Prostate Gland Protection and Natural Prostate Health

The 21 Day Prostate Fix

21 Day Prostate Fix written by Radu Belasco is a healthier alternative to drugs and invasive medical procedures. Radu Belasco is an early prostate problem sufferer, with a family history of prostate pain, problems and cancer. Using a unique system of natural remedies, he fixed his prostate problems and wrote them in his smash hit eBook The 21 Day Prostate Fix. It is about miraculous herbs and fruits from all over the world. These unique foods have the power to cure your prostates inflammation in record time and shrink it to a healthier size. Also, you will learn how to concoct the miracle elixir that will not just cleanse your prostate, but also burn body fat. Aside from these, youll get topnotch information on nutrition, so you can keep your prostate healthy and your sex drive at its peak. Plus, youll learn other health conditions that might be contributing to your prostate issues, so you can also remedy them and get your body in its best shape ever.

The 21 Day Prostate Fix Summary

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Author: Radu Belasco

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I usually find books written on this category hard to understand and full of jargon. But the author was capable of presenting advanced techniques in an extremely easy to understand language.

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Epigenetics in Prostate Cancer213

10 Significance of 5a-Reductase in Prostate Cancer 243 Cancerous Prostate 245 11 Roles of Vitamin E in Prostate and Prostate Cancer 263 Functional Mechanisms of Vitamin E in Prostate Cancer 265 In vivo Animal Study of Vitamin E's Role in Prostate and Prostate Cancer 268 Clinical Study of Vitamin E in Prostate Cancer 269 12 Vitamin D and Prostate Cancer 277 Vitamin D Action 279 Mechanism of Anti-tumor Action in Prostate Cancer in Combination Therapy for Prostate Cancer 283 in Prostate Cancer 285 13 Functions of Estrogen Receptor in Prostate and Prostate Cancer 293 Introduction 293 Distribution of ERa and ER in Prostate Tissues, Estrogen Regulated Genes in Prostate Cancer 296 ER Coregulators in Prostate 297 Histological Changes in Prostates of aERKO and Prostate 298 Estrogen Treatment of aERKO, PERKO, and of Prostate Cancer 14 Epidemiology of Prostate Cancer 315 Prostate Carcinoma 365 Prostate Carcinoma 367 in Prostate Carcinoma 374

Prostate Androgen Receptor383

Introduction 383 Generation of Androgen Receptor Knockout (ARKO) Mice 384 Prostate Development and Carcinogenesis in Prostate-Specific ARKO Mice 385 TRAMP Mice Lacking the Endogenous AR but Carrying ARKO Human Prostate Cancer CWR22R Cells 388 17 Capturing Signal Anomalies of Human Prostate

Influence Of Microenvironment In Prostate Cancer Invasion And Metastasis

Cancer metastasis is established by not only cancer cells but also host tissue cells (seed and soil theory).14 For example, kidney cancer metastasizes mostly to the lung, breast and prostate cancer mostly to the bone, and colon cancer with high incidence to the liver (Fig. 2.3). The influence of organ environment on the growth, invasion and metastasis of human renal cell carcinoma cells,8'10 bladder carcinoma cells15 and prostate carcinoma cells16'17 has been examined in animal models by injecting these cells at orthotopic sites. Renal and bladder cancer cells injected subcutaneously do not produce visceral or lymph node metastasis but, when injected at orthotopic sites, they produce lymph node or visceral metastasis, or both.8'15 Both prostate and bone (not lung or kidney) stromal cells are capable of LNCaP tumor growth in vivo by co-inoculating LNCaP cells with these organ-specific fibroblasts,17 on the speculation that LNCaP cell growth is regulated by growth factors such as bFGF...

Bisphosphonates In Prostate Cancer

A synchronous increase in bone resorption in osteoblastic metastasis has recently come to light. More specific urine markers of bone resorption increase in patients with osteosclerotic prostate cancer metastasis.73-75 Moreover, histo-pathological investigations have demonstrated that the number of active osteoblasts and indices of bone resorption increase significantly at sites of skeletal bone metastasis from prostate cancer, indicating that bone resorption plays a crucial role in the appearance and growth of osteosclerotic lesions and that its inhibition at the level of tumor infiltration might inhibit the progression of metastasis. The clinical usefulness of bisphosphonates has been examined in bone metastasis from prostate cancer, typically osteoblastic lesions,104'105 and with a relatively small number of patients, pamidronate has been shown to inhibit osteoblastic metastasis from prostate cancer.105 Bisphosphonate has a favorable effect on bone pain in patients with osteoblastic...

Pathology Of Highgrade Pin And Other Possible Premalignant Lesions Of The Prostate

Strong support for high-grade PIN as the main premalignant lesion of prostate cancer is based on several lines of evidence derived from prostate cancer animal models, epidemiological, morphologic, genetic and molecular studies. Animal models of prostate cancer Several different animal models of prostate cancer have demonstrated that high-grade PIN is in the direct causal pathway to prostate cancer.41 The transgenic mouse model of prostate cancer (TRAMP) has been shown to mimic human prostate cancer.42,43 In the TRAMP model, the Probasin promoter -SV40 large T antigen (PB-Tag) transgene is expressed specifically in the epithelial cells of the murine prostate under the control of the probasin promoter. The probasin promoter is Prostate Cancer Science and Clinical Practice

Growth Factors And Prostate Cancer

The insulin-like growth factor (IGF) system has been shown to play an important role in proliferation and differentiation of tissues. IGF promotes cancer cell growth in an autocrine paracrine manner via the IGF-1 receptor. It has also been implicated in the process of transformation to human epithelial prostate carcinoma. Recent studies suggest that there is a strong association between serum IGF-1 levels and prostate carcinoma, and that this growth factor may even be an important predictor of risk for prostate cancer.43,44 These growth factors activate their corresponding receptors leading to phosphorylation of second-messenger signaling systems and initiation of their individual downstream effects. IGF-I has been demonstrated to induce apoptotic resistance in various cell types following serum and interleukin-3 withdrawal, etoposide, adriamycin and anoikis-induced apoptosis.45 Its molecular effects on prostate cancer cells have yet to be determined. However, hormone manipulation...

Pathological Features Of Prostate Biopsy When To Stop

Little was reported on the differences in pathological stage, grade and cancer behavior of cancers detected on initial and repeat prostate biopsy. Although optimal predictors of cancer detection on repeat biopsy are crucial, one can spare or delay a repeat biopsy if the cancers detected are 'insignificant'. Certainly the dilemma of prostate cancer is that only a small proportion of men with untreated cancer will die from it, especially if these are small in volume, well differentiated and detected on repeat biopsy. In a recent study, Djavan etal. showed that of cancers detected on initial (n 231) and repeat biopsy (n 83), 148 out of 231 (64 ) and 56 out of 83 (67.5 ) had clinically localized disease, respectively, and were offered radical prostatectomy or radiation therapy.25 Watchful waiting was not offered as a primary option. Ten out of 148 (6.7 ) and 3 out of 56 (5.3 ), respectively, opted for radiation therapy, and thus 138 out of 148 (93.2 ) and 53 out of 56 (94.6 ),...

Morbidity Of Prostate Biopsy

Transrectal ultrasound-guided biopsy of the prostate is generally well tolerated with minor pain and morbidity. Repeat biopsies can be performed 6 weeks later with no significant difference in pain apprehension, infectious or hemorrhagic complications. The morbidity of prostate biopsy in general is very low.

Benign prostatic hyperplasia

D Slowly progressive nodular hyperplasia of the periurethral (transitional) zone of the prostate gland, the most frequent cause of LUTS in adult males. On digital rectal examination, the prostate is often enlarged however, there is poor correlation between the size and symptoms and if nodular, prostate carcinoma should be suspected. Bloods U& Es for impaired renal function, PSA. Midstream urine For microscopy, culture and sensitivity. Imaging Ultrasound imaging of the renal tract to check for dilatation of the upper urinary tract. Bladder scanning to measure pre- and postvoiding volumes. TRUS to measure prostate size and guide biopsies. Flexible cystoscopy to visualise the bladder outlet and bladder changes (e.g. trabeculation). Other Urinary flow studies (flowmetry). Medical Selective a-blockers relax smooth muscle of the internal (bladder neck) sphincter and the prostate capsule (e.g. alfuzosin, tamsulosin). 5a-reduc-tase inhibitors act by inhibiting conversion of testosterone to...

Molecular Targets And Candidate Prostate Cancer Prevention Agents

Discoveries and technologies associated with the National Institute of Health Human Genome Project32 and the National Cancer Institute (NCI) Cancer Genome Anatomy Project (C-GAP)33 promise innovative molecular targets for prostate cancer prevention. When evaluating the role of potential new agents, several critical questions must be considered.34 For example, does the agent inhibit growth or cause regression in existing models of prostate cancer What is the agent's toxicity profile Can it be given effectively in an oral dose Is cost a factor Have phase I trials in humans been conducted Is the mechanism of action known and can its effects be Is there a suitable target population for testing The answer to these and other pressing questions Existing putative prostate cancer prevention agents can be classified into those intended to inhibit ongoing cellular mechanisms, such as sex steroid signaling, differentiation or proliferation, pro-apoptosis and angiogenesis, and those intended to...

The Prostate Risk Assessment Program

Given the need to identify appropriate target populations for prevention and screening studies, many institutions have begun to establish registries for patients at risk. Here we review the findings from one of the first institutional programs designed to collect such information. The Fox Chase Cancer Center (FCCC) Prostate Cancer Risk Registry (PCRR) and Prostate Cancer Risk Assessment Program (PRAP) were founded in 1996. The FCCC is an NCI-designated Comprehensive Cancer Center committed to the support of cancer prevention and early detection. The PRAP has been developed building on the successful history of the FCCC Family Risk Assessment Programs for breast and ovarian cancers. PRAP is a multidisciplinary effort that includes clinicians across multiple disciplines, basic and behavioral scientists, genetic counselors, health educators, biostatisticians and others. This team has developed a program for prostate cancer risk analysis, risk education, early detection, and testing of...

Other Differentiation and Cell Regulatory Proteins in Focal Prostate Atrophy

Further molecular support to indicate that may of the luminal cells in prostate atrophy are intermediate in phenotype between normal basal and luminal cells, and are perhaps in a transient state, is provided by the finding that they generally show low, albeit variable levels of staining for androgen receptors and prostate-specific antigen (33), which are much more highly expressed in the luminal cells of normal glands. Similarly to keratin 5, many of the atrophic luminal cells stain strongly for Bcl-2 (33,35,55). Interestingly, there is an inverse relation between staining intensity for Bcl-2 and androgen receptors, even within the same acini. Both C-met (25,74) and hepatocyte activator inhibi Several proliferation markers have been examined in human prostate, including immunohis-tochemical analysis with antibodies against Ki-67, proliferating cell nuclear antigen, and topoisomerase Il-a (33). Most studies have used Ki-67. In the normal human prostate, the majority of proliferation...

Family History And The Risk Of Prostate Cancer

In a recent study by Kalish and associates using data from the Massachusetts Male Aging Study (MMAS), covering 1149 men with an average of 8.7 person-years of follow-up, the age-adjusted relative risk of prostate cancer incidence associated with prostate cancer family history was 3.78 95 confidence interval (CI) 1.96-7.28 . This association was independent of environmental factors, such as smoking, alcohol use, body mass index, physical activity, education, sexually transmitted diseases, diet and hormone levels.17 In addition, several case-control studies identified a familial pattern of prostate cancer. For example, men with one first-degree relative with prostate cancer have a 2.1-2.8-fold greater risk of being diagnosed with prostate cancer compared to men in the same age without a family history. As mentioned before, approximately 9-10 of all diagnosed cases are attributed to familial genetics.10 In the last two decades, researchers targeted different genes, seeking to explain the...

Localized Prostate Cancer

External beam radiation therapy (EBRT), conventional and more recently three-dimensional conformal radiation therapy (3D-CRT) with dose escalation, including intensity modulated radiation therapy (IMRT), has proven to be a highly effective treatment for men with localized prostate cancer. Treatment results from several series for patients with favorable prognostic factors of prostate-specific antigen (PSA) < 10ng ml, Gleason score < 7 (i.e. well-moderately differentiated), and T1-T2a (i.e. locally-confined, low volume) disease, have been excellent. In a large series from MD Anderson Cancer Center, patients with favorable risk factors experienced a freedom from biochemical failure rate of 88 at 5 years and 84 at 10 years.2 Similar results have been seen in a number of other series across multiple institutions.3-5 Despite these reports showing the clinical benefit of RT in early-stage, low-risk prostate cancer, patients with intermediate risk prognostic factors and with high risk...

Prostatespecific antigen

The most common finding leading to further investigation for possible prostate cancer is an elevated PSA level.2-5,17-19 PSA, a glycoprotein, is an endogenous serine protease and a member of the human kallikrein family. PSA is secreted primarily by the prostatic epithelial cells and epithelial lining of the periurethral glands. The half-life has been determined to be between 2.2 and 3.2 days. Mechanisms responsible for the detectability of PSA in the serum include its production from the prostatic epithelial cells, changes in the prostatic glandular architecture interfering with secretion into the ducts, changes in basement membrane permeability and alterations in metabolism. Specific factors that can affect PSA measurement in the serum, other than the presence of prostate cancer, include benign prostatic hyperplasia, prostatitis, urinary retention, finasteride, cystoscopy, prostatic needle biopsy, transurethral resection of the prostate, ejaculation and vigorous prostatic massage.20...

Tissue Microarrays In Prostate Cancer Research

Many of the initial studies that use tissue microarrays have been performed on prostate cancer tissue (12,19-39), and, therefore, much has been learned regarding optimizing tissue microarray production and use for prostate cancer research. This is reflected in the large number of prostate cancer tissue microarrays in production or already developed. In each case, the tissue microarrays address different scientific questions related to prostate cancer, and, therefore, have been designed to answer such questions. During the preparation and use of tissue microarrays for prostate cancer, specific issues related to this tumor type have been identified and addressed. For example, the architectural features of prostate cancer and the tendency to infiltrate between normal prostate gland tissues results in most cores being composed of both normal and cancer cells. This also makes it difficult for the technician to take cores from an area of tumor and guarantee that tumor is present on each...

Survival In Men With Metastatic Prostate Cancer

Results of Southwest Oncology Group (SWOG) study (8894), a randomized, prospective phase III trial comparing orchiectomy and anti-antigen with orchiectomy and placebo in men with metastatic prostate cancer provided an opportunity to analyze the difference in survival among men with metastatic disease by ethnic background in a rigidly controlled treatment regimen. The large sample size and the lack of uncontrolled variables made this trial a good setting for evaluating whether differences in survival between African American men and Caucasian men can be explained by differences in prognostic variables or whether there may be a difference in the biological activity of meta-static prostate cancer among African American men. Using data from 288 African American men and 975 White men in the trial, they conducted a proportional hazard regression analysis to determine if ethnicity was an independent predictor of survival. The study was double blinded and the primary end-point of the study...

Challenges to association studies of prostate cancer

To date, the bulk of reported association studies have focused on a straightforward design that compares genotype frequency among cases versus controls. However, it is unclear whether the traditional association approaches are likely to reveal hereditary prostate cancer genes. Rather, this approach may be more likely to reveal genes involved in prostate tumor progression. With regard to hereditary prostate cancer and the assessment of risk among unaffected men who may simply be presymptomatic, the most promising association studies focus on genes located within linkage regions, and include probands (the first individual ascertained) from HPC families, along with non-HPC cases and controls in the analyses.

ANNs In The Diagnosis Of Prostate Cancer

Snow and coworkers are among the first to report the application of ANNs to predictive modeling in prostate cancer. In 1994, Snow investigated the use of an ANN to predict positive biopsy in 1787 men from a screening population with PSA levels greater than 4ng ml.23 The inputs included age, PSA level, digital rectal examination (DRE) findings and transrectal ultrasound (TRUS) findings. They reported a sensitivity of 84 and a specificity of 88 for predicting biopsy result at an ANN output cut-off of 0.35. The model's AUROC was not reported. The authors concluded that ANNs may be useful in reducing the number of unnecessary biopsies and detection of clinically insignificant tumors, and thus reducing costs and morbidity. However, the ability of the model by Snow and coworkers to generalize to new patient data may suffer because, according to the report, the test set used to select the best weight matrix was also used to validate the model. In a subsequent study,30 Snow and coworkers used...

ANNs In The Staging Of Prostate Cancer

Pathologic stage is an important predictor of prostate cancer outcome and several ANN models have been developed to predict pathologic stage from clinical variables. In 1998, Tewari and Narayan reported a pilot study using an ANN to develop a staging tool for clinically localized prostate cancer.33 In 2000, Crawford and coworkers developed an ANN staging model to predict lymph node spread in men with clinically localized prostate cancer using data from 6454 patients from concluded that their results suggest a role for ANNs in the accurate staging of prostate cancer. Further work by this group includes a model to predict the risk of non-organ-confined prostate cancer in men who are clinically localized.35 This work resulted in a model with a sensitivity of 72 and a specificity of 67 . The AUROC was 0.76. Another ANN model by this group was able to predict capsular penetration (CP) in 83 of those patients with CP and had a false-negative rate of 16 .36 Several working ANN models...

ANNs For Predicting Prostate Cancer Recurrence

Determination of whether or not cancer will recur or progress is an important goal in prostate cancer management. Snow and coworkers reported a model for predicting recurrence23 using data from 240 men undergoing radical prostatectomy. The inputs to the ANN were age, PSA level, clinical stage, tumor grade, potency and race. The outcome of interest was cancer recurrence, characterized by biochemical (PSA) failure, local recurrence in the prostate bed or distant metastasis. The reported sensitivity was 67 and the specificity was 100 at an output cut-off of 0.5. Although four bootstrap validation and training sets were used, the validation sets were small (5 of the data base). In addition, the validation sets were used to pick the best weight matrices and, thus, the ability of this model to generalize to new patient data is questionable. Douglas and coworkers reported a sensitivity of 100 and specificity of 96 for predicting recurrence in radical prostatectomy patients using 40 clinical...

Polyamine Metabolism is Disturbed in Prostate Cancer

In a recent study, Rhodes et al. (22) conducted a meta-analysis of four independent microarray datasets to identify consistently significant candidate genes for prostate cancer. This study revealed a consistent and significant deregulation of polyamine biosynthesis in prostate cancer. Specifically, they found that enzymes linked to polyamine synthesis (aspartate transaminase, aminoacylase, ODC, and spermidine syn-thase) were overexpressed in prostate cancer, whereas ornithine aminotransferase was underexpressed. The net effect is an increased biosynthesis of polyamines. Biologically this makes sense because polyamines have been implicated in cancer cell proliferation, protection from apoptosis, and DNA-protein binding. Results, as summarized in Table 1, indicate that ODC protein, as well as ODC activity, correlate with the growth rate of prostatic cancer cells (i.e., the amount of ODC protein is highest in the relatively fast growing tumor lines PC-324, PC-374, and PC-346). This is in...

Aspirinnsaids And Prostate Cancer

Again, there are some investigations, albeit preliminary, that aspirin may have a potential role in preventing prostate cancer or the progression of this disease. Studies have suggested that men with ischemic heart disease may be at an increased risk for prostate cancer.69,71 Thus, the potential for investigating this agent for both conditions concurrently seems worthwhile.72,73 A variety of laboratory studies have noted an increased production of prostaglandins in human prostate cancer tissue,74-82 and an overall inhibitory effect of NSAIDs on the cellular growth of both androgen-sensitive and androgen-insensitive human prostate cancer cell lines.83-86 Collectively, these studies suggest that NSAIDs may have a favorable role in the early or latter stages of carcinogenesis.83 Two cohort studies investigating the use of aspirin in relation with multiple cancer sites observed weak inverse relationships for prostate cancer risk (RR 0.90-0.95).87,88 A third cohort studied aspirin use and...

Smoking And Prostate Cancer

Cigarette smoke contains hundreds of carcinogenic substances that have demonstrable effects on all phases of cancer devel-opment.14 Tumor initiation, promotion and progression have been associated with compounds found in tobacco smoke in a variety of experimental tumor model systems.15 The well-accepted associations between smoking and neoplasms of the lung, bladder, and head and neck do not necessarily rule out a potential causal association between smoking and prostate cancer. It must be remembered that weaker (but nevertheless causal) associations between a particular agent and a disease may only be apparent with robust investigations and, indeed, may be almost impossible to prove given the limitations of modern epidemiology. From a methodological viewpoint, it is becoming more and more difficult to assess associations between tobacco and cancers as a larger proportion of the population are ex-smokers. Thus, not only is cumulative exposure data potentially important but so are data...

Alcohol Consumption And Prostate Cancer

Ethanol is a known carcinogen and its consumption is causally associated with many neoplasms including head and neck, esophageal and hepatic cancers.3 Alcohol consumption has been shown to alter sex steroid metabolism and thus could theoretically play a role in prostate cancer causation or even protection.59-62 Alcohol is also known to clear serum androgens.63 Table 22.5 details many of the epidemiological studies that have assessed associations between alcohol use and prostate cancer. As alluded to earlier, case-control studies are naturally biased towards an association between alcohol use and prostate cancer. Despite this, only two of nine reviewed studies suggest an association. In the study by Andersson, users of hard liquor were at 40 increased risk of prostate cancer development, but beer and wine consumers were not at increased risk.42 In addition, no dose-response was noted. In contrast, DeStefani reported that beer consumers and not hard liquor users were at higher risk of...

Exercise And Prostate Cancer

Physical activity is beneficial to health. Demonstrable effects in the realm of cardiovascular health and aging are well accepted.64 In the context of prostate cancer risk, more needs to be known about the effects of exercise on endocrine physiology and other mechanisms that could modulate prostate cancer risk. There are some hypothetical physiological mechanisms by which exercise could influence prostate carcinogenesis. For example, acute bouts of exercise can lower androgen levels.65 Exercise can also improve the physiologic response to oxidative stress66 - a process associated with prostate cancer development.22 Tymchuk and colleagues demonstrated that serum from men on an exercise program inhibited the growth of cultured human prostate cancer cells.67 Table 22.6 outlines the major published studies that have assessed the association of exercise and prostate cancer risk.68-76 It is somewhat intuitive and important to realize that exercise is highly correlated with dietary...

Search for prostate cancer

During the month of January 2002, we utilized 13 widely used search engines to identify all sites found by the key words 'prostate cancer' (Table 23.1). This was done to ensure that the search was broad enough to include websites that focused specifically on urogenital disorders as well as those that had relevant content concerning prostate cancer. Some of these search engines have their own on-site information regarding prostate cancer (usually modest and generic information), and we excluded this from consideration instead the search key words were introduced directly into the search 'box' on each search engine. America On-Line (AOL) was excluded as not being considered a search engine. The number of sites are presented in Table 23.1. For those search engines that returned more than 100 site results, only the first 70 were evaluated. If the search engine returned less than 100 results, all were evaluated. While performing the search and accessing the results generated, we...

Radical Prostatectomy Versus Surveillance

Various studies have questioned the appropriateness of aggressive treatment for localized disease and have suggested surveillance instead.4-9 Advocates for surveillance argue that early radical treatment for PC has not been proven to alter the natural history of the disease and thus treatment-associated morbidities, especially in younger patients, could not be justified.10 An often quoted Swedish study that suggests an advantage to surveillance has reported a 15-year cancer-specific survival of up to 81 .11 However, careful interpretation of the study reveals the following limitations a preponderance of older patients (mean age of 70-72 years), and the majority of the reported cases had favorable histologies in the form of moderate and well-differentiated disease. Accordingly, this study cannot be applied to younger, healthier populations or patients with unfavorable histology. In contrast, another Swedish study has reported 63 mortality rates due to prostate cancer among patients who...

Radical Prostatecomy Versus Cryosurgery

In the early 1990s, prostate cryosurgery experienced a revival as a result of technical advancement in transrectal ultrasound and improved knowledge of cryobiology. However, years of experience have shown cryosurgery to be significantly inferior to radical prostatectomy and radiation therapy. Shinohara etal. reported PSA failure of up to 48 of patients with PSA nadirs between 0.1 and 0.4 ng ml at a follow-up of < 2 years.43 Cohen et al. reported a 60 biochemical NED rate 21 months or more after treatment.44 These results are roughly 30 less than what would be expected with RP. In addition, when With a success rate of almost 30 less than RP and a higher complication rate, cryosurgery should not be considered as a viable option for the vast majority of patients with newly diagnosed prostate cancer. It is obvious that at this point of time, RP offers patients with localized disease a significantly superior and more durable treatment outcome with less morbidity.

Prostatespecific Promoters

Recently, much effort has been made to develop tissue-specific delivery systems that eliminate the threat of harm to the patient. Several studies have demonstrated the importance of tissue-specific vectors, revealing systemic toxicity with the administration of high doses of nonspecific vectors (49,50). Viral vectors with broad tropisms can transduce any cell in the body, provided that the cell expresses the correct receptor specific to the virus. Through the use of prostate-specific promoters and enhancers, the expression of the therapeutic gene can be limited to cells that contain the appropriate activators and transcription factors. Several prostate-specific genes have been identified and well-characterized. Recently, chimeric promoters in which repressor elements have been deleted, activating mutations incorporated or enhancer sequences combined, have achieved greater prostate specificity and stronger transcriptional activity. No promoter is prostate cancer-specific therefore, all...

Innervation Of The Prostate

Autonomic innervation of the prostate is provided by the cavernous nerves, which follow the course of the capsular arteries. Afferent nerves travel through the prostate to the pelvic plexuses with further transmission directed to thoracolumbar and pelvic spinal segments. The prostatic plexus consists of multiple ganglia found at the prostate and bladder base. The careful identification and mapping of the neurovascular bundles has provided a major advance in reducing the morbidity of radical prostatectomy.11 With the preservation of the nerve bundles according to appropriate anatomic guidelines, cancer control may be maintained without unnecessarily compromising erectile function.12'13 The relationship of the nerve bundles to the rectum has been described as fixed, while the size of the prostate can have a significant impact on the relative position of the nerves to the gland (lateral versus posteriolateral). Branches extend from the nerves to the capsule and are in association with...

Nervesparing radical perineal prostatectomy

Nerve-sparing in radical perineal prostatectomy is performed with equal efficacy as in the retropubic approach. It does, however, require an intimate understanding of the course of the neurovascular bundles as viewed from the perineum to prevent unintended injury. The procedure differs in that initially a vertical instead of a transverse incision of the posterior layer of Denonvillier's fascia is made. Reflection of this layer over the apex of the prostate gland and laterally, allows establishing a plane between the prostate and the neurovascular bundles. Posterolateral dissection of the prostate is kept close to the prostatic substance and small clips rather than electro-cautery are used to achieve hemostasis. Finally, care is taken not to inadvertently injure the neurovascular bundles, which course in close proximity, when dissecting out the tips of the seminal vesicles.

Widefield dissection radical perineal prostatectomy

In patients considered at high risk for extracapsular disease, the procedure may be extended to encompass the lateral pelvic fascia with the removed prostate. Wide-field radical perineal prostatectomy always results in sacrifice of the neurovascular bundles because the margin of resection always includes the periprostatic fascia. The prostate is exposed as described. However, after the rectum is displaced posteriorly, a surgical plane is developed between the posterior layers of Denonvillier's fascia - the anterior rectal surface posteriorly and the levator musculature anteriorly. The prostate remains surrounded by the periprostatic lateral pelvic fascia. All fibrovascular pedicles are divided as far distant from the prostate as possible. The seminal vesicles are dissected as described, but clipped and dissected at such a level to include the neurovascular bundle at that level. Additionally, wider margins of the bladder neck may be taken to achieve negative margins followed by...

Formation and Metabolism of DHT in Cancerous Prostate

In 1965, Shimazaki et al. first found that incubation of radiolabled testosterone with tissue extracts of rat prostate or minced tissues of normal and pathological human prostates formed radiolabled DHT and androst-4-ene-3,17-dione.20'21 Three years later, Bruchovsky and Wilson found that DHT could be detected in isolated prostatic nuclei 2 hours after administration of 3H-testosterone to rats.22 Several months later, Anderson and Liao confirmed that nuclei of both rat ventral prostate and seminal vesicles selectively retained 3H-DHT.23 The metabolic rate of DHT formation is high in hyperplastic tissues, moderate in normal tissues, and low in cancerous tissues.20'21 Reduced activity of 5a-reductase in the cancerous tissues was further confirmed by various procedures incubation with minced tissues24 and with homogenate,25'26 RT-PCR,11'27 and microarray.10 Poorly differentiated cancerous tissues showed less activity than well differentiated ones. Metabolic foci in lymph nodes revealed...

In vivo Animal Study of Vitamin Es Role in Prostate and Prostate Cancer

One study has investigated the effects of vitamin E deficiency on pubertal growth and maturation of the rat prostate. The rats were placed on a vitamin E deficient diet at four weeks of age and were followed for 15-26 weeks. The study showed that vitamin E deficiency in the body led to a less significant increase in weight, DNA, and protein in the lateral lobe of prostate compared with control rats. The group also concluded that vitamin E deficiency may contribute to the delay of prostate differentiation.33 In spite of the constructive role of vitamin E in the development of prostate, the role of vitamin E in the incidence and progression of prostate cancer are controversial in animal models. In 3,2'-dimethyl-4-aminobiphenyl (DMBA)-initiated rat prostate carcinogenesis, the modifying effects of six naturally occurring antioxidants, including a-tocopherol, were investigated. Atypical hyperplasias and carcinomas of the prostate were observed in the ventral lobe in all groups treated...

Clinical Study of Vitamin E in Prostate Cancer

There have been numerous studies focusing on the effect of vitamin E supplement and its correlation to cancer occurrence. Results from a finished Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study (n 29,133) of male smokers suggested that the daily supplement of a-tocopherol could reduce the incidence and mortality of prostate cancer.2 In addition, the association between prostate cancer and baseline vitamin E and selenium was evaluated in the trial-based cohort of the ATBC study. During nine years of follow-up, 317 men developed incident prostate cancer. The report found that there were no significant associations between baseline serum a-tocopherol, regular dietary vitamin E, or selenium and prostate cancer.38 Overall, their results indicated a protective effect for total vitamin E among those who received the a-tocopherol inter-vention.38 In another study, the investigators examined the associations between prediagnostic blood levels of micronutrients and prostate...

Molecular Profiling Of Human Prostate Tumor Specimens

Quantum dot (QD)-immunostaining of formalin-fixed, paraffin-embedded human prostate tumor specimens. (A) Fluorescence micrograph of dual-color QD-stained formalin-fixed, paraffin-embedded tissue, see text for details. (B) Quantitative measurement of QD fluorescence intensity. The region of interest can be selected manually (e.g., the blue circle in panel A) and quantified using a wavelength-resolved spectrometer. Fig. 5. Quantum dot (QD)-immunostaining of formalin-fixed, paraffin-embedded human prostate tumor specimens. (A) Fluorescence micrograph of dual-color QD-stained formalin-fixed, paraffin-embedded tissue, see text for details. (B) Quantitative measurement of QD fluorescence intensity. The region of interest can be selected manually (e.g., the blue circle in panel A) and quantified using a wavelength-resolved spectrometer. cer biomarkers. The simultaneous detection of multiple proteins allows interrogation of entire signal transduction pathways in cancer tissues in...

Role of postradiation prostate biopsy to assess for local failure

Some men who undergo definitive radiation treatment for organ-confined prostate cancer will fail locally without distant metastases. Some of these men can be potentially cured with salvage prostatectomy. Most will be identified by a progressive rise in their serum PSA above the nadir value following radiation therapy, without clinical evidence of metastatic disease. In patients considering salvage surgery, prostate biopsy is recommended.33 In men with stable serum PSA levels following definitive radiation, the benefit of routine postradiation biopsies is controversial. The long doubling time of many prostate tumors, coupled with radiobiologic data indicating that cell death following radiation is a postmitotic event, suggests that the time course of disappearance of viable cancer from the prostate is prolonged. As a result, false-positive biopsies may be due to delayed tumor regression, and indeterminate biopsies (usually showing radiation effect in viable tumor cells) are of...

Comparing outcome of radiation and radical prostatectomy

Because a randomized trial comparing radical prostatectomy to radiation for men with clinically localized prostate cancer has not been performed in the modern era, risk stratification must be used to compare contemporaneously treated patients. As an example, in a recent series from the Cleveland Clinic, the biochemical outcomes of 2127 men treated with either external radiation therapy or radical prostatectomy between 1987 and 1998 were compared.35 When patients were stratified by serum PSA, Gleason score and stage, there was no difference in biochemical relapse-free survival at 5 years.35

Development of New Vitamin D Analogs and Their Use in Combination Therapy for Prostate Cancer

The beneficial effects of 1,25-VD against cancer cell proliferation have been supported by many in vitro studies, yet the therapeutic window of 1,25-VD usefulness is extremely narrow and effective doses cannot be administered without inducing hypercalcemia. The increase in calcium is achieved both by enhanced intestinal absorption and by liberation of calcium from the bone, eventually leading to decreased bone mass at higher doses. Therefore, much effort has been directed toward the identification of new analogs, which retain the favorable activities of 1,25-VD while avoiding the side effects. Several synthetic vitamin D analogs have been reported to exert promising anti-cancer effects with reduced hypercalcemia. Skowronski et al. showed that selected vitamin D analogs displayed reduced calcemic effects and that potency was even greater than 1,25-VD.38 Among those vitamin D analogs, one of the most promising synthetic analogs is Seocalcitol (EB1089, Leo Pharmaceutical Products). A...

Loss of Vitamin D Antiproliferative Responsiveness in Prostate Cancer

While current efforts focus on developing strategies to use vitamin D analogs to control prostate cancer, it is possible that prostate cancer cells could become resistant to the tumor suppressive effects of vitamin D. Some prostate cancer cells are already known to be resistant to growth inhibition by vitamin D. Analyses of experimental model systems reveal that prostate cancer cells become less sensitive to vitamin D through loss of vitamin D receptors, loss of signaling molecules that modulate vitamin D action, or through changes in metabolic enzymes, such as 1a-hydroxylase and 24-hydroxylase, that sensitize or degrade vitamin D compounds.51 Such changes have been found in experimental models, yet whether these alterations occur in human prostate cancer tissues in vivo, and the associated frequencies of occurrences still need to be determined. One study suggested that VDR levels were decreased in the prostate after age 60, which might be linked with increased incidence of prostate...

Estrogen Regulated Genes in Prostate Cancer

Estrogens and ER have been shown to play important roles in prostate carcinogenesis.27 The detailed mechanisms however, are not well known. Currently, some estrogen target genes have been identified, which may contribute to the diversified estrogen effect on prostate cancer. Those genes include telomerase,27 endothelin-1,28 eNOS,29 E-cadherin,30 metalloth-ionein II,31 CGA gene,32 androgen receptor,26 and glutathione-peroxidase.33 In addition, PS2 and progesterone receptor (PR), have an estrogen responsive element (ERE) in the promoter regions, and are also expressed in the prostate, suggesting they can be regulated by estrogen in human prostate.11 In mouse prostate, diethylstilbestrol (DES) treatment induces PR synthesis in secretory epithelial cells, which is usually low in the untreated prostate. Although a functional role for progesterone in regulating prostate growth is unknown, PR synthesis is an effective marker of estrogen action in the prostate. It was found that the acute DES...

Neoadjuvant Hormonal Treatment Prior To Radical Prostatectomy

Radical prostatectomy is widely performed in patients with early, locally confined prostate cancer and may lead to cure of the disease, provided that all malignant cells are removed.1,2 Unfortunately, none of the currently used diagnostic tools are able to reliably identify patients with true locally confined disease. As a result, it has been shown in numerous studies that clinical staging regularly underestimates pathological stage about 30 of patients with prostate cancer defined as cT1 or cT2 are found to have T3 tumors.3,4 Positive surgical margins can be found in 10-20 of cT1 patients and in 30-60 of cT2 patients, leading to an adverse prognosis.1,5 Given the well-known androgen sensitivity of prostate cancer, neoadjuvant hormonal treatment has been explored as a way to increase the rate of organ-confined disease and ultimately potentially improve disease progression and survival.6 This idea is not new the first descriptions of using hormonal treatment to shrink the prostate,...

ER Coregulators in Prostate

ERs are ligand-dependent transcription factors which bind to the ERE to regulate the transcription of target genes. The transcription initiation is a complex process which involves the cooperative interaction between ERs and multiple factors at the promoter region of target genes. The occurrence of transcriptional interference between nuclear receptors in early transient receptor reporter co-transfection assays suggested the existence of common rate limiting cofactors, other than general transcription factors (GTFs), required for ERs activation function.35,36 In this regard, coregulators were identified, and defined as coactivators or corepressors required for transcriptional regulation.37 In this chapter, we will mainly focus on the expression pattern of some identified ER coactivators in the prostate tissue and prostate cancer cell lines. To date, there are numerous ER coregulators that have been identified and the most well characterized ER coactivators belong to the p160 family,...

Results of the European study group on neoadjuvant treatment of prostate cancer

From October 1991 to December 1995, 487 patients were randomized in a prospective randomized multicenter trial.27 For inclusion, patients had to have T2-3NxM0 prostate carcinoma, confirmed by histology. PSA had to be below 100. Patients were randomized for direct radical retropubic prostatectomy ('control group') or neoadjuvant hormonal therapy (NHT) using the LHRH analog goserelin (3.6 mg subcutane-ously month) and flutamide (250 mg trice daily) for a period of 3 months followed by radical retropubic prostatectomy ('NHT group'). At randomization, patients were stratified for clinical T category and pathological grade of the tumor for each participating center. Parameters investigated were serial PSA levels, pretreatment and post-treatment prostate volumes (TRUS), clinical stage before and after NHT and ease of surgery. All pathologists used the same standardized prostatectomy step-section protocol and all surgical specimens were classified according to the TNM classification (1987...

Prostate carcinoma 163

D Primary malignant neoplasm of the prostate gland. E Asymmetrical hard nodular prostate gland with loss of the midline sulcus on rectal examination. Prostate-specific antigen Debatable if this is a suitable tool for screening, as values are age-related and may be in benign prostatic hyperplasia, prostatitis, following catheterisation. Refinements to improve sensitivity include PSA velocity (rate of change), PSA density and free and complex PSA values. CT MRI scan Assesses extent of local invasion and lymph node involvement. TRUS and needle biopsy For histological diagnosis. Isotope bone scan For bone metastases. P Macro 70 of prostate carcinoma develops from the peripheral prostatic gland, 10 from the paraurethral tissue and 20 from the transition zone. 85 are diffuse multifocal tumours. Staging TNM system T1a incidental < 5 on TURP T1b incidental > 5 on TURP T1c identified on needle biopsy. T2 confined to prostate (a one lobe, b both lobes). T3 extending through capsule. T4...

Androgendependent And Androgenindependent Prostate Growth

The development of androgen-independent proliferation in prostate cancer is a gradual process and there are a number of Table 47.1 shows the development of the completely endocrine independent cell occurring in four stages. The hormonenaive patient, who has been diagnosed as suffering from prostate cancer that is no longer to be cured by radical prostatectomy or radiotherapy, will respond to the use of monotherapy with androgen receptor antagonists, either steroidal or non-steroidal, or medical or surgical castration. Within a period of 1.5-3 years the cells will show resistance to this monotherapeutic option and require further hormone treatment. In patients who have received monotherapy with an antiandrogen, there will still be normal levels of testosterone in the blood, but in some instances the levels may be slightly elevated. Withdrawal of the patient's own androgens by means of medical or surgical castration will give rise to further response in approximately half of the...

Alterations Of Individual Genes In Prostate Cancer

The genes harboring mutations or epigenetic changes in prostate cancer are summarized in Table 1. As discussed in Subheadings 2.1. and 2.2. of this chapter, many of the putative target genes of the chromosomal regions showing LOH or deletions, that is, the putative tumor suppressor genes, are still not known. This is mainly because mutations in the remaining alleles at the deleted regions have not been detected. Two extensively studied and frequently mutated tumor suppressor genes in prostate cancer are TP53 and PTEN. TP53 is the most commonly mutated gene in human cancers. It encodes for the tumor protein p53, which is a key regulator of the cell cycle, controlling the transition from the G1 phase to the S phase. Mutated TP53 protein accumulates in the nucleus, enabling an indirect detection of TP53 mutations by immunohistochemistry. Both the immunohistochemical detection of the protein and direct sequencing of the gene have been used to study the frequency of TP53 mutations in...

In Prostate Cancer Families With Aggressive Disease

To examine the hypothesis that the tendency to develop aggressive prostate cancer may have an inherited component, and that linkage analysis of an appropriately chosen subset of prostate cancer families could be used to map the genes responsible, the ICPCG recently carried out a genome-wide linkage scan on pedigrees that had at least three men with clinically aggressive prostate cancer as defined by high-grade and or non-organ-confined disease (64). Pedigrees of this type are rare of 1233 prostate cancer pedigrees, 166 (13 ) met these criteria, making such a study possible only by pooling data from multiple family collections. Among the 166 pedigrees with aggressive prostate cancer, the strongest linkage signals were on chromosome 6p (LOD 3.0), chromosome 11q (LOD 2.4), and chromosome 20q (LOD 2.5). For chromosome 11, the linkage signal was largest among pedigrees with an average at diagnosis of 65 years or younger. The results from the analysis of this unique collection of families...

Etiology of erectile dysfunction after radical retropubic prostatectomy

Penile erection is a complex phenomenon that includes coordinated interaction of the nervous, arterial, venous and sinusoidal systems.13 While the neurogenic component to erectile dysfunction after radical prostatectomy is secondary to disruption of the cavernosal nerves,1 the arterial component is thought to arise from the disruption of accessory pudendal arteries or atherosclerosis.25 Breza etal. demonstrated that an accessory pudendal artery supplied additional blood to the penis in seven out of ten cadavers, and because of its close proximity to the prostate and bladder, could easily be compromised during radical pelvic surgery.26 Aboseif et al. showed a 40 incidence of erectile dysfunction after nerve-sparing radical prostatectomy. These patients had a minimal response after surgery to an intracavernosal vasoactive agent despite an adequate response preoperatively.13 This suggests a vascular etiology of postsurgical impotence, which was confirmed with reduced diameter and...

Sexual function after radical prostatectomy

Prostate cancer and its treatment have been associated with decreased sexual desire and function.18 One important component of sexual function, orgasm, is often overlooked. Orgasmic pleasure is accompanied by contractions of muscles in the genital tract and pelvic floor, with stimuli reaching the brain via the somatic pudendal nerve.31 Orgasm is compromised after radical prostatectomy as there are no contractions of the prostate and seminal vesicles, and the ejaculate is decreased or absent.31 The orgasm experienced after surgery is often less intense and may be associated with an involuntary loss of urine. Decreased sexual desire, erection, orgasm and ejaculation are distressing factors affecting patients after radical surgery and must, therefore, be addressed early in the course of treatment.

Sensitive Detection Of Abnormally Methylated Cpg Islands As A Prostate Cancer Biomarker

The use of serum assays for prostate-specific antigen (PSA) for prostate cancer screening has drastically changed the natural history of prostate cancer. Most men now typically diagnosed with nonpalpable, localized, prostate cancer are amenable to treatment with surgery or radiation therapy (46). However, PSA screening is far from perfect. Findings of the Prostate Cancer Prevention Trial, in which men who entered the study with a normal serum PSA level were subjected to prostate biopsy at the end of the trial, revealed prostate cancer in 24.4 of the men treated with a placebo, with cancer in 6.6 of men who had a serum PSA of less than 0.5 ng mL (47,48). Prostate biopsies are also less than perfect. The current ultrasound-guided biopsy strategy features random sampling of prostate tissue, rather than some sort of image-directed approach to detect prostate cancer. The optimal number of random tissue samples needed for accurate detection of clinically significant prostate cancer remains...

Prostate Cancer Funding

Prostate cancer research funding by the NCI has significantly increased since 1998. In the early 1990s, the annual allocation grew from 13 million in 1990 to 71 million in 1996.17 Even with these increases, the 1996 funding level for prostate cancer ranked among the lowest four cancers by incidence. However, with mandates from Congress to expand funding of prostate (and breast cancer), the levels continued to rise. Allocations rose to 135.7 million in 1999 and 203.2 million in 2000. By 2000, prostate cancer funding was second only to breast cancer ( 438.7 million). The expected level for prostate cancer funding within the NCI for FY2003 is 340 million. As demonstrated above, the use of absolute allocations as the measure of funding parity, while interesting, do not account for differences in disease impact on society. While federal support of prostate cancer research rose dramatically in the late 1990s, there remain disparities in allocations when examined in relation to various...

Prostate cancer genetics

Multiple insults are required to form cancer, as cells have back-up mechanisms of protection. As proposed by Alfred Knudson, an individual inherits two copies of genes and both copies must be affected to induce cancer.8 While most prostate cancers appear to be sporadic, 10 are inherited. The first reported prostate cancer susceptibility gene is found on chromosome 1 (HPC1).9 Families that carry the HPC1 gene have multiple affected members and prostate cancer tends to be diagnosed at an earlier age (less than 65). There are other genes that contribute to familial prostate cancer and further characterizations of these abnormalities are active areas of research. Further evidence for a genetic predisposition towards prostate cancer is the difference between racial groups. For example, Black men have a greater incidence of the disease that also tends to present earlier than in White men. However, unlike previously believed, these men do not have more aggressive cancers than their Caucasian...

Novel Therapeutic Delivery Systems In The Treatment Of Prostate Cancer

Tumor cell vaccines are a typical ex vivo gene therapy strategy for cancer and rely on the ability of cancer-specific antigens to elicit an immune response. An approach is to harvest tumor cells from the patient, genetically modify the cells (usually with retroviral transfection) so that they can stimulate the immune system, irradiate the cells so that they are non-tumorigenic, and reinject the cells into the patient. The first tumor vaccine trial for prostate cancer began in 1994 when granulocyte-macrophage colony-stimulating factor (GM-CSF) was transfected using retrovirus into a patient's prostate cancer cells in vitro. The cells were then injected subcutaneously and found to be safe in phase I trials.178 Data from this trial indicate vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight...

Use Of Complementary And Alternative Medicine In Prostate Cancer Patients

We have previously demonstrated that up to 43 of clinically localized prostate cancer patients treated with curative intent were found to use at least one form of CM. In this study, vitamins and herbal therapies were found to be among the most prevalent forms of complementary therapies. It was also demonstrated that higher pretreatment Gleason scores were associated with increased usage of CM.7 Other studies have shown a positive correlation with increased socioeconomic status and education.8 These data led us to carry out another study to query as to the specific complementary therapies being used, the time frame of this usage, and the major motivational aspects and sources of information involved in this decision. In this study, information from 238 patients with localized prostate cancer treated with curative intent by radical surgery or radiation, including brachytherapy, was included. A total of 37 of patients acknowledged using some type of complementary therapy. Our data...

Prostatespecific Antigenactivated Prodrugs

As the average life expectancy in the Western world increases, so does the incidence of prostate cancer. The extracellular serine protease prostate-specific antigen (PSA) is a prostate cancer-associated enzyme. PSA is produced by prostate glandular cells, whereas in the circulation this enzyme is inactivated. As a result, enzymatically active PSA is present only in prostate cancer tissue. Substrate specificity of PSA was investigated using peptide derivatives of 7-amino-4-methylcoumarin (AMC) containing up to seven amino acids coupled via an amide bond to the peptide C-terminus. The sequence His-Ser-Ser-Lys-Leu-Gln (HSSKLQ) was selected because of specificity and serum stability (Denmeade et al., 1997). This sequence was incorporated in a hexa- or heptapeptide doxorubicin prodrug (Denmeade et al., 1998), in which the C-terminal carboxylic acid was coupled to the primary amine of doxorubicin. PSA was unable to hydrolyze the peptide bond between hexapeptide and drug. When an additional...

Potential Prognostic Value Of Telomere Lengths In Prostate Cancer

Telomere shortening has been found to be predictive of poor prognosis in several cancers, including those of the lung, endometrium, breast, and neuroblastoma (65-68). A potential link between telomere length and prostate cancer prognosis was first reported by Donaldson et al., using a slot blot method devised by Bryant et al., which measures relative telomeric DNA content as a surrogate for telomere length (69). In this retrospective case-control study, both lack of biochemical recurrence and overall survival were statistically significantly correlated with tumor telomere length as measured by this assay. Specifically, all seven prostatectomy patients whose tumor telomeric DNA contents were less than that of control samples (placenta) showed evidence of biochemical recurrence (elevated prostate-specific antigen PSA levels) within 10 years after surgery (70). Of nine patients with short tumor telomeres, seven died within 10 years, in contrast to 100 10-year survival for patients with...

Telomerase Activity And Expression Of Telomerase Components In Prostate Cancer

At some point after the onset of genetic instability caused by telomere shortening, the developing tumor must re-stabilize its telomeres to prevent runaway genetic damage that would ultimately accumulate to lethal levels. Prostate cancers, similar to most other human cancers, typically accomplish this by activating the enzyme telomerase. Several studies have assayed telomerase activity in clinical prostate samples, all of which have found detectable activity in tissue lysates from cancerous regions (62,63,90,127-133). The proportion of telomerase positive cases ranges from 47 to 100 , with most reports finding activity in the majority of cases (Table 1). When tested, activity is found less frequently in adjacent normal-appearing regions (no activity in three of five studies) or areas of BPH associated with cancer (10-50 of samples), and, in such cases, the level of activity is typically much less than that found in cancer. Being PCR-based, the telomerase activity assay is highly...

Why Do We Need New Tumor Markers For Prostate Cancer Detection

Although utilization of serum prostate specific antigen (PSA) testing for early detection of prostate cancer is generally accepted, the specificity of the cut-off levels currently used is low. As the threshold value of PSA used in cancer detection is lowered, more curable cancers are detected. However, as the cut-offs for PSA testing are lowered, correspondingly more unnecessary negative, potentially morbid and costly biopsies will be required, unless the specificity of cancer detection is increased. Studies have demonstrated that 70-80 of men with a PSA of 2.5-10 ng ml who had biopsies performed did not have prostate cancer.1 Efforts to improve PSA testing have generally been directed towards enhancing the specificity false-positive tests create an abundance of anxiety in patients and they are increasing the costs. New markers such as PSA density (PSAD), PSA density of the transition zone (PSA-TZ), PSA velocity (PSAV), age-related PSA parameters and f tPSA have been introduced....

Theodor Billroth Prostatectomy 1867

The development of the perineal approach to the prostate may be traced back to the 'blind' perineal lithotomies performed to treat bladder stones through a median perineal incision as early as 400 BC. Theodor Billroth is credited with the first planned perineal prostatectomy for malignancy in 1867, when he enucleated a prostate cancer through a median perineal incision.7 Meanwhile, the origin of modern perineal prostatectomy for prostate cancer dates back to Hugh Hampton Young. In 1902 he developed a prostatic retractor, which he used for enucleating adenomatous tissue through the bladder to relieve outlet obstruction. In so doing he discovered incidental carcinomas in three prostatectomy specimens. After studying the spread of prostate cancer within the prostate and along the surrounding structures, he performed the first radical perineal prostatectomy in April of 1904. Young's radical prostatectomy included removal of the entire prostate, Denonvillier's fascia, both seminal...

Prostate Development and Carcinogenesis in Prostate Specific ARKO Mice

The cre-lox ARKO mouse model provides a much-needed in vivo animal model system to study androgen functions in the selective androgen target tissues in male mice. In this regard, it is of paramount importance to derive a cre recombinant transgenic animal system with robust expression of a biologically active Cre protein in a prostate epithelial cell-specific manner. We selected a rat probasin (PB) promoter to drive expression of the Cre gene.13 The AR gene was gradually deleted during the adolescence stage when increased androgen levels activated the probasin promoter expression. Specific ARKO in prostate epithelium was evidenced by genotyping, RT-PCR and immunohistochemistry (IHC). Hormonal studies revealed normal serum testosterone levels in prostate-specific ARKO as compared to wild-type (WT) mice. The growth of urogenital organs other than prostate remained unchanged after the prostate epithelium no longer has a functional AR, however the size and weight of prostate glands were...

The Impact Of Prostate Volume

The impact of prostate volume in the decision of prostate biopsy technique and of when to perform a repeat prostate biopsy is still a matter of debate. Given that sextant prostatic systematic biopsies sample only about 90 mm of prostate tissue (6 x 15 mm cores), increased prostatic volume may significantly reduce the chance of detecting cancer.2-4 Owing to the wide variation in gland sizes and shapes, it seems logical that in smaller glands the prostate biopsy leads to a more extensive sampling and less extensive or suboptimal sampling of larger prostates with accompanying significant differences in biopsy yields.5,6 Several groups have proposed new biopsy strategies, often increasing the number of biopsies and the sectors to be sampled or performing biopsies more laterally, but controversial data have also been reported about the real advantage of these new techniques.7-10 Concerned by the fact that the original sextant method may not include adequate sampling of the prostate,...

Ar Coactivators And Prostate Cancer Development And Progression

Because a large number of co-regulatory proteins interact with AR (for a comprehensive list see the AR database, http www.androgendb.mcgill.ca), it is not easy to assess the impact of a particular coactivator for AR function. This issue may be relevant when discussing new ways to inhibit AR action in prostate cancer. Although there are several means by which downregulation of AR coactivators could be achieved, it should be emphasized that there is a redundancy in their action. This is additionally supported by data showing that targeted disruption of SRC-1 does not cause an androgen-insensitive phenotype (93). In some experimental studies, there was an effect on in vitro growth of prostate cancer cells in which a specific coactivator was knocked down (94,95). However, in vivo confirmation is still missing. Most early studies with AR cofactors were performed by semiquantitative RT-PCR (96). They largely confirmed nearly universal presence of coactivators in both benign and malignant...

The Icpcg Study Of Prostate Cancer Susceptibility

To increase the power to discover prostate cancer susceptibility genes, the ICPCG, a multicenter collaborative research group (www.icpcg.org), increased sample size by combining genome-wide screen linkage data from 1233 prostate cancer families, and used dominant, recessive, and nonpara-metric models to analyze the data (63). Analysis of the complete family collection revealed suggestive evidence of linkage (logarithm of odds LOD > 1.86) at five regions 5q12, 8p21, 15q11, 17q21, and 22q12 Table 1). The highest overall LOD score in the genome was 2.28 from the non-parametric analysis, found near marker D5S2858 on 5q12 (77 cM from pter). The linkage results by group for each of these five chromosomal regions are shown in Table 2. As seen in this table, with the exception of 17q21, the LOD scores for each of the highlighted regions are higher in the combined analysis than observed in any individual group, only reaching a level of suggestive evidence in the combined family data. This...

Distribution of ERa and ERP in Prostate Tissues Cancer Specimens and Cancer Cell Lines

Estrogen has been used for the treatment of prostate cancer since the early 1940s.3 It is generally believed this action is indirectly mediated at the hypothalamic level to suppress the circulating androgens.4 However, in the early 1960s, a direct action of estrogen via their own receptors in the prostate was proposed by Mangan et al.5 Recently, the evidences that ER expressed in normal prostate, benign prostatic hyperplasia (BPH), prostate cancer specimens, and different prostate cancer cell lines, along with the demonstration of the stimulatory or inhibitory effects of estrogen on prostate cancer cells growth suggested estrogen may exert direct effects on prostate via their own receptors.6-11 The following sections will discuss the distribution of ERa and ERp in prostate tissues, cancer specimens, and cancer cell lines. Both ERa and ERp express in the human prostate tissue.2'12 In normal prostate tissue ERa is mostly expressed in stromal cells with occasional expression in the basal...

The Scope Of The Problem In Prostate Cancer

Smith and associates initially reported on 41 men with locally advanced prostate cancer, without metastatic disease, and who had not yet undergone ADT.11 These men then underwent DEXA scan of the hip and spine. The mean age in this series was 68. Of this group of men, 66 had normal bone densities, while 29 had osteopenia and 5 had osteoporosis. This compares very favorably to our findings in men on therapy for less than 2 years. Stoch etal. studied three groups of men group 1 consisted of controls solicited via a newpaper advertisement group 2 were men with cancer of the prostate, but not on ADT and group 3 were men on ADT for at least 6 months, with a mean of 41 months of therapy.12 The men underwent evaluation of bone mineral density by a variety of techniques including finger, spine and hip DEXA scans. They found that the normal rate of bone loss due to aging is 0.5-1.0 per year, but that LHRH analog therapy was associated with more than a decade increase in this loss. They also...

Hh Signaling In Prostate Development

Shh is the most abundantly expressed Hh ligand in the developing mouse prostate (18). Ihh is also expressed but at comparatively low levels. Dhh expression has not been observed. Shh gene expression in the urogenital sinus (UGS) increases before the initiation of ductal budding at embryonic day 17.5 (E17.5). Expression is most abundant during the period of ductal budding in late gestation. Shh expression gradually diminishes through the first l0 days after birth, a period characterized by continued bud formation and by outgrowth and branching of newly formed ducts. Shh gene expression declines progressively, and, by 30 days postnatal, has approached the low level of expression seen in the adult. This decrease parallels the completion of the ductal branching process. A schematic illustration of how Shh expression fits in the timeline of key morphogenetic events in prostate development is presented in Fig. 2. Shh expression in the human fetal prostate was demonstrated by...

European Alliance On Prostate Cancer

Anatomy Prostatic Cancer

Random sampling core needle biopsies of the prostate peripheral zone region can miss prostatic carcinomas. In a gland with multifocal prostate cancer, biopsy 1 detects a carcinoma lesion whereas biopsy 2 misses two carcinomas. Fig. 4. Random sampling core needle biopsies of the prostate peripheral zone region can miss prostatic carcinomas. In a gland with multifocal prostate cancer, biopsy 1 detects a carcinoma lesion whereas biopsy 2 misses two carcinomas. permits prognostic assessment of prostate cancer natural history, the use of minute core needle biopsy tissue fragments presents considerable challenges to diagnostic surgical pathologists (35). For these reasons, new molecular biomarkers, capable of increasing the sensitivity and specificity of prostate cancer screening, improving the accuracy of prostate cancer diagnosis, and providing stratification for treatment recommendations, are needed. Can somatic changes in DNA methylation patterns serve as useful prostate cancer...

Technique Of Minilaparotomy Radical Retropubic Prostatectomy

Radical Prostatectomy

The radical prostatectomy is commenced with the Mayo blades retracting the rectus muscles laterally and the specifically designed Marshall Y blade retracting the bladder proximally (Fig. 32.2). The surgeon clears the anterior surface of the prostate, removing fibroadipose tissue and securing the superficial branch of the dorsal vein of the penis with either ligature or cautery. The endopelvic fascia is then divided lateral to the prostate and extends down to the levator ani muscle fibers. The incision in the endopelvic fascia extends superiorly to the puboprostatic ligaments and dorsally along the lateral edge of the prostate. The puboprostatic ligaments are generally preserved but may be partially divided near their insertion on the prostate, taking care not to enter the dorsal venous complex and to preserve the portion of the puboprostatic ligament that provides support to the proximal urethra. Preservation of these fibers is likely to be important in the preservation of continence....

Histological Changes in Prostates of aERKO and Perko Mice

To understand the roles of estrogen, ERa and ERp in the development of prostate glands, the gene knockout strategy has been used. The adult male aERKO mouse prostate shows normal development and histology, specifically in the ventral prostate (VP)42'43 and anterior prostate (AP).44 With aging, the weights of aERKO seminal vehicle (SV) and AP increased,45 although they remain histologically indistinguishable from that of WT littermates.42,44 The initial description of targeted disruption of the gene encoding ERp reported some evidence of epithelial hyperplasia in pERKO prostates.46 Weihua et al.26 further reported that pERKO mice had multiple hyperplastic foci in the peripheral and central zones of the VP at five months by one year of age, eight of ten pERKO VPs had multiple hyperplastic lesions, and most epithelial cells stained positively for the proliferation antigen Ki-67. However, other studies of the prostate phenotype in ERp-deficient mice,42,43,47 failed to corroborate the...

Implications For Prostate Cancer Treatment And Prevention

Elevated levels of circulating IGF-1, which are strongly associated with the risk of developing prostate cancer, are measured long before presentation of this cancer. IGF may be a new tool for prostate cancer risk assessment and reduction. Recent research projects indicated that current androgen-targeting therapies alter IGF physiology within androgen-responsive cells in a manner that contributes to apoptosis associated with androgen withdrawal. Several IGF binding proteins undergo an impressive up-regulation following castration but preceding the onset of castration-induced apoptosis.57 Similar results were observed for antiandrogens58 and growth inhibitory vitamin D analogs.58'59 Recent data support the view that, in androgen-dependent tissues, IGFBP expression is suppressed by androgens and that, at the time of androgen withdrawal, IGFBP expression rises, leading to a massive decline in IGF bioactivity, thereby promoting apoptotic cell death, given the known antiapoptotic IGF...

Prostate Epithelial Stem Cells

Neuroendocrine Cells Markers

The existence of prostate epithelial stem cells and their putative role in prostate cancer development was proposed by Isaacs and Coffey (26-28). The stem cell model described in this paper is very similar to the one described above. Prostate cancers arise from prostate secretory acini. These acini are characterized by two cell layers that can be discriminated morphologically as undifferentiated basal cells and luminal cells primarily composed of terminally differentiated exocrine (prostate-specific antigen producing) cells. The neuroendocrine cells are found supra basally, with protrusions through the epithelium. The first evidence for a hierarchical relation between the basal cells and the luminal cells was provided by our group (29,30), using keratin antibodies as differentiation markers. We and others found further indications that the neuroendocrine and exocrine cells have a common progenitor, termed the transiently amplifying (TRANSIT) cell (31-34). Clearly, most of these...

Pinatypia And Prostate Biopsy

High-grade prostatic intraepithelial neoplasia (PIN) is most likely a precursor of prostate cancer and is frequently associated with it, whereas the direct link between low-grade PIN and cancer is not established. The clinical evolution of isolated high-grade PIN has been the object of much concern because of the possibility of undiagnosed prostate cancer or the evolution of this premalignant lesion in invasive carcinoma. High-grade PIN has been identified in approximately 4-14 of prostate needle biopsies.48-50 Evaluation pathology trends show that, of 62 537 initial prostate needle-core biopsies submitted by office-based urologists, processed at a single pathology laboratory, isolated high-grade PIN was diagnosed in 4.1 of the biopsies, a number which probably reflects the real incidence of this entity in general practice as opposed to reference centres.47 According to Zlotta et al. and Raviv et al.,51-53 analyzing 93 patients with diagnosis of isolated PIN without concurrent...

Challenges to linkage studies of prostate cancer

Paralleling studies of other complex diseases, segregation analyses have suggested a heterogeneous genetic etiology of inherited prostate cancer that is characteristic of complex diseases. The suggestion of multiple modes of inheritance implicates the presence of multiple genes in hereditary prostate cancer susceptibility. In linkage studies, the presence of genetic heterogeneity dramatically decreases the power to detect the effect of any single major gene when the LOD scores of multiple families (presumably with a spectrum of inherited mutations) are tabulated. As if genetic variability were not enough of a barrier to the detection of prostate cancer susceptibility genes, linkage analysis of prostate cancer has also proven difficult because the natural history and clinical characteristics of this disease beget many pedigrees that are only marginally informative for linkage analysis. Commonly samples from affected men in multiple generations of a family are not available because,...

New Issues In The Radical Retropubic Prostatectomy

Without a doubt, experienced prostate surgeons will identify numerous points of our technique that they perform differently. The point to emphasize for surgeons in training is that there are many ways to perform this operation that will be successful, so long as the principles of oncologic surgery are followed, while trying to minimize the side effects of incontinence and, when indicated, impotency. Again, we emphasize that careful ongoing review of one's personal pathologic and quality of life results is needed. Walsh has even recently described keeping video coverage of each case so that outcomes can be correlated with the original surgical technique. Cavernous nerve stimulation has recently been described. The Cavermap Surgical Aid (Uromed Corp., Boston, MA) is a system composed of a control unit, a probe handle with disposable tip containing eight stimulation electrodes in a 1.2 cm linear array,36 and a penile tumescence sensor. The device detects a 0.5 increase in penile girth as...

Candidate Prostate Cancer Susceptibility Genes Identified Through Linkage Studies

As described under Subheading 2, overwhelming evidence now exists to support a strong genetic influence in the etiology of at least some fraction of prostate cancer cases. However, the definition and characterization of this genetic influence is far more nebulous. Several major approaches have Fig. 2. Regions of implicated to harbor prostate cancer susceptibility genes from linkage studies of prostate cancer families. (Adapted from Simard et al. 2003). Fig. 2. Regions of implicated to harbor prostate cancer susceptibility genes from linkage studies of prostate cancer families. (Adapted from Simard et al. 2003). been taken to define the genes involved in inherited susceptibility for prostate cancer. Based on the foundation laid by segregation analyses, many groups worldwide have pursued linkage studies of families with multiple men affected with prostate cancer to map genes affecting prostate cancer susceptibility. Systematic searches using family-based linkage scans with genetic...

Conclusions And The Injury And Regeneration Hypothesis Of Prostate Carcinogenesis

Focal prostate atrophy has several recognizable morphological patterns. It is rapidly becoming of great interest to many investigators. Although its etiology remains unknown, its relation to inflammation, PIN, BPH, and carcinoma is being explored by a number of new molecular approaches, as well as by traditional pathological association studies. Prostate inflammation also has several morphological patterns and is exceedingly common. Except in relatively rare cases in which infection can be demonstrated, prostate inflammation is also of largely unknown etiology. Animal studies have implicated dietary factors, such as lack of soy, and neonatal estrogen exposure, as potential factors that trigger an autoimmune response (99-101). A model has been proposed (3,4) that suggests that repeated bouts of injury to the prostate epithelium, presumably as a result of inflammation in response to unknown pathogens or autoimmune disease and or dietary factors, result in proliferation of epithelial...

Proteomic Approaches for Assessing Gene Expression in Prostate Carcinoma

Isotope Coded Affinity Tag

While important information has been gained through the profiling of transcripts, it is important to keep in mind that the end-point for gene expression is the protein, as proteins represent the actual scaffolds, molecular engines and communication mechanisms utilized by cells. In addition, the development of most biomedical interventions center on protein endpoints. Large-scale efforts are underway to analyze the proteome the total protein complement of the genome.32 However, the proteome represents a complex dynamic entity due to the many forms of a given protein that result from alternative transcript splicing and the numerous post-translational modifications that often define functional protein states.33'34 A core technology developed for the global analysis of proteins involves the electrophoretic separation of proteins along two dimensions size and charge, using polyacrylamide gels (2D-PAGE).35 Comparisons of gel profiles from two different cell states (e.g. normal versus...

Functional Mechanisms of Vitamin E in Prostate Cancer

Currently, a new clinical trial, SELECT,20,21 has been initiated in the US, and an earlier epidemiological study also indicated that daily supplements of Vitamin E could reduce the incidence and mortality of prostate cancer.2 However, the functional mechanisms remain largely unclear. We summarize the functional mechanisms of vitamin E as follows. Vitamin E and Its Analogs Induce Proapoptotic Properties in Prostate Cancer Cells a-Vitamin E (a-tocopherol) has been shown by researchers to have proapoptotic properties in human prostate cancer LNCaP cells. Their data showed that vitamin E administration resulted in reduced DNA synthesis and enhanced DNA fragmentation, as well as a general inhibition of cell proliferation.22 Another study by Gunawardena and colleagues, showed that a-tocopherol stimulated apoptosis in three different human prostate cancer cell lines DU-145 (androgen-unresponsive), LNCaP (androgen-responsive), and ALVA-101 (moderately androgen-responsive). The group cited...

Steroid Hormone Regulation Of Telomerase In The Prostate

In the prostate, telomerase activity is subject to regulation by steroid hormones, particularly andro-gens. Normal prostate tissues free of cancer, as well as cultured normal prostate epithelial cells, are typically negative for telomerase activity in the presence of androgen (Table 1). However, androgen withdrawal leads to the activation of telomerase. This was first observed in the involuted residual prostate and seminal vesicles of the Copenhagen rat, in which telomerase activity becomes strongly positive after castration (199). This activity remains undiminished even at 2 years after castration, despite the near total lack of ongoing cell proliferation in the quiescent, involuted glands. These residual glands are highly enriched for prostatic stem cells, as evidenced by the rapid induction of cell division and regrowth of these glands after restoration of testosterone. During androgen-induced glandular regeneration, telomerase activity subsides (199). Based on the kinetics of the...

Abnormal Dna Methylation Changes In Prostate Cancer

The first gene found to be silenced via somatic CpG island hypermethylation in prostate cancer was GSTP1, encoding the n-class glutathione-S-transferase (GST), an enzyme capable of detoxifying electrophilic and oxidant carcinogens (28) (Fig. 1). This genome change remains the most common somatic genome abnormality of any kind (> 90 of cases) reported thus far for prostate cancer, appearing earlier and more frequently than other gene defects that arise during prostate cancer development (29). The associated loss of n-class GST function likely sensitizes prostatic epithelial cells to cell and genome damage inflicted by dietary carcinogens and inflammatory oxidants, perhaps explaining the well-documented contribution of diet and lifestyle factor to prostatic carcinogenesis (29-31). Mice carrying disrupted Gstp1 2 genes are more prone to develop skin tumors after exposure to a topical carcinogen than wild-type mice (32). Provocatively, GSTP1 CpG island hypermethylation, which is not...

ARKO Human Prostate Cancer CWR22R Cells

The advantage of using gene targeting in human somatic cells is that it provides a tool to study the roles of the signaling of interest in human cells instead of ARKO animal model. For this purpose, we attempted to disrupt AR signaling in human androgen-refractory prostate cancer cells in order to investigate the biological importance of AR signaling in those prostate cancers. Human prostate cancer CWR22R cells were transfected with the AR targeting vector using Superfect transfection kit (Qiagen) and selected with 400 pg ml neomycin reagent.18 The genotypes of the surviving clones were detected by Southern blotting using a DNA probe containing the 5'-UTR sequences of the AR gene. The untargeted and targeted loci produced approximately 9.0-kb and 3.46-kb bands, respectively. AR expression was reduced in those heterozygous clones compared to that in the parental CWR22R cells19 confirming that one of the AR genes is targeted by homologous recombination. Therefore, this method provides a...

Estrogen Imprinting Effect on the Development of Prostate

Although estrogen levels are low or undetectable in adult male mice, administration of exogenous estrogens during development48 dramatically affects prostate growth and function.49-54 The effects of estrogens vary according to timing and duration of exposure, in addition to the type and dose of estrogen administered. Furthermore, the individual lobes of the prostate exhibit varied degrees of response to estrogens and androgens. The neonatal period after birth is very fundamental for the rodent prostate development in which the prostate involves branching morphogenesis followed by functional differentiation. In this period, brief exposure of male rats or mice to high-level estrogens will cause irreversible alterations in development and function of the prostate gland and a reduced responsiveness to androgens during adulthood.50'55-57 The estrogen imprinting effect is associated with an aging-related prostatic lesion, which includes the hyperplasia of prostatic epithelial cells or...

Contribution Of Nonsteroidal Activation Of The Ar To Prostate Cancer Progression

Most steroid receptors can be activated in a ligand-independent manner or in a synergistic manner by a ligand and a cytokine or other compound that increases intracellular kinase levels. For example, human estrogen receptor-a exhibits ligand-independent activation, whereas progesterone and glucocorticoid receptor activity is regulated in a cooperative manner. This type of activation of the AR is of importance for advanced stage prostate cancer. Because of androgen-ablation therapy, the levels of active androgens in serum are low, whereas AR is expressed at appreciable levels. For the clinical situation, it is particularly important that nonsteroidal activators reduce the threshold needed for maximal stimulation of the receptor. The most important consequence of cross talk between steroid and peptide regulators of prostate growth is, thus, full functionality of the AR despite endocrine therapy. The extent of ligand-independent or synergistic AR activity varies between different cell...

Alternative Approaches To Find Prostate Cancer Susceptibility Genes

Another important approach to find prostate cancer susceptibility genes has been to perform association studies in populations of men with and without prostate cancer, typically without regard to family history. These case control studies have been greatly aided by the increased understanding of the variability of the human genome sequence among different individuals and the concept that common diseases may be caused by common genetic variants in the population (65). Thus, by simply examining the frequency of polymorphic alleles, typically single-nucleotide polymorphisms, among cases and controls, associations between genes and disease risk can be rapidly assessed. A large number of genes involved in critical processes that occur in prostate cells, such as androgen action and metabolism, growth factor signaling, carcinogen detoxification, and DNA repair and inflammation, are being systematically evaluated in this fashion. Additionally, genome-wide association studies of prostate...

Radical Prostatectomy Versus External Beam Radiation

Although early reports comparing the two modalities demonstrated a clear advantage for RP over external beam radiation therapy (EBRT),16'17 the studies were shown to have several flaws. More recent retrospective studies have evaluated the treatment outcomes of EBRT and RP in comparably staged prostate cancer patients. When stratified by preoperative biopsy grade, T stage and serum PSA, the rates of biochemical relapse-free survival and cause-specific survival for the two modalities were similar at 5 and 7 years post-treatment.18-23 However, since EBRT is a treatment that does not remove the cancer-harboring organ (the prostate), it is more likely to fail at > 10 years than a modality that eliminates the source of the cancer (surgery). Accordingly, 7 years treatment outcomes may not be long enough to demonstrate any difference. Limited data have been presented that the addition of hormonal therapy may impact on the outcomes of high-risk prostate cancer treated by radiation. At...

Sun Exposure And Prostate Cancer

Subsequently hydroxylated in the liver and kidney to its active form, 1,25-dihydroxy vitamin D. In 1990, Schwartz and Hulka published their hypothesis about vitamin D and prostate cancer.77 They rationalized that many of the known risk factors for prostate cancer could potentially be explained by vitamin D deficiency. Table 22.7 lists some of the risk factors associated with increased or decreased risk of prostate cancer and how these mechanistically could relate to Vitamin D. Age is a well-accepted risk factor for prostate cancer. Data have shown that synthesis of vitamin D diminishes with advancing age.78 In addition, the elderly have less sun exposure, in part due to residence in homes for the aged. African American's are at highest risk for prostate cancer and tend towards a more aggressive disease phenotype.79 Although, numerous genetic, epigenetic and environmental hypotheses may explain this observation, melanin skin pigmentation can inhibit vitamin D synthesis.80 Asian's are...

Estrogen Effect on Initiation Growth and Progression of Prostate Cancer

While androgens play essential roles in the development and growth of prostate and pathogenesis of prostate cancer, extensive in vivo and in vitro studies suggested that estrogens are required for carcinogenesis of prostate cancer. It was demonstrated that treatment with both estrogen and testosterone will induce 100 dorsolaterol prostate carcinoma in rats.77 In human, direct estrogen effects and the balance of androgens and estrogens may contribute to these estrogen activities. Men synthesize both estrogens and androgens and as men age, the plasma levels of androgen decreases while estrogen remains constant. However, the expression pattern and activity of aromatase, the enzyme that turns testosterone into estrogen, suggests that local synthesized estrogen may have significant consequences in tumorigenesis of prostate.78'79 Here we will focus on estrogens effects on prostate cancer cells from in vitro and in vivo approaches. While this approach provides some insights to explain the in...

Ar Structure And Function In The Prostate

The androgen hormone dihydrotestosterone (DHT) is the principal regulator of prostate development and growth during embryonal development and puberty (5). In the adult prostate, it is required for maintenance of tissue homeostasis and secretory function. The circulating steroid hormone, testosterone, diffuses into the cells and is there converted by the 5-a reductase enzymes to the more potent androgen, DHT (6). DHT and other androgen hormones present in the prostate cells bind to a high-affinity binding protein required for mediating their effects, the AR. It is a member of the superfamily of nuclear receptors, its closest relatives are the progesterone, glucocorticoid, and the other steroid hormone receptors (7,8). Binding of androgen hormones triggers activation of the receptor to a transcription factor that interacts with and regulates the activity of gene promoters containing androgen-responsive elements (AREs). Activation involves a cascade of activation processes and the...

Complex Psa Following Radical Prostatectomy

PSA has become the most valuable tool for detecting, staging and monitoring prostate cancer in the past decade.31 After suggesting that the half-life of PSA might be a possible factor for the prognosis after radical prostatectomy, the pharmaco-kinetics of PSA gained more attention.32,33 PSA half-life is 2-3 days34 and a biphasic model for t fPSA elimination was established.34 Lein etal. confirmed the biphasic elimination and suggested the first phase of free PSA loss might be the result of its rapid binding to a2-macroglobulin and ACT.35 Other investigators have assumed that the initial free PSA decrease was related to renal clearance or caused by the operation itself.36 In another study, the authors determined whether the assumed binding of PSA to its protease inhibitors after release into the circulation could be a possible reason for the elimination of free PSA. During the first 6 hours after radical retropubic prostatectomy, they found nearly constant levels of ACT-PSA and cPSA,...

Microarray Studies of Gene Expression in Prostate Carcinoma

Microarray analysis has been used in several published studies designed to profile gene expression alterations in prostate carcinoma (Table 1). Importantly, although all of these experiments used microarrays, there are important differences that preclude a simple comparison of the reported results. These include the use of different patient samples, microarrays with different genes represented and variations in experimental and analytical approaches. Magee et al. used oligonucleotide arrays to characterize the expression of 4712 genes in four benign and 11 prostate cancer samples.17 Most of the neoplastic samples represented primary tumors of various Gleason grades, though two metastatic lesions were also characterized. The samples were enriched for epithelial cells using macrodissection procedures. Analyses of the gene-expression profiles identified four genes with significant changes associated with carcinoma, including Hepsin, a type-II membrane-bound serine protease. Luo et al....

Prostate Evolution Growth And Differentiation

Prostate cancer is the most common non-cutaneous malignancy in American men.10 It is also primarily a disease of men beyond their reproductive years, thereby severely limiting the evolutionary selective process against cancer.11 Observational data suggest that environment plays an important role in determining the risk of prostate cancer. First, there is tremendous species specificity of prostate cancer, with a significant incidence of spontaneous prostate cancer observed only in humans and dogs.11 None of man's closest primate relatives are susceptible to carcinoma of the prostate. Second, there is tissue specificity for cancer among men's reproductive organs. Despite sharing similar genetics and microenvironments, the human vas defer-ens and seminal vesicle rarely undergo malignant transformation. In addition, ethnic and geographical variations exist in the incidence of prostate cancer. Compared to the USA, the risk of prostate cancer is as much as tenfold less in Asian countries, a...

Hereditary Prostate Cancer

The problem with studying familial prostate cancer is that, as prostate cancer is so common, there is a high incidence of sporadic cases amongst the familial cluster. Furthermore, these families are screened for prostate cancer and these PSA-detected tumors may behave differently from the rest of the population. Nevertheless, a man with a first-degree relative with prostate cancer has a relative risk of 2.0 (1.2-3.3, 95 confidence interval), with a second-degree relative risk of 1.7 (1.0-2.9) and with both a first- and second-degree relative an 8.8 (2.8-28.1) relative risk of developing prostate cancer.13 Further evidence to support a hereditary predisposition is that the incidence of prostate cancer is higher in men who have relatives with breast cancer.14'15 Conversely, the risk of breast cancer is doubled in families with a history of prostate cancer.16,17 Hereditary prostate cancer is usually defined by the pedigree as no associated genes have yet been identified. This definition,...

Mechanism of Antitumor Action in Prostate Cancer by Vitamin D

A key feature of cancer cells is their increased rate of growth relative to normal cells, and this can be attributed to increased cell proliferation, decreased cell death, or a combination of the two. 1,25-VD has been demonstrated to regulate cellular differentiation and proliferation in a number of normal and malignant cells, including prostate cancer cells, however the response to 1,25-VD in cancer cells appears to be cell type-specific. The majority of the 1,25-VD-mediated signals function through the VDR. The sensitivity and responsiveness of cells to vitamin D are therefore partly dependent on the activation of VDR. Miller et al. first demonstrated the presence of VDR in the LNCaP human prostate cancer cell line.23 VDRs have since been found in other prostate cancer cell lines, as well as in normal prostate epithelial and stromal cells grown in cul-ture.24 Several studies have demonstrated that 1,25-VD and its analogs inhibit the growth of prostate cancer cell lines as well as...

In Vivo Prostate Tumor Targeting And Imaging

For active tumor targeting, Gao et al. have used antibody-conjugated QDs to target a prostate-specific cell surface antigen, prostate-specific membrane antigen (PSMA) (Fig. 6D). Previous research has identified PSMA as a cell surface marker for both prostate epithelial cells and neovascular endothelial cells (57). PSMA has been selected as an attractive target for both imaging and therapeutic intervention of prostate cancer (58). Accumulation and retention of PSMA antibody at the site of tumor growth is the basis of radioimmunoscintigraphic scanning (e.g., ProstaScint scan) and targeted therapy for human prostate cancer metastasis (59).

Somatic Changes In Prostate Cancer

One of the most widely used techniques for examining chromosomal alterations is comparative genomic hybridization (CGH). This allows the detection of DNA sequence copy number changes throughout the genome and can, therefore, identify regions where deleted TSG or amplified oncogenes may be harbored. Researchers in Finland have used this technique and shown that locally recurrent hormone refractory prostate cancers contain almost four times as many alterations than the untreated primary tumors.52 Their findings are summarized in Table 11.2 and suggest the early development of prostate cancer is as a result of inactivation of TSG, whereas later progression, including the development of hormone refractory disease, is associated with oncogenic activation (Fig. 11.1). CGH and LOH (loss of heterozygosity) studies have demonstrated the most common chromosomal aberrations in prostate cancer are deletions in chromosome regions 3p, 6q, 7q, 8p, 9p, 10q, 13q, 16q, 17q and 18q and gains in 7p, 7q,...

Radical Prostatectomy Versus Brachytherapy

Clinical stage (T1 a-T2a) Gleason sum (2-6) PSA (< 10 ng ml) Prostate volume < 60 cm3 Urine flow rate > 15 cm3 second AUA symptom score < 10-12 Again, there is a widespread perception that there is no impairment in sexual function with brachytherapy. After reviewing 66 references published over the last 10 years, Peneau observed an impotence rate of 25 associated with brachytherapy and progressive decrease in sexual potency with time.38 In a study comparing general and disease-specific health-related quality of life in men undergoing brachytherapy to those undergoing radical prostatectomy and age-matched healthy controls, sexual function and bother were equivalent in RP and brachytherapy groups, and both were worse than in healthy controls.39 The same study has shown that general health-related quality of life did not differ greatly among the three groups. Urinary leakage was better in the brachytherapy group than in the prostatectomy group however, both were worse than...

Salvage Cryosurgical Ablation Of The Prostate

Radiation therapy for localized prostate cancer is a main form of therapy for patients with newly diagnosed and localized prostate cancer. It has been estimated that nearly one-third of newly diagnosed prostate cancer patients will choose one form of radiation therapy as their primary treatment.9 Despite modifications of delivering radiation to the gland, such as intensity modulation, three-dimensional (3D) conformal and computer-guided seed implantation, a number of these patients will have a rise in the serum prostate specific antigen (PSA) value in the years after radiation. According to the recent literature, the number of biochemical failures has ranged from 20 to 66 .10 One of the criticisms in the past is that many of the investigators in the past have differed with regards to their definition of biochemical failure. One of the advances with regards to following patients came out of the 1997 ASTRO Conference.11 At that meeting, a biochemical failure was defined as three...

Dissection of the prostate

Classic perineal prostatectomy then proceeds with a transverse incision of Denonvillier's fascia just below the apex of the prostate. The posterior layer of Denonvillier's fascia is dissected away from the prostatic surface. A combination of sharp and blunt dissection is then used to develop the membranous urethra distal to the prostatic apex but beneath the puboprostatic dorsal venous complex (Fig. 33.2). A right-angled clamp is then passed behind the urethra, the Lowsley retractor is removed and the urethra is sharply divided using a scalpel on a long handle. At this point the urethral stump can be tagged. Alternatively the two anterior anastomotic sutures may be placed in the urethra. A Young retractor or straight Lowsley is placed through the prostatic urethra into the bladder and the wings are opened. With pressure on the retractor to displace the prostate posteriorly, and alternating sharp and blunt dissection, a plane can be developed on either side of the mid-line beneath the...

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