, and clinical trials are under way to prevent PCa through the reduction of androgen receptor (AR) activity. However, there are no animal models of AR-mediated prostatic neoplasia, and it remains unclear whether the AR is a positive or negative regulator of cell growth in normal prostate secretory epithelium. To assess the direct effects of the AR in prostate epithelium, a murine AR transgene regulated by the rat probasin promoter (Pb) was used to generate transgenic mice expressing increased levels of AR protein in prostate secretory epithelium. The prostates in younger (<1 year) Pb-mAR transgenic mice were histologically normal, but Ki-67 immunostaining revealed marked increases in epithelial proliferation in ventral prostate and dorsolateral prostate. Older (>1 year) transgenic mice developed focal areas of intraepithelial neoplasia strongly resembling human high-grade prostatic intraepithelial neoplasia (PIN), a precursor to PCa. These results demonstrate that the AR is a positive regulator of cell growth in normal prostate epithelium and provide a model system of AR-stimulated PIN that can be used for assessing preventative hormonal therapies and for identifying secondary transforming events relevant to human PCa.

Animals↗
PubMed2001

Prostate cancer, benign prostatic hyperplasia and physical activity in Shanghai, China.

BACKGROUND: Studies suggest that increased levels of physical activity might decrease the risk of prostate cancer. We ascertained lifetime measures of activity in a population-based case-control study of prostate cancer in Shanghai, China to investigate physical activity in a population where the incidence of prostate cancer is low but rising. METHODS: In all, 238 men with prostate cancer, diagnosed 1993-1995, were identified through a rapid reporting system. A second group of 206 men with benign prostatic hyperplasia (BPH) was matched to prostate cancer cases, and 471 age-matched and population-based controls were identified from urban Shanghai. Through personal interviews, we ascertained all daily, occupational, and recreational activities at ages 20-29, ages 40-49, and in 1988 to generate hours spent sleeping, sitting, in moderate activity, and in vigorous activity. Time spent per week in different activities was converted to metabolic equivalents (MET-h) and energy expended. RESULTS: Time spent in, MET-h of, and energy expended in physical activities were not consistently related to either prostate cancer or BPH when compared to controls. Few men reported regular vigorous activity. Occupational activity, based on an energy expenditure index using job titles, was suggestively associated with a decreased risk of BPH, but not associated with prostate cancer. Associations did not vary according to age or stage of prostate cancer at diagnosis. CONCLUSIONS: Our results, based on regular physical activity, occupational activity, hours in activities, MET-h, and energy expended, did not support a protective role of physical activity in prostate cancer or BPH for men in a low-risk population.

Adult↗
PubMedDate not supplied

CD4 and CD8 T-lymphocyte recognition of prostate specific antigen in granulomatous prostatitis.

In order to develop immunotherapies for prostate cancer, many groups are exploring vaccination strategies to induce an immune response against prostate specific antigen (PSA). To determine if T-cell recognition of PSA might be a feature of a naturally occurring human disease, we have studied patients with prostatitis, a poorly understood clinical syndrome of men in which there is evidence that an immune response directed against the prostate may be occurring. We wished to determine if a T-cell response to PSA might be occurring in these patients. We generated long-term T-cell lines from peripheral blood mononuclear cells (PBMC) of one patient with granulomatous prostatitis using purified PSA as an antigen. Several CD4+ and CD8+ TcR alpha/beta+ T-cell lines were selected for PSA reactivity as measured by at least a threefold increase in IFN-gamma secretion in response to PSA presented by irradiated autologous PBMC. CD4 and CD8 T-cell lines recognized PSA in the context of HLA-DRbeta1*1501 and HLA-B*0702, respectively. The specificity and HLA restriction of the lines was confirmed using EBV-B cell lines infected with a recombinant PSA-expressing vaccinia virus and also engineered to express PSA by retroviral transfection. HLA-matched targets infected by control vector as well as HLA-mismatched PSA-expressing targets did not induce the response. The data demonstrate that PSA-specific T cells are present in the PBMC of this patient with granulomatous prostatitis, who may be manifesting naturally the type of immune response directed at the prostate that is the goal of prostate cancer immunotherapy. However, the Class I-restricted epitope has not yet been demonstrated to be expressed on the surface of prostate cancer cells. To our knowledge, this is the first demonstration of HLA-DRB1*1501- or HLA-B*0702-restricted responses to PSA and extends the number of HLA molecules accommodating the use of PSA antigen as a candidate vaccine for prostate cancer immunotherapy.

Amino Acid Sequence↗
PubMedDate not supplied

Prostate volume before and after permanent prostate brachytherapy in patients receiving neoadjuvant androgen suppression.

PURPOSE: Limited duration neoadjuvant cytoreductive hormonal therapy (NHT) is used before the definitive radiotherapeutic management of prostate cancer to decrease target volume size and/or to decrease urinary obstructive symptoms. The purpose of this study is to examine the effect of NHT on prostate volume before permanent prostate brachytherapy (PPB) and on prostatic edema after PPB. METHODS AND MATERIALS: Between May 1998 and February 2004, 408 patients underwent PPB at our institution and provided research authorization for the use of their records. Of these, 122 (30%) underwent NHT. Of the 122, 78 (64%) underwent transrectal ultrasound before the start of NHT. Patients undergoing PPB who received NHT were compared with a similar non-NHT group (N = 286). Detailed measurements of prostate volume were performed by transrectal ultrasound before and after NHT, if applicable. In addition, intraoperative preimplantation transrectal ultrasound and post-implantation transrectal ultrasound were also performed. Post-implantation computed tomography was per formed within 1 day of PPB. RESULTS: The mean duration of NHT was 4.0 +/- 1.1 months (range, 1-8 months). The mean prostate volume before NHT was 63.3 +/- 22.8 cc (range, 19-138 cc), and after NHT (before PPB), it was 41.6 +/- 16.4 cc (18-98 cc). The median prostate volume decrease after NHT was 22.7 cc or 34.9%. There was no significant difference in the degree of postimplantation prostate edema, as measured by the postimplantation to preimplantation ratio (1.18 +/- 0.05 [range, 0.8-1.9]) for the NHT group and 1.21 +/- 0.03 (range, 0.8-1.9) for the non-NHT group (P = 0.5). CONCLUSIONS: Prostate volume decreased by approximately one third after 4 months of NHT. NHT did not affect the degree of post-PPB prostatic edema.

Aged↗
PubMed2005

The healthy rat prostate contains high levels of natural killer-like cells and unique subsets of CD4+ helper-inducer T cells: implications for prostatitis.

PURPOSE: Chronic nonbacterial prostatitis spontaneously develops in aged Lewis and Wistar rats but not in Sprague-Dawley rats. We report the unique profile of lymphocyte subsets present in the healthy Sprague-Dawley rat prostate. MATERIALS AND METHODS: We compared enzymatic and mechanical methods of intraprostatic lymphocyte isolation in healthy 8 to 10-week-old Sprague-Dawley rats. Mechanical isolation was chosen because of its superior preservation of surface antigens. Intraprostatic lymphocyte subsets were analyzed by flow cytometry. RESULTS: Levels of prostatic alphabetaTCR+ T cells were similar and levels of prostatic B cells were decreased 5 to 10-fold compared with those found in other tissues (p </=0.005). Unexpectedly two-thirds of the total prostatic lymphocytes expressed the natural killer (NK) marker CD161a+. They were divided equally between NK (CD161a+alphabetaTCR) and NKT (CD161a+alphabetaTCR+) cells. Of prostatic CD161a+ cells 50% to 60% were also CD8+. Levels of NKT cells were dramatically lower in other tissues (p </=0.005) and they never accounted for more than 8% of total lymphocytes. The prostate contained lower levels of CD4+ T cells than all tissues except the liver (p </=0.005) and higher levels of CD8+ T cells than any other tissue studied (p </=0.05), resulting in an inverted CD4-to-CD8 ratio. CD45RC+CD4+alphabetaTCR+ T cells and CD161a+CD4+alphabetaTCR+ NKT cells were elevated in the prostate (p </=0.02). CONCLUSIONS: The healthy rat prostate contains an unusually high proportion of NK and NKT cells. The balance between the CD45RC+CD4+alphabetaTCR+ T cells, which initiate the cell mediated immune response, and CD4+ NKT cells, which can suppress autoimmunity, may be a key in understanding the resistance of Sprague-Dawley rats to chronic nonbacterial prostatitis.

Animals↗
PubMed2005

Prostate specific antigen levels in young adulthood predict prostate cancer risk: results from a cohort of Black and White Americans.

PURPOSE: Prostate specific antigen (PSA) is a serine protease produced by normal and malignant prostate epithelial cells. Serum PSA increases with age, due largely to age related increases in the prevalence of benign prostatic disease. Little is known about PSA distribution in young adulthood, when benign and malignant prostatic diseases are rare, or about how PSA within the normal range in youth relates to subsequent prostate cancer risk. MATERIALS AND METHODS: We evaluated serum PSA and subsequent prostate cancer occurrence in a cohort of young black and white American men with a median age at blood draw of 34 years, who in 1959 to 1966 participated as the fathers of newborns enrolled in the Child Health and Development Study, and who were followed for several decades for prostate cancer. We examined associations between PSA in young adulthood and subsequent prostate cancer risk using a nested case-control design based on 119 black and 206 white cases with 2 control men matched to each case on race and year of birth. RESULTS: Prostate cancer risk increased with increasing PSA in black and white men. The OR comparing risk in the highest to lowest quartiles of PSA was 4.4 (95% CI 2.0 to 9.6) in black men and 3.5 (95% CI 2.0 to 6.1) in white men. ORs relating risk to PSA were higher when analysis was restricted to cases diagnosed before age 65 years. CONCLUSIONS: These findings suggest that PSA levels in young adulthood indicate increased risk of prostate cancer and, thus, they may be useful for targeting men for screening and early diagnosis.

Adult↗
PubMed2005

Comparison of the incidence of latent prostate cancer detected at autopsy before and after the prostate specific antigen era.

PURPOSE: Most data regarding the prevalence of latent prostate cancer found only at autopsy are from old reports. To determine if significant differences exist in the prevalence of latent prostate cancer between periods before and after the advent of screening for prostate cancer, we compared 2 groups of men undergoing autopsy during the 2 periods. MATERIALS AND METHODS: Our institutional autopsy record database was searched to identify all men found to have prostate cancer before or after death between 1955 and 1960 (total 3,307 men and 1,578 men older than 40 years), and between 1991 and 2001 (total 2,938 men, 1,380 men older than 40 years). We calculated the age based incidence of latent prostate cancer detected only at autopsy in an at risk population of men (older than 40 years). We also compared Gleason grade distribution and proportion of stage cT3 or greater cancers between the 2 periods. RESULTS: Between 1955 and 1960 the prevalence of latent prostate cancer detected only at autopsy in men older than 40 years was 4.8% compared to 1.2% (p < 0.0001) between 1991 and 2001. A significant decrease in the prevalence of latent, autopsy detected cancers was observed in men 70 to 89 years old at death. Autopsy detected cancers were found to be grossly invading adjacent structures (stage cT3 or greater) in 17 of 76 (22%) cancers discovered between 1955 and 1960, while none of the latent prostate cancers found in the 1991 to 2001 period were found to extend grossly beyond the prostate. CONCLUSIONS: Autopsy rates are decreasing at our institution. With the more widespread use of screening, the prevalence of latent prostate cancer has decreased 3-fold. The decrease in the prevalence of latent prostate cancer is especially dramatic in men older than 70 years. Further study will determine the significance of many of the tumors currently detected clinically, which may have been latent and found at autopsy if not for screening.

Adult↗
PubMed2006

Immunohistochemical staining of precursor forms of prostate-specific antigen (proPSA) in metastatic prostate cancer.

Precursors of prostate-specific antigen (proPSA) have been previously shown to be more concentrated in prostate cancer tissue. This study characterizes the immunohistochemical staining (IHS) of proPSA forms in metastatic prostate cancer compared with prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). A tissue microarray, consisting of 74 cases of metastatic prostate carcinoma and control tissues, was used. IHS, using monoclonal antibodies against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), native ([-5/-7]pPSA), PSA, and PAP, was analyzed. The monoclonal antibodies were specific for both benign and malignant prostatic glandular tissue. IHS with [-5/-7]pPSA showed the least number of cases with negative staining (3%), and the most number of cases with moderate or strong staining (76%). In the 60 cases where all 4 stains could be evaluated, none of them were negative for proPSA and positive for PSA or PAP, and all 7 cases that were negative for both PSA and PAP showed IHS to proPSA. [-5/-7]pPSA (native proPSA) may be a better marker than PSA and PAP in characterizing metastatic prostate adenocarcinoma, with most of the cases showing positivity for the marker. Even cases that were negative for PSA and PAP, were reactive for proPSA. Such enhanced detection is particularly important in poorly differentiated carcinomas involving metastatic sites where prostate carcinoma is a consideration. A panel of markers, including proPSA, should be performed when metastatic prostate carcinoma is in the differential diagnosis.

Acid Phosphatase↗
PubMed2005

Value of prostate volume measurement using transabdominal ultrasonography for the improvement of prostate-speci fi c antigen-based cancer detection.

PURPOSE: To examine value of prostate-speci fi c antigen (PSA) adjusted by prostate volume measured using transabdominal ultrasonography in prostate cancer detection among men with elevated PSA. METHODS: 238 men aged 79 years or younger with serum PSA levels of 2.0-20.0 ng/mL and normal digital rectal examination fi ndings were studied in terms of total and free PSA, prostate volumes with transrectal (TRUS) and transabdominal (TAUS) ultrasonography and transition zone volumes with TRUS prior to transrectal 10-core biopsy. In addition to sole PSA values and the free-to-total PSA ratio, volume-adjusted PSA values, PSA densities determined by TRUS (PSAD(TRUS)), and TAUS (PSAD(TAUS)), and PSA transition zone densities (PSATzD) were compared using receiver operating characteristic (ROC) analysis. RESULTS: Prostate cancer was diagnosed in 58 (24.4%) of the 238 men who underwent prostate biopsies. Of the areas under ROC curves (AUC) of studied parameters, PSATzD (AUC 0.751) was the best and signi fi cantly superior to PSAD(TAUS) (AUC 0.664, P = 0.007). However, PSAD(TAUS) exceeded PSA (AUC 0.559, P = 0.004) and showed potential capability of a one-fourth reduction in unnecessary biopsies without spoiling sensitivity (90%). Cancer detection rate was only 4.2% in the 48 patients whose prostate volume in TAUS was > 50 mL and PSAD(TAUS) was < 0.075. CONCLUSIONS: Since PSAD(TRUS) and PSATzD were signi fi cantly superior to PSAD(TAUS), TRUS is feasible as the standard fashion to determine prostate volume in the diagnosis of prostate cancers. However, TAUS is also worthwhile as it can improve the prostate cancer detection using sole PSA, and primary use of TAUS has the potential to reduce the substantial number of unnecessary biopsy safely.

Adult↗
PubMed1995

Kinetic analysis of prostatic volume in patients with stage D prostatic cancer treated with LHRH analogues in relation to prognosis.

OBJECTIVE: To evaluate the clinical usefulness of the kinetic analysis of prostatic volume in the prognosis of patients with Stage D prostatic cancer treated using luteinizing hormone-releasing hormone (LHRH) analogues. PATIENTS AND METHODS: The reduction of prostatic volume was monitored in 12 patients with Stage D prostatic cancer using transrectal ultrasonography (TRUS) after treatment with LHRH analogues. Data obtained from the kinetic analysis of prostatic volume were compared with the prognosis. RESULTS: All the patients having a reduction time, tau (derived from the kinetic analysis of prostatic volume change with time), of less than 41 days had neither clinical progression within 15 months nor death caused by prostatic cancer during the 5-year follow-up, while the disease-specific 5-year survival rate in patients having a tau of greater than 42 days was as low as 17%. The difference in both the progression and disease-specific survival between these groups was statistically significant (P < 0.05) despite the limited number of patients. In contrast, conventional prognostic parameters showed no significant predictability for prognosis with the exception of prostatic acid phosphatase, which correlated strongly with the occurrence of progression within 15 months. CONCLUSION: The kinetic analysis of the change of prostatic volume using TRUS shows promise in the prognosis of the patients with Stage D prostatic cancer.

Aged↗
PubMed2006

Impact of prostate-specific antigen level and prostate volume as predictors of efficacy in photoselective vaporization prostatectomy: analysis and results of an ongoing prospective multicentre study at 3 years.

UNLABELLED: In a multicentre study from the USA, 3-year results of the high-power KTP laser prostatectomy are presented. The authors used preoperative PSA level as a marker of prostate volume and assessed its potential predictive value on the level of clinical efficacy for treating symptomatic BPH. They found that the overall results from the technique were positive and durable, and suggested that there was a significant difference in efficacy between patients presenting with a total PSA of <6 or >6 ng/mL. Many patients who have had a radical prostatectomy are followed for a prolonged period and several observations are presented from an Italian study of urinary incontinence. The authors present their detailed results, finding a considerable trend in incontinence and anastomotic stricture, which decreased over time. OBJECTIVE: To report the 3-year results and analyse whether total prostate-specific antigen (tPSA) levels and prostate volume before treatment can predict the level of clinical efficacy of photoselective vaporization prostatectomy (PVP) for treating obstructive benign prostatic disease, as high-power potassium-titanyl-phosphate (KTP) laser prostatectomy was previously shown to be safe and to efficiently vaporize prostatic adenoma secondary to benign prostatic hyperplasia (BPH), with minimal bleeding and morbidity. PATIENTS AND METHODS: From October 2001 to January 2003, 139 men (mean age 67.7 years, sd 8.7) diagnosed with obstructive lower urinary tract symptoms secondary to BPH, had PVP with an average 80 W of KTP laser energy, at six investigational centres. A subanalysis evaluating each patient for tPSA and prostate volume before PVP was conducted, with a long-term assessment of the primary efficacy outcomes at 3 years after PVP. Each patient was assigned to one of two subgroups according to the tPSA level (group 1, < or = 6.0 ng/mL; group 2 > or = 6.1 ng/mL) and evaluated separately. Each subgroup was assessed for changes from baseline in American Urological Symptom Index (AUA SI) score, quality of life (QoL) score, peak urinary flow rate (Q(max)), prostate volume, and postvoid residual urine volume (PVR) at 1, 2 and 3 years after PVP. RESULTS: All tPSA subgroups had a sustained improvement in all efficacy outcomes maintained through the 3 years. There was a statistically significant difference in the level of improvement between groups 1 and 2 (P < 0.05) in AUA SI and Q(max) at 1, 2 and 3 years. The mean (sd) prostate volume for group 1 was 48.3 (16.7) mL (87 men), and was 83.1 (30.6) mL (52 men) in group 2. The mean percentage improvement in the AUA SI at 1, 2 and 3 years in group 1 and 2, respectively, was 86%, 92% and 85%, and 69%, 74% and 76%; the corresponding percentage improvement in Q(max) was 194%, 185% and 179%, and 124%, 145% and 139%, respectively. Overall treatment efficacy in all patients evaluated showed a mean 83%, 79%, 71% and 165% improvement in AUA SI, QoL, PVR and Q(max), respectively. Adverse events were minimal and the re-treatment rate was 4.3%. CONCLUSIONS: These results suggest that there is a significant difference in efficacy in patients with a tPSA of < or = 6.0 ng/mL or > or = 6.1 ng/mL before PVP. However, the overall results achieved with PVP were very positive and durable to 3 years, irrespective of tPSA level and prostate volume.

Aged↗
PubMed2006

Insulin-like growth factor I secreted from prostate stromal cells mediates tumor-stromal cell interactions of prostate cancer.

Prostate cancer shows high expression of type I insulin-like growth factor (IGF-I) receptor (IGF-IR) and prostate stromal cells (PrSC) produce IGF-I. Although high plasma level of IGF-I is a risk factor of prostate cancer, the significance of the prostate stromal IGF-I in the regulation of prostate cancer remains elusive. Here we show that the stromal IGF-I certainly regulates the development of prostate cancer. Coinoculation of PrSC increased the growth of human prostate cancer LNCaP and DU-145 tumors in severe combined immunodeficient mice. The conditioned medium of PrSC, as well as IGF-I, induced phosphorylation of IGF-IR and increased the growth of LNCaP and DU-145 cells. PrSC, but not LNCaP and DU-145 cells, secreted significant amounts of IGF-I. Coculture with PrSC increased the growth of DU-145 cells in vitro but the pretreatment of PrSC with small interfering RNA of IGF-I did not enhance it. Furthermore, various chemical inhibitors consisting of 79 compounds with approximately 60 different targets led to the finding that only IGF-IR inhibitor suppressed the PrSC-induced growth enhancement of DU-145 cells. Thus, these results show that the prostate stromal IGF-I mediates tumor-stromal cell interactions of prostate cancer to accelerate tumor growth, supporting the idea that the IGF-I signaling is a valuable target for the treatment of prostate cancer.

Cell Communication↗
PubMed2005

Ghrelin and a novel preproghrelin isoform are highly expressed in prostate cancer and ghrelin activates mitogen-activated protein kinase in prostate cancer.

PURPOSE: There is evidence that the hormone ghrelin stimulates proliferation in the PC3 prostate cancer cell line although the underlying mechanism(s) remain to be determined. A novel, exon 3-deleted preproghrelin isoform has previously been detected in breast and prostate cancer cells; however, its characterization, expression, and potential function in prostate cancer tissues are unknown. EXPERIMENTAL DESIGN: Expression of ghrelin and exon 3-deleted preproghrelin was investigated in prostate cancer cell lines and tissues by reverse transcription-PCR and immunohistochemistry. Proliferation and apoptosis assays were done in the LNCaP prostate cancer cell line to determine if ghrelin stimulates proliferation and/or cell survival. Stimulation of mitogen-activated protein kinase (MAPK) pathway activation by ghrelin was determined in PC3 and LNCaP cells by immunoblotting with antibodies specific for phosphorylated MAPKs. RESULTS: Prostate cancer tissues display greater immunoreactivity for ghrelin and exon 3-deleted preproghrelin than normal prostate tissues, and prostate cancer cell lines secrete mature ghrelin into conditioned medium. Treatment with ghrelin (10 nmol/L), but not the unique COOH-terminal peptide derived from exon 3-deleted preproghrelin, stimulates proliferation in the LNCaP cells (45.0 +/- 1.7% above control, P < 0.01) and rapidly activates the extracellular signal-regulated kinase-1/2 MAPK pathway in both PC3 and LNCaP cell lines. Ghrelin, however, does not protect prostate cancer cells from apoptosis induced by actinomycin D (1 microg/mL). The MAPK inhibitors PD98059 and U0126 blocked ghrelin-induced MAPK activation, as well as proliferation, in both cell lines. CONCLUSIONS: These data suggest that these components of the ghrelin axis may have potential as novel biomarkers and/or adjunctive therapeutic targets for prostate cancer.

Apoptosis↗
PubMedDate not supplied

Frequent detection and immunophenotyping of prostate-derived cell clusters in the peripheral blood of prostate cancer patients.

BACKGROUND: Recent scientific studies have failed to determine parameters for the assessment of prostate cancer aggressiveness. The present study deals with the detection of blood-borne cancer cells based on polymerase chain reaction (PCR) and cell enrichment methods. The contradictory results reported in the literature have called into question the clinical usefulness of this diagnostic method in the preoperative staging of clinically localized prostate cancer. METHODS: We established a combined method of density gradient centrifugation and immunomagnetic separation using epithelium-specific antibodies, i.e. cytokeratins, to isolate prostate-derived circulating cells from the peripheral blood of patients with prostate cancer. Isolated cells were characterized by DNA staining and immunocytochemistry using antibodies for the detection of prostate-specific antigen (PSA), proliferation-associated proteins (MIB-1, H1 and H3) and apoptosis-associated proteins (M30, c-FasR). RESULTS: We applied these methods to 68 prostate cancer patients and were able to isolate cell clusters in 98%. Immunophenotypic and morphological characterization of PSA-positive prostate-derived cell clusters found in the peripheral blood of prostate cancer patients showed two main populations: 1) in 35% of the investigated prostate cancer patients we detected rounded cell aggregates of probable cancer cells expressing proliferation-associated proteins and lacking apoptosis-associated protein expression; 2) in all cases there was a high frequency of circulating dysmorphic cell clusters positive for apoptosis-associated protein expression. CONCLUSION: Our results demonstrate the existence of at least two different types of blood-borne prostate-derived circulating cell clusters. Of these, only the less frequent, round, small cell clusters harbor features that are probably necessary for the cells to survive for metastatic spread.

Biomarkers, Tumor↗
PubMed1989

Effect of long-acting gonadotropin-releasing hormone analog (leuprolide) therapy on prostatic size and symptoms in 15 men with benign prostatic hypertrophy.

To determine the effects of reversible medical castration on prostatic size and symptoms we treated 15 patients with benign prostatic hypertrophy with a long-acting GnRH analog, leuprolide (1 mg/day sc), for a minimum of 4 months. The men's serum testosterone, dihydrotestosterone, and estradiol concentrations fell to very low levels within 4-6 weeks after the initiation of treatment. Transrectal ultrasonography of the prostate demonstrated an average shrinkage of 40% after 4 months of treatment (n = 15) and 46% after 6 months of treatment (n = 11). All 15 men had improvement in urinary flow and, to a lesser extent, in nocturia and frequency. The side-effects of the therapy were decreased potency and flushing. The most dramatic improvement occurred in 4 of the 5 men who had complete urinary obstruction before treatment. One man had a suprapubic cystotomy tube removed during the fifth treatment month. Two other men who had Foley catheters before treatment are voiding well without catheters since their third treatment month. Another man who had a very large prostate (300 g) before treatment had one successful voiding trial, although he still has a suprapubic cystotomy tube. One man decided to stop treatment after 6 months. Two months later his hormone values and prostate size had returned to pretreatment levels. One man treated during the fourth and fifth months with fluoxymesterone in addition to leuprolide had regrowth of his prostate while receiving this androgen. We conclude that leuprolide treatment of men with benign prostatic hypertrophy results in shrinkage of prostatic size and concomitant improvement in the obstructive symptoms of prostatism. The prostatic shrinkage reverses when treatment is discontinued or combined with androgen.

Aged↗
PubMed2002

Preclinical studies in normal canine prostate of a novel palladium-bacteriopheophorbide (WST09) photosensitizer for photodynamic therapy of prostate cancers.

Photodynamic therapy (PDT) uses light to activate a photosensitizer to achieve localized tumor control. In this study, PDT mediated by a second-generation photosensitizer, palladium-bacteriopheophorbide WST09 (Tookad) was investigated as an alternative therapy for prostate cancer. Normal canine prostate was used as the animal model. PDT was performed by irradiating the surgically exposed prostate superficially or interstitially at 763 nm to different total fluences (100 or 200 J/cm2; 50, 100 or 200 J/cm) at 5 or 15 min after intravenous administration of the drug (2 mg/kg). Areas on the bladder and colon were also irradiated. The local light fluence rate and temperature were monitored by interstitial probes in the prostate. All animals recovered well, without urethral complications. During the 1 week to 3 month post-treatment period, the prostates were harvested for histopathological examination. The PDT-induced lesions showed uniform hemorrhagic necrosis and atrophy, were well delineated from the adjacent normal tissue and increased linearly in diameter with the logarithm of the delivered light fluence. A maximum PDT-induced lesion size of over 3 cm diameter could be achieved with a single interstitial treatment. There was no damage to the bladder or rectum caused by scattered light from the prostate. The bladder and rectum were also directly irradiated with PDT. At 80 J/cm2, a full-depth necrosis was observed but resulted in no perforation. At 40 J/cm2, PDT produced minimal damage to the bladder or rectum. On the basis of optical dosimetry, we have estimated that 20 J/cm2 is the fluence required to produce prostatic necrosis. Thus, the normal structure adjacent to the prostate can be safely preserved with careful dosimetry. At therapeutic PDT levels, there was no structural or functional urethral damage even when the urethra was within the treated region. Hence, Tookad-PDT appears to be a promising candidate for prostate ablation in patients with recurrent, or possibly even primary, prostate cancer.

Animals↗
PubMed2000

Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines.

The action of androgens is essential for the development of benign prostatic hyperplasia and carcinoma of the prostate. The androgen receptor is a ligand-dependent nuclear transcription factor. The transcriptional activation domain of the androgen receptor gene contains a polymorphic CAG repeat sequence. A shorter CAG repeat sequence within the normal range has been reported to be associated with increased risk of prostate cancer and symptomatic benign prostatic hyperplasia. Here, we examine the in vitro transcriptional activity of the androgen receptor (AR) with different numbers of CAG repeats within the normal range in a number of different cell lines of prostatic (LNCaP, PC3) and non-prostatic (COS-1, MCF7) origin. We utilize a luciferase reporter driven by the rat probasin promoter (-286/+28) containing two androgen receptor binding sites. Transcriptional activation of the androgen responsive reporter was observed to be greater with the AR containing 15 vs 31 CAG repeats in COS-1 cells (123.2+/-16.6 vs 78.2+/-10.9, P value 0.01) and the well differentiated prostate cancer cell line LNCaP (103.4+/-17.7 vs 81.4+/-7.7, P value 0.045). No difference was observed in the poorly differentiated prostate cancer cell line, PC3 (106.9+/-21.9 vs 109. 6+/-21.4, P>0.5) or the breast cancer cell line MCF7 (120.4+/-39.4 vs 103.1+/-23.1, P value >0.5). Dose-response experiments with varying quantities of ligand (0.01, 0.1, 1 and 10 nM dihydrotestosterone) or AR cDNA did not demonstrate significant differences in transactivation of the androgen responsive reporter in PC3 cells by the different AR constructs. This suggests that the lack of influence of CAG number in this prostatic cell line is not related to dose of ligand or quantity of androgen receptor. Western immunoblot analysis of androgen receptor protein in transiently transfected COS-1 cells did not demonstrate a difference in the expression of the androgen receptor protein with different numbers of CAG repeats following incubation in the presence or absence of androgen. Gel shift assay did not demonstrate increased DNA binding by androgen receptor with a shorter CAG repeat sequence. These experiments using a relatively androgen- and prostate-specific reporter provide evidence for an inverse relationship between androgen receptor transcriptional activity and the number of CAG repeats in the transcriptional activation domain. The effect of CAG repeat number was cell specific suggesting the involvement of accessory factors expressed differentially between different cell lines.

Animals↗
PubMed1995

Estrogen receptors in the human male bladder, prostatic urethra, and prostate. An immunohistochemical and biochemical study.

The distribution and quantity of estrogen receptors (ERs) in the human male bladder, prostatic urethra and the prostate were studied in eight males with recurrent papillomas of the bladder or monosymptomatic hematuria (median age 61 years), 14 men undergoing transurethral resection due to benign prostatic hyperplasia (median age 70 years), and nine men undergoing cystectomy due to malignant tumour of the bladder (median age 70 years). In the first group of patients, biopsies for immunohistochemical examination were obtained from the bladder vault, bottom, both side-walls, the trigone area, and the mid-portion of the prostatic urethra, and in the second group from three locations of the prostatic urethra (bladder neck, mid-portion and veramontanum). In the third group, tissue specimens were taken from the vault of the bladder, prostatic urethra, and the prostate, for immunohistochemical as well as biochemical analysis. In the first group, ERs were found in three out of eight specimens of the prostatic urethra, and in one of these, ERs were confined to periurethral glands. ERs could not be demonstrated in any of the bladder-biopsies. In the second group, ERs were not found in the bladder neck, but were seen in four preparations from the veramontanum and in two from the midportion of the urethra. ERs were located in the urothelium and periurethral glands. In the third group, ERs were seen immunohistochemically in the prostatic urethra (two cases) and the prostatic stromal tissue (two cases). ERs could be demonstrated in the bladder neither by immunohistochemistry nor biochemically.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗