Natural and Traditional Cures for Prostatitis

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 Overview

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The Molecular Pathogenesis of Human Prostate Cancer

Prostate cancer (PCA) has become the most commonly diagnosed cancer among men in the USA, with an estimated 189,000 cases diagnosed in 2002 (1). Encouragingly, over the past several years, increased use of serum prostate-specific antigen (PSA) screening has increased the fraction of men diagnosed with PCA confined to the prostate gland, leading to more effective use of surgery and radiation therapy for treatment, and to a decline in PCA mortality (2, 3). Despite these improvements, some 30,200 men will likely died of progressive metastatic cancer in 2002 (1). Furthermore, even though men with early PCA can be cured using surgery or radiation therapy, the side effects of treatment frequently include erectile dysfunction, urinary incontinence, or rectal irritation (4-6). New insights into the etiology of PCA are needed so that new strategies for its prevention can be developed. Recent studies of the earliest molecular steps in the development of human PCA have generated new evidence...

Benign Prostatic Hyperplasia BPH

Interestingly, the virtually ubiquitous process of BPH originates in the TZ of the prostate (62), and approximately 20 of all PCA occur in the TZ. Adenocarcinomas originating in the TZ are usually well-differentiated tumors with Gleason score generally lower than tumors from the PZ (63), and with architectural features that closely resemble foci of BPH. Over the years, the findings of BPH and PCA together in standard transurethral resection ofthe prostate (TURP) specimens has led to speculations that carcinomas may arise from hyperplastic lesions (64-66). Leav, et al. recently reported the possibility to define areas of transition from hyperplasia to carcinoma in six BPH nodules using AMACR (P504S), p63, or 340E12 antibodies (67). They reported enhanced AMACR expression in benign glands within cancer-containing nodules, as well as in BPH lesions adjacent to carcinomas and suggested that the up-regulation of the enzyme may precede morphological evidence ofneoplastic transformation....

Establishment of Models for Studying Prostate Cancer Cell Progression

Isolate A-insensitive cells, named IS cells. IS cells express very low levels of AR and are not stimulated or suppressed by A in the culture medium (Figure 2). These cells resemble human prostate PC-3 cells, since they do not have AR and can grow in the absence or presence of A.

Growth Suppression of Prostate Cancer Cells in Culture by Androgen

The cellular level of AR mRNA was 2-3 fold higher in the LNCaP 104-R1 and 104-R2 cells than in LNCaP 104-S cells. AR protein level increased 10-20 fold during this transition from A-dependent 104-S cells to A-independent 104-R1 or 104-R2 cells. The growth of both 104-R1 and 104-R2 cells, as well as CDXR cells in culture was suppressed by physiological concentrations (< 1 nM) of testosterone, 5a-DHT, or R-1881. Non-androgenic steroids, such as 5P-DHT, 17p-estradiol, medroxyprogesterone, and cortisol, did not suppress 104-R tumor growth (24). AR in 104-R (R1and R2) cells was functional, since A induction of prostate-specific antigen (PSA) mRNA increased up to 20 times in these 104-R cells.

EGCG Suppression of Prostate and Breast Tumors

For a better understanding of the ability of green tea to control different forms of prostate tumors, we produced tumors in athymic mice by subcutaneously inoculating athymic mice with AR positive and A-dependent LNCaP 104-S cells, AR positive LNCaP 104-R2,104-R1 or CDXR cells whose growth is repressed by A, or AR negative PC-3 or IS cells whose growth is neither stimulated or repressed by A. We found that green tea EGCG (> 98 pure, 1 mg 20g body weight daily), injected intraperitoneally (ip), significantly inhibited the growth and rapidly (in 1-2 week) reduced the size of all types of human prostate tumors in athymic mice. Structurally-related catechins, such as epicatechin gallate (ECG) that lacks only one of the eight hydroxyl groups in EGCG, were inactive. Epicatechin (EC) and epigallocatechin (EGC) were also inactive (25). Since both A-dependent and A-independent prostate tumors respond to tumor suppression by EGCG. EGCG action was not related to modulation of A activity or due...

Expression of the Androgen Receptor in Prostate Tumor Models and Clinical Specimens

Among human PCA cell lines widely used, only LNCaP and MDA PCa 2a and 2b cells express AR. These cell lines are derived from PCA metastatic lesions (3,4). The reasons for AR down-regulation in other cell lines are not completely clear. It is assumed that some peptide hormones present in serum are responsible for down-regulation of the AR. For example, basic fibroblast growth factor is a potent inhibitor of AR expression (5). PC-3 and DU-145 cells, which do not express the AR, could be used for transient and stable transfections with AR cDNA. PC-3 cells stably transfected with the AR proliferate less rapidly than the cells transfected with an empty vector (6). Also, these cells are less invasive than their counterparts. AR expression is low in rat Dunning tumour sublines that rapidly metastasize (7). For this reason, it was believed for a long time that AR expression decreases during tumor progression. AR expression was studied with respective antibodies in clinical specimens obtained...

Challenges And Opportunities In Prostate Cancer

Prostate cancer presents specific opportunities for novel therapies such as cytokine gene therapy but also has specific challenges. Standard therapy for localized disease involves radical prostatectomy or radiation therapy which are often associated with significant morbidity (3). Despite a significant increase in the number of men diagnosed and treated with curative intent for localized prostate cancer, a considerable number of men develop local recurrence or distant disease following surgery or radiation performed with curative intent. Every year tens of thousands of men experience rising serum prostate-specific antigen (PSA) levels as a result of local recurrence after presumptive definitive therapy for prostate cancer because of the limited capacity to accurately determine the virulence and stage of presumed localized disease and the limited efficacy of surgery and or radiation therapy. Treatment options for these men are few and unproven (5) and the ability to predict...

Therapeutic Potential Of Adenovirus Mediated Interleukin12 Gene Therapy For Prostate Cancer

Key words Interleukin-12 prostate cancer orthotopic prostate cancer model in situ gene therapy metastasis Abstract Prostate cancer is characterized by extreme heterogeneity and multifocality of the primary tumour. The available clinical, pathological and molecular data suggest a lack of substantial clonal expansion at the primary site, yet metastatic progression of the disease often proceeds in an unpredictable and clinically undetectable fashion. Clinical and experimental data suggest that primary prostate cancer tumour cells can seed from relatively small tumour foci at the primary site. Overall, this unique biological pattern of progression presents unique and challenging problems regarding the detection and treatment of the disease. In general, currently used potentially curative therapies involve a single cytoablative modality (radical prostatectomy or radiation therapy) and are exclusively directed at the malignant cells within the prostate gland. At present the widespread use...

Benign Prostatic Hyperplasia

Benign prostatic hyperplasia is a common disease of aged males. It is associated with low urinary tract syndrome and can result in serious complications including renal failure. The main pathophysiological factors, and consequently, therapeutic targets, are sex hormones and sympathetic activity. Testosterone, dihydrotestosterone, and estradiol play crucial roles, and their effects are influenced by several genetic factors. The models of benign prostatic hyperplasia can be divided into in vivo and in vitro models. Animal models include spontaneous and hormonally or pharmacologically induced prostatic hyperplasia, as well as newly generated transgenic models. Cell cultures are simple and cost effective, but the research in vitro is difficult to interpret for human pathology. The number of various models indicates that an ideal model of benign prostatic hyperplasia does not exist. Thus, further improvements are awaited to enhance the biomedical research with clinical outcome on this...

Bladder and prostate gland

Inflammation of the prostate causes a variety of urinary symptoms, which can include perineal and penile pain, as well as and a dull suprapubic or ill-defined rectal discomfort. These symptoms form part of the chronic pelvic pain syndrome. This syndrome can also affect women. In a minority of cases a diagnosis of interstitial cystitis can be made (see below).

Fibroblast Growth Factors And Their Receptors In Metastases Of Prostate And Other Urological Cancers

Key words Acid and basic fibroblast growth factor, prostate cancer, bladder cancer, renal cell carcinoma, invasion, metastasis, angiogenesis Abstract Theraputical options for advanced carcinoma of the prostate, bladder or kidney are limited. Therefore it is important to understand their invasion and metastasis, processes in which fibroblast growth factors play an important role. Basic fibroblast growth factor (bFGF) is expressed in androgen-insensitive prostate cancer cell lines PC-3 and DU-145 and in some clinical specimens. During progression of prostate cancer, the expression of the FGF receptor 2 isoform Illb, which preferentially binds keratinocyte growth factor (KGF) decreases and the expression of the isoform iiic, which preferentially binds bFGF increases. A similar phenomenon was observed in bladder cancer. Several FGFs are proposed to act as andromedins, proteins that mediate the effects of androgens in target tissues FGF-7 (KGF), FGF-8 and FGF-10. In prostate and bladder...

Dietary Prostate Cancer Risk Factors

There are at least seven major dietary macro- or micronutrients that are under intense scrutiny currently as dietary risk or protective factors (Table 15.1). Prominent among these is dietary fat or some component of fat (e.g., saturated fat), which first received attention as a mechanism to possibly explain the low risk in native Asian populations and the apparent rapid shift in risk upon migration of Asian populations to the United States. There are suggestive data that increased fat consumption is associated with higher circulating testosterone levels, providing a possible mechanism for a fat-prostate cancer relation ship.9 Both case-control and cohort data tend to support a relationship between fat consumption overall and prostate cancer risk 10,11 however, there are sufficient inconsistencies in the data, and the magnitude of risk even between extreme categories of estimated fat intake is sufficiently modest that fat is still not considered a proven prostate cancer risk factor....

Nondietary Prostate Cancer Risk Factors

Although most attention has focused on possible dietary risk or protective factors for prostate cancer as the most likely environmental risk factor category to explain the racial ethnic variation in incidence and the impact of migration on risk modification, other factors have also been evaluated over the past few decades. Among these, cigarette smoking and a history of any type of sexually transmitted disease are among the most reproducible. As there are no highly suspected carcinogens to the prostate found in cigarette smoke or any direct evidence of an infectious etiology of prostate cancer, it has been proposed that both of these risk factors might be indices of an androgenic profile associated with prostate cancer development.27 Smokers have higher circulating testosterone levels than nonsmokers.28 While there is no direct link between androgen levels and sexually transmitted diseases, androgen levels may be modestly correlated with indices of sexual activity.29 The substantial...

Risk Pathways For Prostate Cancer

Several molecular etiological pathways have been suggested for prostate cancer. Although androgen transactivation pathways clearly have received the greatest attention, others have been the focus of increasing research activity. Among the most prominent of these additional pathways are vitamin D metabolism, insulin-like growth factor (IGF) signaling pathways, and chemical carcinogenic pathways (Fig. 15.1). Hsing and Devesa39 developed an etiological model that integrates these pathways and incorporates many of the possible risk factors suggested for prostate cancer.39 With the availability in the past decade of polymerase chain reaction technology to study polymorphic variants in genes on a large-scale population basis, epidemiologists and molecular biologists have been afforded an opportunity to begin detailed evaluation of these pathways with special attention to the contribution of polygenic variation in prostate cancer development within and between populations. In the section...

Hormonal Therapies For Metastatic Prostate Cancer

Due to the advent of screening with serum prostate-specific antigen (PSA) in the 1990s, the majority of prostate cancer cases are now diagnosed with clinically organ-confined disease. However, the assumption that earlier diagnosis would result in improved survival has not been ratified. In particular, approximately 30 of patients with organ-confined disease and 60 -80 of those with extraprostatic disease who receive potentially curative local therapy will eventually relapse.114 These data suggest that mi-crometastases are already present at the time of diagnosis. men with prostate cancer, targeting the andro-gen-signaling pathway remains the predominant form of treatment for patients who are either diagnosed with or subsequently develop metastatic disease (Fig. 16.4).4,5 A myriad of therapeutic agents that target the androgen-signaling pathway have been developed since the initial observation of Huggins and colleagues.115 The majority of these agents reduce circulating levels of...

Familial Aggregation Clues For Genetic Influences In The Etiology Of Prostate Cancer

Evidence of familial clustering of prostate carcinoma is well documented in many case-control studies.13-24 Three major conclusions can be drawn from these studies. First, estimates of the relative risk of developing prostate cancer are higher in first-degree relatives of prostate cancer cases compared to the general population. This increase of relative risk among relatives of prostate cancer patients has been demonstrated in several ethnic and racial groups, including African Americans, Caucasians, Hispanics, and Asians. Second, the risk of prostate cancer increases with increasing number of affected relatives. For example, in the study conducted by Lesko et al.,23 the odds ratio (OR) was 2.2 for subjects with a family history of prostate cancer in one relative and went up to 3.9 for subjects with a family history of two or more affected relatives. Third, the risk of developing prostate cancer among first- and second-degree relatives is negatively correlated with a decrease in the...

Linkage Studies Identifying Major Prostate Cancer Susceptibility Loci

Linkage analyses test for association between genetic markers at known chromosomal locations and disease phenotypes, to help identify and define specific chromosomal regions associated with prostate cancer. Genomewide screens for linkage have revealed several chromosomal regions that are likely to harbor prostate cancer susceptibility genes. Smith et al.7 reported the first genomewide screen for prostate cancer susceptibility genes and identified the first prostate cancer susceptibility locus, HPC1, at chromoso In a combined analysis of 772 HPC families by the International Consortium for Prostate Cancer Genetics,12 weak evidence of linkage to HPC1 was confirmed, with a small proportion (6 ) of families linked to this locus. A second prostate cancer susceptibility locus was reported to be at 1q42-43 (PCaP) in a genomewide screen by Berthon et al.8 Evidence of linkage to PCaP was found in 47 families of French and German origin, with a maximal two-point LOD score of 2.7. This locus is...

Androgen Levels And Risk Of Prostate Cancer

The role of the androgens in the process of car-cinogenesis to prostate cancer has been hypothesized and examined in many studies. Given that exogenous androgens can initiate and or promote prostate cancer in rodents and humans and that eunuchs rarely develop prostate cancer,58-61 circumstantial evidence implicates androgen levels in the etiology of prostate cancer. Further, a reduced risk of prostate cancer has been associated with certain hyperestrogenic-hypoandrogenic states,62 and estrogen therapy has a palliative effect in advanced cases.61 However, studies comparing hormone levels in men with and without prostate cancer have produced widely varying results.63,64 Several possibilities may explain these variations small sample sizes, analyses of hormone levels in blood collected after the diagnosis of cancer, nonrepresentative control subjects, no adjustment for other related hormone levels and hormone-binding protein levels, and no adjustment for other potential confounding...

Importance Of Androgens In The Carcinogenesis Of Prostate Cancer

The prostate is an androgen-dependent organ. Testosterone and androgen precursors freely diffuse into prostate cells. Through a coordinated network of enzymes, they can be rapidly and irreversibly converted to their reduced and more potent metabolic form, dihydrotestosterone (DHT). Both DHT and, to a lesser extent, testosterone bind to and induce the conformational change and activation of the androgen receptor (AR). The activated androgen-receptor complex then binds to the androgen response element (ARE) of androgen-responsive genes and initiates or inhibits their transcription.69-72 After fulfilling their role in transcriptional regulation, DHT and testosterone are oxidized to biologically inactive derivatives by another set of enzymes. The intracellular steady-state active androgen level, which is balanced by the availability of testosterone and dehydroepiandrosterone (DHEA), the formation of DHT, and the degradation of DHT and other androgens, is thought to be an important...

Genes In The Androgen Pathway As Candidates For Hereditary Prostate Cancer

A variety of genes are involved in the metabolic pathway of androgens and the mediation of the effects of androgens. Functionally important polymorphisms in genes that encode enzymes involved in androgen metabolism and transport may lead to differences in individual susceptibility to prostate cancer by altering the levels and effects of androgens, as proposed by Ross et al.75 (see Chapter 15) Thus far, studies of androgen-pathway genes and the risk of prostate cancer have focused mainly on sporadic prostate cancer. In addition, studies of HPC have primarily focused on the identification of novel major susceptibility genes. However, we cannot exclude the possibility that mutations (or polymorphisms) in androgen-pathway genes are involved in the etiology of HPC for the following reasons. First, given the biological relevance of andro-gens in the etiology of prostate cancer in general, it is possible that mutations in the andro-gen-pathway genes that significantly affect androgen...

Continuation Of Hormoneablative Therapy In Hormonerefractory Prostate Cancer

When prostate cancer becomes hormone-refractory, the decision to continue or stop LHRH agonist therapy is a difficult one. Evidence in the literature is contradictory. A review of Southwest Oncology Group cytotoxic chemotherapy trials in patients with hormone-refractory prostate cancer failed to define a difference in outcome based on continued LHRH therapy or previous orchiectomy opposed to cessation of prior LHRH-based treatment.138 However, another sizeable retrospective analysis (of patients treated with estrogens) suggested a modest benefit for continued hormonal ther-apy.139 Given the evidence in support of both cessation and continuation of LHRH agonist therapy once hormone-refractory prostate cancer is present, many clinicians opt to continue it after commencing chemotherapy. However, a case can be made for discontinuation of hormonal therapy in individual patients, depending on the side effects of the therapy balanced against a modest chance of disease acceleration after...

The Role Of Fibroblast Growth Factors In Prostate Cancer

Prostate cancer, which is the most commonly diagnosed malignant tumour in the Western world, could be cured with radical prostatectomy in its early stages. All other prostate tumours need to be treated with androgen ablation therapy. This therapy is only palliative and nearly all tumours progress to the therapy-refractory stage. Various experimental treatments for advanced disease have been tried with little success. Progression of prostate cancer involves alterations in expression and function of several positive and negative growth factors and their receptors, including those of the FGF family. The three peptides, aFGF, bFGF and, more recently, FGF-8 have been intensively investigated in prostate tumours with regard of their expression, interaction with the respective receptors, effects on growth in vivo and in vitro and regulation of angiogenesis and invasion. Importance of fibroblast-derived growth factors for prostate cancer was recognized in series of studies in which formation...

Prostate Cancer

Considerable evidence indicates that IL-6 is a pathologic agent in prostate cancer, with serum IL-6 concentrations correlating with tumor burden and patient morbidity (103). The growth of prostate cancer cells in vitro can be regulated by exogenous IL-6 in a paracrine or an autocrine manner (104,105), whereas chronic exposure to IL-6 may facilitate prostate tumor growth (106). Inhibition of IL-6 signaling through the gp130 subunit blocks IL-6-mediated proliferation of the PC-3 prostate cancer cell line and sensitizes the cells to cytotoxic drugs (107). In vitro studies with prostate cancer cell lines has shown that IL-6 is able to increase androgen receptor expression and induce an androgen receptor response in prostate cancer cell lines (108,109). Aromatase has a pivotal role in controlling estrogen synthesis, and aromatase inhibitors have been used to treat hormone-dependent breast cancer in postmenopausal women (110). Exogenous IL-6 can stimulate aromatase activity in cultured...

Properties As Protein

Isoelectric points of various TGases are somewhat variable. Using agarose gel electrophoresis at pH 7.4, human blood clotting Factor XIII and rat tissue TGase migrate toward the anode (22), while two iso-forms of secretory TGase in rat prostate gland (coagulating gland) move toward the cathode (5, 23). Using isoelectric focusing, TGases in the crude extracts were focused at pH 7.8. On the contrary, the analysis of pure enzymes revealed an additional isoelectric point at pH 8.7 (5, 23). Rat testicular tissue TGase was focused at pH 5.25 (5). Isoelectric points of many TGases have not been accurately determined. However, they can be calculated from data of their amino acid compositions (24). The primary structures of various TGases have been predicted by nucleotide sequence analysis of cDNAs or genomic DNAs blood coagulation Factor XIII human, A subunit (25, 26) B subunit (27)' , keratino-cyte TGase rat (28) mouse (20) , rat prostate gland (platelet) Prostate gland

Properties As Enzyme

Figure 5 Molecular phylogenetic relationship among vertebrate transglutaminases. A tree was constructed by the neigbor-joining method (42) using the program MEGA (43). Bootstrap values > 50 are shown above or below branches. Filled diamond, open circle, open diamond, open square, and filled circles indicate blood-clotting Factor XIIIA, keratinocyte TGases, prostate gland TGases, erythrocyte band 4.2 (pallidin), and tissue TGases, respectively. The groups of them are considered to be paralogous to each other. The evolutionary distance is expressed in terms of amino acid substitutions per site. The tree is rooted with mesenchyme TGase of Ciona intestinalis embryo. Figure 5 Molecular phylogenetic relationship among vertebrate transglutaminases. A tree was constructed by the neigbor-joining method (42) using the program MEGA (43). Bootstrap values > 50 are shown above or below branches. Filled diamond, open circle, open diamond, open square, and filled circles indicate blood-clotting...

Transglutaminase

In addition to secretory TGases such as blood-clotting Factor XIII and copulatory plug-forming TGase in secretions from prostate gland, tissue TGases frequently occur in cytosol and are therefore extractable by homogenization of materials such as tissue and organ with conventional buffer solutions. Some TGases bind to cell membrane, cellular particles, or extracellular matrix. As described above, egg envelope TGases of rainbow trout, extracellular matrix TGases, were nearly completely extracted by repeated homoge-nization with isotonic saline (0.143 M NaCl, 10 mM Tris-HCl, pH 7.2) (11-14). Rat liver particulate TGase has been partially extracted by three times homogeni-zation of pellet fractions with a sucrose buffer. However, the extraction was not complete. The TGase was further extracted by homogenization of the remaining particulate fractions with 1 Lubrol-WX (96). In contrast to these TGases, the TGase activity in egg envelope of the fish medaka (Oryzias latipes) was never...

International Variation In Rates

The remarkable international variation in cancer rates, for many of the common cancers, such as breast and prostate, seemed to many to support the traditional view that endogenous hormones could not be the sole or primary cause. The low rates of breast, prostate, and several other cancers in Asian populations and their increase toward Western rates upon migration to the United States or Europe suggested that chemical factors or other environmental agents were the major causes of these cancers. While cigarette smoking was one such obvious chemical carcinogen, which would help to explain the international variation in lung and other smoking-related cancer sites, the most obvious cause of the other cancers seemed to be diet, other lifestyle factors, or unidentified environmental agents. In 1964, an expert committee of the World Health Organization stated that the categories of cancer that are thus influenced, directly or indirectly, by extrinsic factors . . . collectively account for...

Dependenceresistance 209

16 Four Stages of Prostate Cancer Suppression and Eradication by Androgen and Green Tea Epigallocatechin Gallate 17 Androgen Receptor and Interleukin-6 Signaling in Prostate Cancer Progression 18 Role of the Androgen Receptor and P13K Akt in the Survival of Androgen-Refractory Prostate Cancer Cells

Hormonal Carcinogenesis

Logically, identifiable murine mammary tumor virus or type B virus in human breast milk. We undertook our first epidemiological study of breast cancer in young women to address the possibility that a transmissible agent causing breast cancer might also exist in human breast milk. We were unable to substantiate this hypothesis as there was no evidence of excess risk associated with breast-feeding, and the excess familial risk of breast cancer was seen in both the paternal and the maternal family trees.12 However, we were very impressed with the evidence supporting a role for endogenous estrogen and the key importance of age at menarche as an expression of this susceptibility. Over the subsequent 25 years, we as well as others13,14 have continued to utilize epidemiological and sero-logical studies to accumulate evidence that endogenous estrogens played a pivotal role in breast cancer.15 At the same time, it became increasingly clear that endogenous hormones were likely to be important...

Oncolytic Adenoviruses

Two techniques have been used to create CRADs. In the first, a tumor-specific promoter is used to control the expression of an essential early gene, most frequently E1A. Several CRADs whose E1A gene is driven by a tissue-specific promoter have been reported to elicit tumor-specific cell lysis (77). The promoters used in these studies included the prostate-specific antigen (PSA) promoter for prostate cancer (77), the a-fetoprotein promoter for liver cancer, and human telomerase reverse transcriptase for various cancers (78). Similarly, expressing the viral E1B and E2 genes from the promoters controlled by the Tcf4 transcription factor targeted CRADs to colon cancers, which resulted in the constitutive activation of the wnt signaling pathway (79).

Current Trends In Hormonerelated Cancers

While we propose that genetic variation influences cancer risk in hormone-responsive tissue by programming endogenous hormone production, transport, and response, other lifestyle, diagnostic, and treatment factors appear to explain short-term trends in incidence and mortality. For example, trends in hormone-related cancers, such as breast, ovarian, prostate, and uterine cancers, show that incidence and mortality rates are influenced by several factors, including changing patterns of hormone-replacement therapy, oral contraceptive use, disease-screening practices, reproductive characteristics, and other lifestyle factors that vary over time and by racial ethnic group. During the past two decades, efforts to diagnose early stage cancer through screening have resulted in artificial increases in breast and prostate cancer incidence. The impact of changing reproductive factors and screening efforts on the incidence and mortality of each of these hormone-associated cancers is discussed...

Chromosomal Aberrations

Comparative genomic hybridization (CGH). Shown is a normal metaphase spread competitively hybridized through use of two differently labeled whole genomic probes in equal amounts. The fluorescence intensity ratio between the two fluoro-chromes reveals gains and losses along each chromosome. Right panel CGH metaphase spread after CGH analysis using prostate cancer DNA. Arrows show gain of long arm of chromosome 8 determined by stronger FITC signal derived from the trisomy 8 within the tumor DNA. Left panel Composite CGH profile composed of several karyotyped metaphase spreads of prostate cancer sample. Lines to the left of the median indicate chromosomal loss lines to the right of the median indicate chromosomal gain. Note that the confidence intervals have been removed for simplicity. (Courtesy of Jeremy Squire, Ontario Cancer Institute.) Fig. 2. Comparative genomic hybridization (CGH). Shown is a normal metaphase spread competitively hybridized through use of two differently...

Diagnostics Therapy Prevention

Factors important for virulence (e. g. adherence factors) and therapy (e. g. resistance factors) of UTI. In therapy, certain antibiotics are essential. A simple cystitis should be treated three days, pyelonephritis 10 to 14 days and a prostatitis over three months. Trimethoprim and other substances are well established in therapy of urinary tract infections. It will be certainly possible to use new drugs in the near future. For prevention antibiotics and oestrogens are used for certain groups of patients. It is doubtful, whether vaccination against uropathogens will play a major role in the future. Newly developed display systems, such as the FimH-molecule or the Flagella-protein, however, will certainly lead to new dead and live vaccine strains of potential importance for prevention of UTI. In addition, immue stimulation may also play a role in prevention of this infectious disease.

Factors Affecting Efficacy Of Ad As An Anticancer Agent

Another approach to limit the replication of oncolytic viruses to tumor cells is by transcriptional regulation of the expression of genes essential for virus replication (e.g., E1A, E4, or both). Most CRADs developed using this strategy possess E1A or a combination of E1A and E4 genes under the control of tumor- or tissue-specific promoters, like the human telomerase reverse transcriptase (hTERT) (17), the prostate-specific antigen (PSA) (18), and the a-feto-protein (AFP) (19). Thus, by using the a-fetoprotein promoter to control E1A gene expression, selective replication of CRADs in human hepatocellular carcinoma cells was demonstrated (19,20). Similarly, using rat probasin (21) or human PSA promoters (22), Ad vectors were generated that replicated specifically in prostate cancer cells. Despite the fact that the feasibility of these approaches has been convincingly demonstrated in multiple preclinical animal models of human cancers (8,23-26), a series of clinical trials with multiple...

Somatic Genome Alterations in PCA Cells

Normal prostate epithelium normal prostate epithelium Table 1. GSTP1 CpG Island Hypermethylation in Prostate Cancer. Tissue 91 PCA5, 29 BPH6 Urine Plasma 54 PCA, 3 BPI l6 Prostate Biopsy Washings Post-Biopsy Urine 58 PCA5, 33 non-PC A, 67 atypia PIN Tissue (LCM8) 91 PCA5, 69 PIN7, 6 PI A9, 0 normal Prostate Secretions 76 PCA5 6 BPH, benign prostate hypertrophy 5 PCA, prostate cancer 7 PIN, prostate intraepithelial neoplasia GSTP1, encoding the Tu-class GST, likely acts as a caretaker gene in the prostate, preventing the acquisition of somatic genome changes in response to exposure to genome damaging agents. In mice, targeted disruption of GSTP genes leads to an increased susceptibility to skin carcinogenesis after exposure 7,12 dimethylbenz a anthracene (DMBA) (35). In the human prostate, GSTP1 is consistently expressed in normal basal epithelial cells, but not in normal columnar epithelial cells (36, 37). This enzyme expression is highly induced in cells comprising PIA lesions (7)....

New Opportunities for PCA Prevention

The convergence of PCA epidemiology, indicating a possible role for prostate inflammation, and a significant role for the diet, in PCA development, with molecular pathology, revealing that neoplastic prostate cells may have acquired an increased vulnerability to carcinogen damage, provides an opportunity for the discovery and development of rational new approaches to PCA prevention. Possible strategies include reduced exposure to genome damaging oxidants and other carcinogens, and intake of antioxidant micronutrients, including vitamin E, selenium, and carotenoids such as lycopene, which may be able to intercept reactive oxygen species before they inflict genome damage in the prostate. Administration of anti-inflammatory agents, when distributed into prostate tissues, may reduce oxidant production by prostate inflammatory cells. Consumption of cruciferous vegetables, containing the isothiocyanate compound, sulforaphane, an inducer of GSTs and other carcinogen-detoxification enzymes,...

Frank Z Stanczyk Philip Bretsky

In the human body, a balance exists between production and clearance of steroid hormones. Production of steroid hormones occurs de novo by biosynthetic pathways in specific endocrine glands, i.e., the adrenals and ovaries in women and the adrenals and testes in men. In addition, steroid hormones can be produced in peripheral (nonendocrine gland) tissues from circulating precursors that originate from the endocrine glands. Important sites of peripheral steroid hormone formation include the liver, kidney, breast, prostate, and sexual and nonsexual skin. After steroid hormones are secreted by the endocrine glands, they enter the systemic circulation, where they are mostly bound to proteins. The low-affinity bound and non-protein-bound (free) steroids, sometimes referred to as bioavailable steroids, are available for binding to steroid hormone receptors (progestogen, androgen, estrogen, glucocorticoid, mineralocorticoid) and if active, they exert a biological effect. Alternatively, they...

Formation of 5Androstene317Diol and Testosterone

Deficiency of 17fi-HSD type 3 causes a form of male pseudohermaphroditism referred to as 17fi-HSD deficiency,53 in which there is a deficiency in the biosynthesis of testosterone from androstenedione. The deficiency is confined to individuals with a 46 XY karyotype these individuals have testes, wolffian duct-derived male internal genitalia (with the exception of a prostate), female external genitalia, and gynecomastia.54,55

General Health Benefits

Studies examining the benefits of sexual activity on physical health have suggested sexual activity improves physical and psychological health in a number of domains. Sexual activity (1) Increases longevity Men with increased orgasmic frequency (i.e., had sex at least two times per week) had a 50 lower risk of mortality at a 10-year follow-up (Davey Smith et al, 1997) (2) Lowers the risk of chronic disease (e.g., heart disease and cancer) Among men, frequency of sex was associated with a lower risk of fatal coronary heart disease (Ebrahim et al, 2002). Furthermore, a national survey of US men found high ejaculation frequency (i.e., > 21 ejaculations per month) was associated with decreased risk of total prostate cancer (Leitzmann et al,

The Clinical Significance of FAS

Ten years after our studies on this progesterone-induced enzyme, FAS was revealed to be a marker associated with high BC risk, and a potential target for cancer therapy. Different independent laboratories using various approaches came to this same conclusion. First, Pasternak, et al. at the John Hopkins Institute developed antibodies to haptoglobin and found that the corresponding antigen (OA-519) was of poor prognostic value in BC (41,42). The antibodies reacted with contaminating FAS, which was actually the antigen responsible for the increased staining detected in aggressive BCs. Later, Kuhadja proposed FAS as a new therapeutic target in cancer. FAS inhibitors, such as cerulenine and C75 (43, 44), have been proven efficient in blocking breast and ovarian cancer cell growth, at least in vitro and in nude mice. FAS mRNA and protein were shown by other laboratories to be increased in several solid tumour cells, including prostate cancer, compared to normal cells. The group of Dana...

Metabolism Of Steroids

Steroid hormones undergo extensive metabolism by biochemical reactions in a variety of peripheral tissues, which include the liver, kidney, genital and nongenital skin, prostate, as well as adipose tissue. However, the liver is the primary site of steroid metabolism. Extensive steroid metabolism is due to the fact that steroids contain functional groups (e.g., double bond, ketone group, hydroxyl group) that are vulnerable to reduction or oxidation. Reduction of double bonds and ke-tone groups gives rise to hydrogens and hydroxyl groups that are in either the a or 3 orientation. Consequently, multiple isomers of a metabolite can be formed, as with progesterone metabolites. In addition to steroid metabolism involving oxidation reduction reactions, estrogens are especially vulnerable to hydroxylation reactions, which may occur on most of the carbons of the estrogen molecule. A third important source of steroid metabolites results from conjugation reactions. For a steroid to be eliminated...

Telomerase function genetic instability cell proliferation and cancer metastasis

Control may involve the cell cycle control genes, p53 and rb. It has been postulated that diminution of the telomere beyond a critical length might activate p53 leading to Ml senescence. But telomerase-dependent immortalisation of cells, together with the inactivation of p53 or rb genes by allelic loss or mutation, is postulated to lead to M2 immortalisation. Furthermore, M2 immortalisation is postulated to lead to progression of tumours to the metastatic state (Healy, 1995). This fits in with the picture of a late contribution by p53 to the progression of colorectal cancers (see page 172 and Figure 18). The M2 immortalisation concept is also compatible with the finding that telomerase activity is detected in colorectal carcinomas but not in adenomatous polyps (Chadeneau et al, 1995). Eddington et al. (1995) believe that the activation of telomerase may be a late event in cancer progression and this may be associated also with loss of p53 gene function by genetic alteration or allelic...

Metastatic Carcinoma of Unknown Primary Origin

In most patients, the site of origin of a metastatic carcinoma of unknown primary origin cannot be reliably determined by light microscopy (Hammar, 1998). Almost 60 of metastatic carcinomas of unknown primary origin are adenocarcinomas. Some metastatic adenocarcinomas (e.g., colonic adenocarcinomas) have distinctive histologic features that allow for determination of their site of origin. For most other metastatic adenocarcinomas of unknown primary origin, immunohistochemical analysis can help to identify the primary site. Immunophenotyping for cytokeratin 7, cytokeratin 20 (Chu et al, 2000), and other antigens used in conjunction with histologic analysis is effective in narrowing the potential primary site of origin of adenocarcinomas (Table 2-2), although these and other antigens are not absolutely site specific and cannot be reliably used to determine the site of origin. Other antigens that help determine the site of origin are thyroglobulin for thyroid, prostate-specific antigen...

AHydroxysteroid Dehydrogenases

Salts using gel-filtration chromatography of human liver cytosol.96 Subsequently, the enzyme was purified and its gene cloned and identified as 3a-HSD type 3.95 The gene is expressed in multiple tissues, including the liver and hormone-responsive tissues such as the prostate and breast.97 The AKR1C2 enzyme has high affinity for DHT and may be the predominant 3a-HSD that reduces DHT in the prostate. Although the AKR1C3 enzyme was originally identified as 3a-HSD type 2, it has low affinity for DHT and is currently considered to be 17fi-HSD type 5.98 Finally, the AKR1C4 enzyme, originally identified as 3a-HSD type 1, has the highest affinity for DHT but has been identified only in the liver.99

Urinary Bladder Dysfunction

Winge et al. (61) conducted detailed urodynamic studies in 32 PD patients without regard to whether they had bladder symptoms. Using the Danish Prostate Symptom Score (Dan-PSS), they found that 43.8 of patients met criteria for symptomatic bladder dysfunction. Irritative bladder symptoms were more commonly seen in patients with greater severity of PD as assessed by motor scoring. On urodynamic testing, bladder capacity was lower in the group with high Dan-PSS scores, and capacity increased when dopaminergic drugs were administered. Detrusor overactivity was also seen in this group, but medication administration did not impact this feature. The authors suggested that since bladder capacity improved following dopaminergic drugs, dopamine deficiency may in part underlie the irritative bladder symptoms in PD. Whether this is due primarily to central or peripheral dopaminergic cell degeneration is unknown.

Risks of Other Cancers in BRCA1BRCA2 Carriers

In addition to the marked excess of breast and ovarian cancer in BRCA1 and BRCA2 carriers, there is also evidence of more moderate risks of other cancer types. The largest study of cancer risks in BRCA1 carriers, based on 699 carrier families, found an overall cancer risk in male carriers very close to that in the general population, but the risk of cancers other than breast or ovarian in female carriers was increased by approximately twofold (44). Specifically, significant excesses were seen for cancers of the corpus uteri, the cervix, the fallopian tubes, and the peritoneum. There was also some evidence of a twofold relative risk of pancreatic cancer in carriers of both sexes and prostate cancer below age 65. In a parallel study based on 173 BRCA2 families, the risk of other cancers was approximately twofold in both male and female carriers (42). The largest excess risk was for prostate cancer, with an estimated 4.7-fold relative risk, increasing to sevenfold in men below age 65. A...

Oncogenic Capacity Of The Jakstat Signaling Pathway

Extensive data describe activated Stat3 and Stat5 in tumors. Activating mutations of Stat3 and Stat5 and specific inhibition of Stat3 and Stat5 by gene deletion, antisense oligonucleotides, or dominant negative approaches have highlighted the importance of Stat3 and Stat5 in tumor formation. Mutations of Stat3 that allow spontaneous dimer-ization of the monomers in the absence of interactions between phosphorylated tyrosines and SH2 domains are sufficient to cause transformation and induce tumor formation in nude mice (98). Inhibition of Stat3 signaling using antisense Stat3 or by a Jak-selective tyrosine kinase inhibitor, AG490, restored the sensitivity of cells from patients with large granular lymphocyte (LGL) leukemia to Fas-mediated apoptosis (99). Downregulation of Fas correlates with an increase in metastatic potential and resistance of tumors to chemically and physically induced apoptosis. This effect is mediated, at least in part, by an interaction between Stat3 and c-jun,...

The Quantitative Burden Based On Cancer Statistics

Understanding the burden of cancer survivorship also requires a quantitative appreciation of the incidence of cancer, the mortality of the disease, and the resulting number of accumulating survivors. The American Cancer Society publishes an annual summary of cancer statistics.14 Based on data from the National Cancer Institute and mortality data from the National Center for Health Statistics, it is estimated that in the United States for 2005, a total of 1,372,910 new cancer cases and 570,280 deaths are expected. Since 1999, cancer has surpassed heart disease as the leading cause of death for persons younger than 85 years. The estimated number of cancer cases in 2005 and the death rate, by various cancer sites, are shown in Figure 1, demonstrating which cancers are most common in incidence and those with the highest mortality.14 The incidence of prostate, lung, and colorectal cancer for men Treatment success and survival rates, similar to incidence, are heterogeneous when calculated...

Working With What You Have Tactics To Augment The Oncolytic Ability Of y1345 Mutant Derivatives

Although y134.5 mutant derivatives appeared safe in preclinical animal studies, their restricted replication resulting from their inability to counter components of the innate host response needed to be addressed if they were to emerge as efficacious oncolytic agents. One approach to deal with this concern combines conventional chemotherapy and radiotherapy with oncolytic virus treatment of mice with human tumor implants, taking advantage of specific properties associated with each treatment modality (46-50). On the one hand, traditional systemic treatments, although highly toxic, are able to effectively debulk a tumor. Oncolytic y 4.5 mutant derivatives, on the other hand, appear safe but have limited replicative ability in many human tumor cells. The question at hand then, was if the two therapeutic components together were more effective than each individual component. In support of this idea, head and neck derived squamous cell carcinomas implanted into mice subcutaneously and...

Building A Better Virus Genetic Strategies To Increase Virulence In Tumor Cells

A dramatic improvement in the ability of the virus to inhibit tumor growth. A single injection of subcutaneous human prostate cancer tumors with 106 pfu of the suppressor virus reduced tumor volume by 50 or more in 60 of the treated animals, whereas animals treated with the y34.5 mutant were indistinguishable from mock treated animals (see Fig. 5) (56). Although inhibition of tumor growth was observed in animals treated with the y34.5 mutant at 10-fold higher doses of virus, equivalent doses of the suppressor virus still proved more effective. In addition, long-term responders were only seen in animals treated with the suppressor virus (56). A second study arrived at similar conclusions using an independently constructed virus (G47D) that contained a suppressor mutation in a G207 genetic background using a different tumor model. Following two treatments with 106 pfu of G47D, 66 of subcutaneous human gliomas implanted into athymic mice completely regressed and exhibited no signs of...

P53 cancer progression and prognosis

Over-expression of p53 protein was reported in > 50 of breast cancers (Horak et al., 1991). Mutations of the gene are also common (25-40 incidence) in sporadic breast cancer, with the frequency of G-T transversions generally higher than expected, and these occur predominantly in the conserved exons 5-8. In many cases mutation of one allele is also accompanied by deletion of the second allele. In summary, p53 mutation characterises a highly aggressive form of the disease, associated with poor prognosis in both node-positive and node-negative patients (Lemoine, 1994). But, in contrast to colon cancer, these tend to be early events. It may be that the distinction lies in the fact that in tumorigenesis in the colon results from mutations in a series of genes, including the DCC gene, which produce a progressive alteration in the phenotype and p53 may have a complementary role (see page 172). Abnormalities of rb, another suppressor gene that actively regulates cell cycle progression, are...

Subcellular localisation of p53 protein

On the basis of these observations, it may be suggested that the subcellular localisation of p53 protein might yield valuable information about the pathways of p53 functioning, especially in relation to its cooperation with other cellular proteins which might be involved with or impinge upon the processes of cellular transformation. It is conceivable, therefore, that the patterns of p53 protein staining may be related to tumour development and progression. There are several indicators in this direction. Nuclear p53 staining is far more predominant in aneuploid tumours than in diploid tumours (Sun et al, 1993). In breast cancer where both nuclear and cytoplasmic staining is seen, p53 accumulation correlates strongly with DNA ploidy, among other variables (Stenmark-Askmalm et al, 1994). There are also indications that p53 staining pattern might be related to cancer prognosis. p53 staining of both the nucleus and the cytoplasm of colorectal tumours was associated with poor survival of...

Centrosome Amplification in Cancer

Recent studies implicate centrosome abnormalities in the pathogenesis of cancer (4, 10-14). The term centrosome amplification refers to centrosomes that appear larger than normal, centrosomes that contain more than four centrioles, and or when more than two centrosomes are present within a cell. In addition to these structural abnormalities, amplified centrosomes also show protein hyperphosphorylation and altered functional properties such as an increased microtubule nucleating capacity (4, 8, 15-17). Electron microscope studies revealed supernumerary centrioles in centrosomes of humans and animal model tumors, including leiomyosarcoma, neuroblastoma, glioma, and thymic carcinoid tumors (18-23). Systematic analyses of centrosomes in human breast carcinomas and a mouse model for prostate cancer revealed a range of abnormalities in centrosome structure including excess number of centrioles, increased pericentriolar material, abnormal centriole orientation, and inverted polarity of...

Correlation of Centrosome Amplification Aneuploidy and Chromosomal Instability

The development of aneuploidy may be a consequence of centrosome amplification, which can lead to the formation of multipolar spindles and miss-segregate sister chromatids during mitosis, and as a result to high CIN. CIN occur exclusively in aneuploid tumors and tumor-derived cell lines in contrast to diploid tumors, which contain centrosomes that are functionally and structurally normal (4, 26,28). The degree of genomic instability in aneuploid tumors parallels the degree of centrosome abnormalities in cell lines from breast (29), pancreas (13), prostate (30), colon (28), and cervix tumors (31), from short-term culture of mouse mammary tumors (32), and from SV40 ST over-expressing fibroblasts (33). When tissues were examined, centrosome abnormalities were higher in high-grade prostate tumors (30) and high-grade cervical tumors (31) than in low-grade tumors. In prostate cancer, centrosome amplification has been implicated in the development of abnormal mitoses and CIN facilitating...

Alphavirus For The Transfection Of Tumor Cell Lines

The broad host range of alphaviruses has made it possible to obtain transgene expression in various cell lines including human tumor cell lines. Using the SFV-LacZ virus for the expression of the -galactosidase reporter gene, it was demonstrated that human prostate tumor cell lines such as JCA-1, PPC-1, TSU-PR1, ALVA-1, PC-3, DU-145 and LnCaP could not only be efficiently infected, but that SFV also induced an apoptotic response (29). Moreover, the same apoptotic response has been observed in prostate biopsies from patients transduced ex vivo with SFV-LacZ. In another study, tumor cell lines were infected with SFV vectors carrying a fusion construct of the green fluorescence

Deregulation of the Centrosome Cycle in Cancer

Centrosome abnormalities in cancer are correlated with loss of p53 function in carcinomas of the breast, head and neck, and prostate, and in neuroectodermal tumors (14, 34, 71). In tumors that retained wild-type p53, amplified centrosomes were frequently associated with overexpression of MDM2, which abrogates p53 function by promoting its degradation (71). Furthermore, gain-of-function p53 mutations and p53 null mice can result in deregulation of centrosome duplication leading to the generation of functionally amplified centrosomes and aberrant mitoses (72-74). Interestingly, in some cancers p53 mutations and cyclin E overexpression may act synergistically since together they increased the frequency of centrosome defects in cultured cells and in mouse models (75).

Intratumoral Gene Delivery By Alphavirus

The capacity of SFV particles to induce apoptosis in infected cells has allowed tumor regression responses also after intratumoral expression of reporter genes only. For instance, intratumoral delivery of SFV-GFP particles into human lung tumor xenografts in nude mice showed a rapid regression of tumor volumes (34). The best efficacy was achieved after three injections on consecutive days followed by three additional injections 1 wk later. Expression of proapoptotic genes such as Bax from SFV vectors increased cell death in BHK-21 cells and also in AT3, a rat prostate cancer cell line, where the antiapoptotic gene Bcl-2 was overexpressed (35). However, the production of SFV-Bax virus was problematic as the proapoptic Bax gene killed the cells needed for amplification of the virus, resulting in very low virus titers. Reduction of the growth temperature to 33 C improved to some extent the virus production. Applying SFV-Bax particles to nude mice with implanted AT3-Neo and AT3-Bcl-2...

Tumor Targeting Of Alphavirus Vectors

Yet another approach to obtain tumor selective transfection was attained by encapsulation of recombinant SFV particles in liposomes (40). By this procedure, targeted gene delivery to human LnCaP prostate tumors implanted in severe combined immunodeficiency (SCID) mice was achieved after systemic delivery of encapsulated SFV-LacZ particles. Systemic administration of encapsulated SFV particles expressing the p40 and p35 subunits of IL-12 to SCID mice with human Panc-1 pancreatic tumors resulted in statistically significant reduction in tumor growth after a single injection (41). Furthermore, an initial phase I study on advanced melanoma and kidney carcinoma patients demonstrated the safe use of this SFV vector in humans. In this study the maximum tolerated dose (MTD) for encapsulated SFV-IL-12 particles was 3 x 109 particles m2, which might seem relatively low compared with doses for other viruses, usually administered in the range of 1011 particles. However, in this case the dose is...

Examples Of These Models In

This case highlights the shortcomings of all the models when a family history falls outside the strict remit of the model. The family history depicted in the pedigree is strongly suggestive of a mutation in BRCA2 to the experienced clinician, given the additional prostate cancer and melanoma on a background of early-onset breast cancer and ovarian cancer. Both these types of cancer have been found to be associated with BRCA2 mutations rather than BRCA1 mutations in recent studies EMBRACE, unpublished, Thompson et al. (37) . Out of the models above, only the Manchester scoring system and BOADICEA consider the additional cancers, and neither of them incorporates melanoma into their calculations yet. It is unexpected that the Myriad risk assessment for this family is identical to that for the family in Pedigree 1. This reflects the limitations of that model in terms of the number of relatives it assesses and the cancers it will consider. This pedigree also serves to demonstrate further...

Vitamin D3 and Thyroid Receptors

The vitamin D3 receptor is involved in bone mineralization and calcium deposition in response to levels of 1,24-dihydrotachysterol (produced by the liver and kidney), as illustrated by kindred studies of mutations within the human VDR gene (Tables 3.6, 3.7).320 These mutations fall into two classes point mutations within the DBD that interfere with vitamin D-dependent transcription and mutations that affect ligand binding, rendering individuals insensitive to the actions of vitamin D3. Both mutations result in clinical phenotypes of general vitamin D3 resistance, including hypocalcemia and rickets.359 As a dimerization partner with RXR, VDR is also a candidate for hormone therapy in certain cancers. For example, activation of VDR in breast, lung, prostate, and colon tumors can have an-tiproliferative effects, which may influence RXR activity in these cells.360 Additionally, VDR can activate the cyclin-dependent kinase inhibitor

The Genotoxic Mechanism

Genomic imprinting is an epigenetic modification of a parental allele of a gene in the gamete or zygote, resulting in differential expression of the paternal and maternal alleles in the offspring. This unequal expression is a departure from Men-delian genetics, but it is frequently observed in mammalian genetics. Alternations of the imprinted genes have been observed in many human cancer cells (such as Wilms' tumor, hepatoblastoma, rhabdomyosarcoma, Ewing's sarcoma) (108-110). This change is referred to as loss of imprinting (LOI). A possible consequence of LOI, as related to carcinogenesis, is the activation of an inactivated cancer gene or the inactivation of a tumor suppressor gene. The mechanism of imprinting is DNA methylation, because abnormal methylation patterns are observed in LOI regions. Moreover, studies with 5-aza 2'-deoxycytidine, an inhibitor of methylation, and in methyltransferase-deficient mice indicated that methylation is responsible for imprinting (109, 111). The...

Genetically Engineered VSV as a Gene Therapy Tool Against Cancer

In summary, VSV has now been shown to be efficacious against malignant glioma, melanoma, hepatocellular carcinoma, breast adenocarcinoma, selected leukemias, and prostate cancer based tumors (21,23,31,34,59,70,97,103-108). Genetically engineered VSVs have also now been generated with the intention of making these agents more specific, safer, and effective. Such viruses will be geared toward enhancing the immune system against the tumors and will take advantage of what we know about defects in the innate immune system. The evident ability of VSV to be manipulated clearly creates the possibility of generating many new vectors and strategies to combat cancer. However, VSV is not the only RNA virus to be evaluated as an anticancer agent. The next section briefly summarizes the potential utilization of other RNA viruses as gene therapy vectors for use against malignant disease.

Retinoblastoma susceptibility gene rb abnormalities in cancer

Loss of heterozygosity at the rb locus occurs frequently in oesophageal cancers (Boynton et al., 1991). Structural changes of the gene are associated with human soft tissue tumours (Friend et al., 1987 Stratton et al., 1989). Other tumour types with rb involvement are cancer of the prostate (Bookstein et al, 1990a), leukaemias (Cheng et al, 1990 Furukawa et al, 1991), and osteocarcinomas (Toguchida et al., 1988 Shew et al., 1989).

Paramyxoviruses Measles virus and Newcastle Disease Virus

NDV and even mumps virus was first noted to replicate in selected tumors in the 1950s. NDV, which binds to sialic acid containing glycoconjugates whose exact identification remain to be elucidated, has been found to exhibit oncolytic effects against human neuroblastoma, fibrosarcoma, colon, breast, and prostate xenografts in nude mice (129). Based on these studies, a replication-competent strain of NDV, referred to as PV701 has been examined in phase I studies on a variety of advanced solid tumors, that were unresponsive to standard therapy (100). Approximately 10 tumor responses were reported using PV701 and phase II trials are now in progress (130-132). In addition to this study, another live attenuated NDV strain, referred to as MTH-68 H was used in patients with glioblastoma multiforme (133). Although a small study, four cases of advanced high grade glioma that had failed standard therapies responded well to the treatment with survival rates of 5 to 9 yr (as opposed to 6 mo using...

Cristina Magi Galluzzi and Angelo M De Marzo Introduction

Prostate cancer (PCA) is the most common non-skin malignancy diagnosed in men in the USA and the second leading cause of cancer deaths among North American and Western European men. The incidence of PCA and the rate of death due to the disease increase with age. Less than 1 cases of PCA are diagnosed under the age of40, although small PCAs have been detected in up to 29 men 30 to 40 years of age in autopsy series (1). The incidence and mortality rates are highest among African American men, being 2.0-fold higher than in Caucasian Americans, whereas lower rates are characteristic of the Asian population (2). Accumulating data suggests that normal and neoplastic prostate cells may be subjected to multiple genome-damaging stresses, and that both diet and male sex steroids may modulate the level of threatening insults. A model of carcinogenesis and progression similar to colon cancer has been proposed for PCA (Figure 1) (5). This model predicts multiple steps in the process from normal...

Prostatic Intraepithelial Neoplasia PIN

PIN represents the neoplastic transformation ofthe epithelial lining of the prostatic ducts and acini without invasion ofthe basal layer (6). In high-grade PIN (HGPIN), the glandular units of the prostate are lined by cytologically malignant, enlarged epithelial cells with a high nuclear cytoplasmic ratio. HGPIN has been extensively studied and is thought to be the precursor lesion ofPCA, particularly for the lesions occurring in the PZ. In 1941, McClintock suggested that telomere dysfunction is one potential mechanism of chromosomal instability (23). Telomeres are specialized structures that cap the ends of linear chromosomes, essential for maintaining chromosomal stability. Natural shortening with each cell division serves as a mitotic clock. Shortening has been hypothesized as a protective mechanism against proliferation. As compared with normal prostate tissue, telomere shortening had previously been reported in PCA (24-26). More recently telomere shortening was shown to occur...

Proliferative Inflammatory Atrophy PIA

Since chronic inflammation of long-standing duration has been linked to the development of carcinomas in several organ systems, such as liver, stomach and esophagus (29, 30), inflammatory cell-mediated oxidant stress may be a key pathogenetic mechanism driving PCA (31). In prostate, chronic inflammation is associated with focal atrophy. Atrophy of the prostate is identified as a reduction in the volume of preexisting glands and stroma and can be divided in two major patterns diffuse and focal. Diffuse atrophy results from a decrease in circulating androgens and involves the entire prostate in a relatively uniform manner (32). In contrast, focal atrophy is not related to decreasing circulating androgens, and it occurs as focal areas of atrophic epithelium within a background of surrounding normal appearing non-atrophic epithelium. Franks (33) indicated that focal prostatic atrophy lesions occur predominantly in the 'outer portion ofthe prostate' referred also as PZ by McNeal (34)....

Atypical Adenomatous Hyperplasia AAH or Adenosis

The data that exist on the prevalence of atypical adenomatous hyperplasia (AAH) also known as adenosis (53,54) is controversial. The vast majority ofadenosis foci are found in the TZ. They are usually associated with benign prostatic hyperplasia (BPH) nodules and may share some morphologic features with well-differentiated carcinoma (55). The prevalence of AAH in the literature is highly variable (from 1.6 to 19.6 ) (56). A study of a series of needle biopsy specimens reported a lower prevalence, approximately 0.8 (57). Data reporting higher numbers of TZ cancers in African Americans than in Caucasians may imply a higher prevalence of adenosis in the former (58). The relationship between adenosis and PCA remains somewhat disputed and ill defined, although adenosis lesions may at times express elevated levels ofracemase (59) and show genetic alterations characteristic ofPCA (60, 61).

Psychophysiological Pathways

Another body of work examines disease progression. Studies have shown that denial coping and lower satisfaction with social support relate to the progression from HIV to AIDS (Leserman et al, 2000). Optimism, active coping, and spirituality show some evidence of predicting slower disease progression (Ironson and Hayward, 2008). A meta-analysis of coping among men with prostate cancer found that approach coping (both problem-focused and emotion-focused) improved physical outcomes such as self-reported fatigue and physical well-being, and that avoidance coping was associated with lower self-reported physical functioning (Roesch et al, 2005).

Relationships of Norms to Health Behaviors

Both injunctive and descriptive norms are related to screening behaviors however, research supports the superiority of injunctive norms in this realm. Smith-McLallen and Fishbein (2008) found that intentions to obtain a mam-mogram, colonoscopy, and screening test for prostate cancer were more strongly associated

Is the wafl dpi gene altered in cancer

Reported in colorectal cancer and somatic mutations have not been found in codons 9 through 139 that were screened (Li YJ et al, 1995). Multiple polymorphisms were seen in human brain tumours, most frequently of codon 31 - again there were no somatic mutations (Koopmann et al, 1995). Codon 31 polymorphism occurs also in normal individuals (Li YJ et al, 1995 Marchetti et al., 1995c) and, in the brain tumour study, the polymorphisms did not relate to histological type (Koopmann et al, 1995). Jung et al (1995b) also investigated gliomas for wafl cipl abnormalities. Surprisingly, wafl cipl protein levels were low in normal brain tissue and in reactive gliosis, but were highly elevated in gliomas irrespective of grade. Glioblastoma multiforme showed elevated protein levels, in tumour samples carrying either wild-type or mutated p53- No elevation of protein occurred in anaplastic astrocytomas carrying mutant p53-Jung et al (1995b) also stated that wafl cipl gene is not deleted in gliomas....

Familial Clustering Of Hormoneresponsive Cancers

Multiple large studies8 indicate that the risk of the most common hormone-responsive cancers (breast, prostate, and ovary) is significantly influenced by inherited differences in genome sequence. Specifically, the MZ twin of a patient with cancer is two to three times more likely to get the same cancer than a DZ twin. These studies suggest that 27 -57 of the variation in population risk is due to gene effects and the remainder to non-genetic (environmental and random) factors.9,10 While these studies show that inherited factors play a causal role, they also demonstrate that genes are far from the whole story in MZ twins, the rate of concordance for prostate cancer is on the order of 25 , showing that even genetically identical people can have very different outcomes with regard to can-cer.9,10 Moreover, in most cases, the genetic contribution is not attributable to a single gene (which would produce a recognizable mendelian pattern of inheritance) but rather must be divided among a...

Linkage Analysis in Families

Because linkage analysis is unbiased and genomewide, it represents a critical starting point for any study of disease genetics. This approach has been used successfully to identify BRCA1 and BRCA2, implicated in breast and ovarian cancers.5,6 Although linkage studies have implicated several chromosomal regions in prostate cancer,34-39 only two genes have been identified to date. ELAC2 (HPC2) was identified in 2001,38 with both rare and common mutations that showed association to disease, although the consistency of this association remains unclear.40-42 Mutations in RNASEL were proposed (via positional cloning) to be responsible for a subset of familial cases of prostate cancer.43 While these are exciting developments, it is not yet clear whether these genes or the pathways they identify play a significant role in the inherited basis of the common forms of these diseases.

The Androgen Receptor Gene

Under this model if a single repeat increment results in a 10 increase in androgen activity and, therefore, in prostate tissue aging, this would translate into potentially as much as a 2.4-fold lifetime increase in PCA risk a 2 increase would translate into a 20 increase in risk, whereas a 1 increase would translate into a 9 increase, and a 0.5 into a 5 lifetime increase (Table 2).

The role of testosterone metabolites in nonhuman males

In the 1960s, it was discovered that a testosterone metabolite, 5a-dihydrotesto-sterone, was formed from circulating testosterone in peripheral target organs like the prostate or seminal vesicle. The enzyme responsible for the transformation of testosterone into dihydrotestosterone, 5a-reductase, was found to be present in target tissues. Dihydrotestosterone has a higher affinity for the testosterone receptor than testosterone itself and it was soon suggested that testosterone was a pre-hormone and that it needed to be transformed into dihydrotestosterone before having any physiological effect (Wilson and Gloyna, 1970). It was quite logical to suppose that this would also be the case for the actions of testosterone within the central nervous system, particularly since 5a-reductase had been shown to be present in the brain (Jaffe, 1969). To the surprise of many scientists, this was not the case. Dihydrotestosterone turned out to be quite inefficient for the restoration of copulatory...

The Steroid 5aReductase Type 2 Gene

The other gene that our research program has focused on is the steroid 5a reductase type 2 (SRD5A2) gene. There are at least two 5a reductase isozymes encoded by 2 genes on different chromosomes (43). Although early work suggested that only the type II enzyme was expressed in prostate tissue, more recent work suggests that the more ubiquitous type I enzyme is as well (44). We began our work with the SRD5A2 gene by systematically sequencing the gene in a group of men with very high or very low circulating levels of androstanediol glucuronide, an index ofwhole body reductase activity. We identified initially 25 single nucleotide polymorphisms (SNPs) in the protein coding region - 10 missense and 15 silent (i.e., third base pair substitutions) (45). We have subsequently identified 11 additional SNPs in the putative promoter region and 5' and 3' UTRs. We have reconstituted each ofthe missense coding region SNPs by site directed mutagenesis in the SRD5A2 cDNA, and then overexpressed these...

The role of aromatization in men

Although the total number of men having participated in the studies outlined in the preceding paragraphs is rather small, the consistent results inspire some confidence. It does not seem too adventurous to propose that aromatization, and hence estrogen receptors, are not of any crucial importance for human male sexual behavior. In that way, humans may be different from rats and some strains of mice. At the same time, there is a curious report describing a man who had been castrated bilaterally because of severe post-vasectomy orchialgia. He maintained an adequate sexual functioning with a combined treatment of estrogens + progesterone. In fact, this regimen seemed more effective than treatment with testosterone enanthate (Davidson et al., 1983). The significance of this single individual should not be overestimated, but some additional data suggest that estradiol may contribute to the maintenance of sexual functioning in men who have been castrated because of prostate cancer (Ellis...

Secretion of Soluble MICA into Serum in HCC and NKG2D Expression in NK Cells

Recently, it has been reported that some MICA expressed in tumor cells are truncated and their extracellular domains are secreted into culture solutions as soluble forms (Groh et al., 2002 Salih et al., 2002). It is known that soluble MICA (sMICA) is detected in the serum of patients with prostate cancer, colon cancer, brain neoplasm, and leukemia. The importance of this phenomenon is that MICA expression in tumor cells is decreased due to cleavage and NK responsiveness is decreased due to induced NKG2D internalization. These events might be involved in the ability to evade the immunomechanism.

Detection of Id1 Overexpression in PCA in the Rat Model

Using this model, we studied the gene expression profile during prostate carcinogenesis using a cDNA array method. The results were confirmed by RT-PCR, western blotting, and immunohistochemical (IHC) analyses. Seventeen genes were differentially expressed, and three of them with the highest level of overexpression were selected for further analysis. They included Testosterone-repressed prostatic message-2 (TRPM-2), matrix metalloproteinase-7, (MMP-7), and inhibitor ofdifferentiation or DNA binding (Id-1) (6). Increased expression of TRPM-2 and MMP-7 was observed in both pre- and malignant samples after sex hormone treatment, indicating their role in the early stages of hormone response and PCA development. In contrast, Id-1 was expressed at relatively low levels in all pre- malignant samples, but its level of expression increased in malignant

Role of Id1 in Human PCA

Since in the Noble rat model, the levels of Id-1 expression correlate to those of PCA, we hypothesize that Id-1 over-expression occur in human PCA. In addition, if Id-1 levels are positively correlated with tumor malignancy, Id-1 may serve as a useful PCA prognostic marker. To test our hypothesis, we examined the expression of Id-1 protein and mRNA by IMH and in-situ hybridization analysis in human normal prostate, benign prostatic hyperplasia (BPH), and cancer biopsies (Figure 2) (17). In addition, we correlated the difference in Id-1 expression with PCA grade using the Gleason classification (17). Figure 2. Id-1 in-situ hybridization in normal prostate, BPH, and malignant prostate specimens. (A). Normal prostate. Note the absence of Id-1 mRNA expression (200 x). (B). BPH. Note the very weak to undetectable Id-1 mRNA expression (200 x). (C). Well-differentiated PCA showing moderate levels of Id-1 mRNA expression (200 x). (D). Moderately well- differentiated PCA. Note the relatively...

Cancers Other Than Breast and Ovarian Cancer

Carriers families rectal Stomach bladder Pancreas Liver duct Uterine Pertonium tube Cervix Prostate Lymphoma cell skin Leukemia Melanoma combined Prostate Cancer Early linkage studies suggested an RR of prostate cancer of 3.3 among the 33 multiplex kindreds studied (51). When broken down by BRCA1 versus BRCA2, the linkage consortium found no increased risk in BRCA1-linked kindreds (106), but in BRCA2 mutation carriers, a statistically significant increase in the risk for prostate cancer was noted (RR 4.6) (36). The RR was higher for prostate cancer before the age of 65 years (RR 7.3). Sigurdsson et al. (105) ascertained 53 mutation-positive first-degree male relatives of breast cancer probands in known Icelandic BRCA2 kindreds. Among these men, the estimated RR of prostate cancer was 4.6. Among mutation-positive second-degree male relatives, the corresponding RR was 2.5. The 383 men in another study by Johannsson et al. (104) were all from known Icelandic BRCA2-linked kindreds and had...

Studies on men with spontaneous gene deletions

There is one report of a man lacking a functional estrogen receptor because of a premature stop codon in exon 2 of the estrogen receptor gene (Smith et al., 1994). This man showed no response to administration of estradiol despite a large increase in blood estradiol concentration. The patient had normal male genitalia with bilateral descended testes, each with a volume of 20-25 ml, and a normal-sized prostate gland. Semen analysis showed a reduced sperm motility (viability of 18 against around 50 in normal men) with a normal sperm count of 25 million per millilitre. He indicated strong heterosexual interests and reported normal sexual functioning, including presence of morning erections and nocturnal emissions. From the clinical data reported, it is quite evident that the man lacked the estrogen receptor a. Although data from a single case study are far from sufficient for any firm conclusion, the evident lack of alterations of sexual behaviors in this man is remarkably different from...

Control of Androgen Action and Medicinal Applications

In the early 1960s, we found that As can rapidly enhance RNA synthesis in target organs, such as the ventral prostate of rats, suggesting that As act by modulating gene expression in target cell nuclei (2-4). Subsequently, we (5, 6) and Bruchovsky and Wilson (7) showed that, in many target organs, testosterone, the major A produced by testis and circulating in blood, is converted by 5a-reductase to 5a-dihydrotestosterone (5a-DHT). 5a-DHT is the active A that binds to a specific nuclear androgen receptor (AR) (8-12). The 5a-DHT-AR complex, apparently in conjunction with other chromosomal proteins (13), then regulates specific transcription of genes and production of specific proteins that modulate cellular activities and organ functions. Cloning and sequence determination of the genes for AR (10, 11) and 5a-reductase (14) have shown that mutations of these genes are responsible for A-insensitivity syndromes, including pseudo-hermaphroditism. are now being utilized as therapies for...

AReductase Inhibitors

The reductase have been prepared by pharmaceutical companies. The synthetic 4-aza-steroid, finasteride, is now prescribed as Proscar for benign prostate hyperplasia (BPH), and as Propecia for male pattern baldness. Two isozymes of 5a-reductase have been identified (14). The specific roles of the individual isozymes are not well understood. Finasteride is a selective inhibitor of the type 2 isozyme of 5a-reductase whereas GLA, curcumin, alizarin, can inhibit both the type 1 and type 2 isozymes. EGCG was a better inhibitor of the type 1 isozyme than of type 2. The biomedical significance of this difference is unclear. While oral Proscar has been shown to be effective in treating BPH, the effectiveness of natural inhibitors for benign or cancerous prostate growth has not been demonstrated.

Pathologypathophysiology

The primary infection can also occur in the rectal or pharyngeal mucosa of either sex. Gonococci attach to the mucosal epithelium and then penetrate between and through the epithelial cells to reach the subepithelial connective tissue by the third or fourth day of infection. An inflammatory exudate quickly forms beneath the epithelium. In the acute phase of infection, numerous leukocytes accumulate (many with phagocytosed gonococci), causing a characteristic profuse yellow-white discharge in males. In the absence of specific treatment, the inflammatory exudate in the subepithelial connective tissue is replaced by macrophages and lymphocytes. Direct extension of the infection occurs through the lymphatic vessels and less often through the blood vessels. Acute urethritis is the most common manifestation in males, and the infection can then spread to the posterior urethra, Cowper's glands, seminal vesicles, prostate, and epididymis, which leads to...

Overexpression of Tumor Suppressor Genes and Apoptosis Inducing Genes

Therapeutic benefit of recombinant TRAIL protein is frequently attenuated by weak antitumor activity and resistance. Interestingly, however, cancer cells resistant to TRAIL protein can be effectively killed by the TRAIL gene (66-68), as has been found in certain breast cancer cell line (66), prostate cancers (67), and hepatomas (68). Because most of the proapoptotic genes mentioned above induce apoptosis regardless of a cell's p53 status, they are effective in both p53-sensitive and p53-resistant cancer cells (69).

EGCG Modulation of Food Intake and Endocrine Systems

The mechanism by which EGCG suppresses prostate tumor growth may be very complex. Many in-vitro effects of EGCG, including inhibition of cancer cell mobility, inhibition of key enzymes and protein factors, induction of apoptosis, and inhibition of angiogenesis, have been shown (1). It is very difficult to assess whether these in-vitro observations are related to in-vivo effects because EGCG and other catechins can interact non-specifically with enzymes or other macromolecules as well as cellular membranes. After 7 days of daily ip treatment with EGCG, circulating levels of testosterone are reduced by about 75 in male rats and 17(3-estradiol levels by 34 in female rats. The weights of A-sensitive organs, such as ventral prostate and seminal vesicles and estrogen-sensitive organs, such as the uterus and ovary were reduced by about 50 . Other catechins were not as effective as EGCG. We also found that the serum level of LH is reduced by 40-50 , suggesting that low LH production led to...

Concluding Remarks

Anti-androgens should not be employed for treatment of the R1 or R2-form tumors since they can interfere with the A suppression of these tumors. R2-tumors after A treatment eventually lose the ability to produce AR and become IS-form tumors that cannot be stimulated or suppressed by As. Fortunately, green tea EGCG is an effective treatment for the A-insensitive tumors and may be used at this final stage of PCA progression. In fact EGCG is effective for suppression of all forms of prostate tumors regardless of their A sensitivity. Therefore, infusion of EGCG-rich green tea beverage or polyphenol products may be advisable for patients with prostate tumors at any stage. Since we have shown that rodents may gradually adapt to the continuous use of EGCG (1), possibly due to induction of enzymes or proteins that can degrade EGCG or increase its excretion, an intermittent use of EGCG may be advisable for PCA treatment. anti-androgens for treatment of PCA patients needs careful evaluation of...

Family History and Inherited Susceptibility

Although BRCA1 and BRCA2 are often described together, there are important epi-demiological distinctions between them. The BRCA1 gene has been associated with increased risk of ovarian cancer, while BRCA2 has been suggested to play a role in male breast cancer and possibly other cancers, such as pancreatic and prostate. The BRCA1 gene is associated with an early age at onset, but this is less clear for tumors associated with BRCA2. The histology of BRCA1- and BRCA2-associated tumors differs from sporadic cases and from each other.

Intracellular Signal Transduction by the FGFR Complex

The kinase domains of the four FGFR isotypes exhibit greater than 80 homology 2 . In some systems, the four FGFR isotypes elicit similar and redundant effects on cell responses and activate similar downstream signal transducers 27-30 . In others, individual isotypes exhibit dramatically different effects on cell phenotype, some of which are in opposition. The quantity of or sustained signaling from a single isotype can also affect quality of the response. For example, although FGFR1 and FGFR3 intracellular domains appear redundant in eliciting neurite outgrowth in PC12 neural cells 30 , only the FGFR1 kinase elicits neurite outgrowth when the FGFR ectodomain is utilized 31 . The FGFR3 kinase failed to sustain outgrowth and Ras-dependent gene expression, but instead induced neural-specific gene expression pathways that were Ras independent 32 . In bladder 33 , prostate 34,35 , and salivary tumor epithelial cells 36 , the resident FGFR2 kinase promotes homeostasis and suppresses the...

HSPs in cancer and their possible relevance to prognosis

HSP expression has also been examined in other forms of human cancer. The expression of high molelcular weight (60-90 kDa) HSP levels are said to be significantly higher in circulating cells of patients with acute myeloid leukaemia than in cells from patients with chronic myeloid leukaemia, and in both these cases HSP levels were higher than in mononuclear cells of normal peripheral blood (Chant et al, 1995). The occurrence of high molecular weight HSPs has also been described in lung cancers (Bonay et al, 1994). Prostate cancers have been reported to show positive cytoplasmic staining for both p53 and HSP72 73 (van Veldhuizen et al, 1993). The median intensity of immunochemical staining for HSP70 did not differ markedly between oral squamous cell carcinoma, epithelial dysplasia and benign oral mucosal lesions (Sugerman et al, 1995). In summation, it may be premature to judge the value of HSP expression as a marker of cancer progression and as a tool for predicting prognosis.

Enhancement of Androgen Receptor Function by Nonsteroidal Activators

The AR is also activated by stimulators of the protein kinase A pathway, such as forskolin or cAMP analogues (31). These are pleiotropic compounds that differentially affect tumor growth. Interestingly, an inhibitor ofthe protein kinase A pathway reversed not only the effect of forskolin on AR activity, but also partially reduced androgen-stimulated AR transcriptional function. This indicates that the protein kinase A pathway is implicated in both steroidal and non-steroidal activation of the AR. In cells transfected with AR cDNA, non-steroidal regulators do not change AR levels. In contrast, in LNCaP cells effects on AR expression by non-steroidal compounds were observed.

Extent and Associations

Scott and colleagues (2002) found individuals with low health literacy to be less likely to have received an influenza or pneumococcal vaccination, mammogram, or Papanicolaou smear, if eligible. Dolan and colleagues (2004) found that low literacy was significantly associated with poor knowledge and negative attitudes toward use of colon cancer screening tests. Davis et al (1996a) had found earlier that knowledge, attitudes, and screening intention for mammogra-phy were strongly associated with literacy skills in a group of screening eligible women. Bennett and colleagues (1998) reported that racial disparities in advanced stage presentation of prostate cancer were partly explained by lower literacy levels among African-Americans, suggesting that low literacy may be associated with late or less frequent screening. These findings were confirmed using more recent data in the current era where a blood test to measure Prostate Specific Antigen (PSA) is widely used for determining the...

Interleukin6 and Related Cytokines in Regulation of PC A Cell Growth and Androgen Receptor Activity

An important activator ofthe AR is interleukin-6 (IL-6), a pleiotropic cytokine that regulates growth of various tumors following binding to the IL-6 receptor. In several studies, it was revealed that IL-6 levels increase in sera from patients with metastatic PCA (32,33). PCA cells PC-3 and DU-145 also produce high levels of IL-6 into their supernatants (34). IL-6 was not detectable in LNCaP cells. In patients with organ-confined PCA, both IL-6 and IL-6 receptor levels increase (35). It was demonstrated that primary prostate epithelial cell cultures, a cell line derived from prostate intraepithelial neoplasia, PC-3, and DU-145 cells are growth-stimulated by IL-6 (34, 35). For LNCaP cells, contrasting results as to IL-6 responsiveness were reported (35 , 40). These data may be explained by the use of different LNCaP passages in various laboratories. An important issue in IL-6 signaling in prostate are changes in recruitment of signaling pathways during continuous IL-6 treatment. We...

The Role for Androgen Receptor Coactivators in PCA

We focused on the role of the cofactor CBP in carcinoma of the prostate (45). It potentiates activation of the AR by androgen and non-steroidal anti-androgens, hydroxyflutamide and bicalutamide. The effects on AR-induced activity by hydroxyflutamide were more pronounced that those stimulated by bicalutamide. These effects were observed in DU-145 and LNCaP cells with the wild-type and two mutant receptors. CBP is expressed in PCA cell lines LNCaP, PC-3, and DU-145, and also in clinical specimens. Regulation of CBP in PCA by peptide and steroid hormones is being investigated. In other studies, it was shown that the expression of the cofactor RAC3 correlates with tumor grade and stage (46). Interestingly, nuclear localization of the cofactor Tip60 is enhanced during androgen withdrawal (47). Gregory, et al. investigated the expression of AR cofactors in relapsed PCA and found that SRC 1 and TIF 2 are up-regulated (48).

Screening and Cancer Control

This chapter focuses on the use of screening for cancer. Cancer is a leading cause of death worldwide, and in 2007 accounted for 7.9 million deaths (around 13 of all deaths), a figure that is predicted to rise to 12 million by 2030 (WHO, 2009). Screening represents a major part of the cancer control effort, particularly in developed countries. The Papanicolaou (Pap) test for the detection of pre-cancerous cervical lesions is the most widely used cancer screening test. It was developed in 1928 and is now available to women across the globe albeit with different technologies and test frequencies. Some cervical cancer screening programs now also incorporate DNA testing for human papillomavirus (HPV), the viral precursor to cervical cancer. Mammography screening was developed in the 1950s for early diagnosis of breast cancer and involves taking a low-energy X-ray of the breast which is then examined for signs of calcification or soft tissue masses. More recently, colorectal cancer (CRC or...

Haojie Huang and Donald J Tindall Introduction

Surgical or pharmaceutical ablation of testicular androgens has been the most effective treatment of metastatic prostate cancer (PCA) since 1941 (1). Both normal and malignant epithelial cells ofthe prostate undergo programmed cell death (apoptosis) in the absence of androgens (2, 3). However, a majority of PCA patients usually relapse with tumors becoming refractory to androgen ablation therapy, suggesting that relapsed cells are able to resist androgen withdrawal-induced cell death (4). Overexpression ofthe anti-apoptotic protein Bcl-2 appears to promote the survival of androgen-refractory PCA cells (5-7). Bcl-2 protein is expressed intensely in 77 of androgen-refractory prostate tumors compared to 32 in androgen-sensitive tumors (5, 8, 9). It is possible that the increased expression ofBcl-2 in androgen-refractory PCA may result from outgrowth of cells expressing high levels of Bcl-2 before androgen ablation treatment. It is also possible, but not necessarily mutually exclusive...

Characteristics of Good Screening Tools

It is also important to consider the possible side effects of screening. Clearly a test with common and harmful side effects would not be useful for example, the risk of bowel perforation during colonoscopy must be considered when deciding whether it is suitable as a population-based screening tool. Consequences of screening follow-up must also be considered one reason why cervical screening is often deemed inappropriate for women under 25 years is that many HPV-related abnormalities regress spontaneously at this age while treatment can compromise future pregnancies. Distress and anxiety should also be considered when the costs and benefits of a screening test are evaluated. Another potential harm, which is gathering more attention at present, is the risk of over-diagnosis, i.e., detecting disease that may never have resulted in significant morbidity or mortality. Topical examples of screening tests that have attracted concern regarding possible over-diagnosis include PSA testing to...

Provision of Cancer Screening Services

Controversy surrounding the specificity of the PSA test means there are currently no organized prostate cancer screening programs. In combination with the Digital Rectal Exam, PSA testing is offered opportunistically to men over the age of 50 years in several countries including the USA, Canada, the UK, and Australia. In the USA, men are offered the test annually as part of a regular health check. The UK allows any man over the age of 50 who asks for a PSA test to have one, but only after discussion of the implications with the provider.

Optimizing Screening Uptake

Prostate cancer screening using PSA testing is only offered opportunistically. The most recent estimates from the US suggest that around half of 50-79 year olds have had a PSA test in the past 2 years (Ross et al, 2008 Weller et al, 2007). UK estimates based on a survey of general practitioners suggest that the rate of PSA testing in asymptomatic men is only 2 (Melia et al, 2004).