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PubMedDate not supplied

Development of the VCaP androgen-independent model of prostate cancer.

Prostate epithelial cell growth is dependent on the presence of androgens, and transition of prostate cancer to an androgen-independent phenotype results in a highly aggressive, currently incurable cancer. We have developed a new preclinical model of androgen-independent prostate cancer derived from the VCaP prostate cancer epithelial cell line. VCaP cells were subcutaneously implanted and serially passaged in castrated male severe combined immunodeficient mice. Androgen independence was confirmed by WST-1 (a tetrazolium salt) cell proliferation assay in the absence or presence of dihydrotesterone (1-100 nM). VCaP androgen-sensitive cells responded dose dependently to dihydrotesterone, whereas VCaP androgen-independent cells did not alter their proliferation in response to dihydrotesterone. Gene expression of androgen receptor, B-cell lymphoma-2, prostate cancer antigen 3, prostate acid phosphatase, 6 transmembrane epithelial antigen of the prostate, and survivin was determined by polymerase chain reaction amplification. B-cell lymphoma-2 expression was up regulated in the VCaP androgen-independent lines compared to the VCaP androgen-sensitive, suggesting a possible mechanism of androgen independence. Furthermore, tumor-associated angiogenesis was assessed by immunofluorescence confocal microscopy of CD31. VCaP androgen-independent tumors showed enhanced angiogenesis compared to VCaP androgen-sensitive tumors. These results illustrate the development of a novel model of prostate cancer androgen independence and provide a new system to study angiogenesis and the transition to androgen independence.

Androgens↗

PubMed1992

Serum prostate specific antigen as pre-screening test for prostate cancer.

Prostate cancer has become the most common cancer and the second cause of death due to cancer in men in North America. Since curative therapies are limited to early stages of the disease, the availability of an efficient, easy to perform, widely acceptable and cost-effective method of early detection of prostate cancer is particularly important. Thus, digital rectal examination, transrectal ultrasonography of the prostate as well as measurements of serum prostate specific antigen (PSA) were performed independently in a series of 1,002 men between 45 and 80 years old randomly selected from the electoral rolls of Quebec City and its vicinity as part of a screening program for prostate cancer. Using this population of randomly chosen men, various cutoff serum PSA values were selected in an attempt to find the optimal decision threshold that would indicate a much greater risk of having prostatic cancer. At a threshold value of 3.0 micrograms./l. the sensitivity and specificity of the test are 80.7 and 89.6%, respectively, while the area under the receiver operating characteristic curve reflecting the accuracy of the test is 87.8 +/- 3.3% (plus or minus standard deviation). Moreover, the negative predictive value was estimated at 98.6%, thus leaving only a 1.4% chance of missing cancer when the serum PSA value was 3.0 micrograms./l. or less. Most importantly, such a threshold level of serum PSA retains only 19% of the whole cohort as candidates for transrectal ultrasonography and expensive diagnostic procedures, thus leading to the finding of 1 prostate cancer of 4 such examinations. The present data indicate that simple measurement of serum PSA can be used efficiently as a pre-screening test for prostate cancer in the general population to identify, at a low cost, the subpopulation of men at a much greater risk of having prostate cancer, and who should then be submitted to the more elaborate and expensive diagnostic procedures.

Age Factors↗

PubMed2005

The SERCA pump as a therapeutic target: making a "smart bomb" for prostate cancer.

Prostate cancer is uniformly fatal once it has spread outside of the prostate gland. Prostate cancers have a remarkably low proliferative rate, which may in part explain their relative unresponsiveness to conventional antiproliferative chemotherapy. New therapies for prostate cancer that activate proliferation independent cell death are therefore needed. The endoplasmic reticulum (ER) has emerged as an organelle that plays a major role in cell signaling pathways, cellular response to stress and cellular activation of apoptosis. In this review, the SERCA pump is identified as an ER protein whose normal function is required by all cells and represents a potential therapeutic target for cancer therapy. Sustained SERCA inhibition by agents such as thapsigargin results in activation of ER-stress response and simultaneous activation of apoptotic pathways within the ER and the mitochondria. Due to the SERCA pump's critical role in normal cellular metabolism, agents like thapsigargin directed toward inhibiting SERCA function would likely produce significant toxicity to normal cells and, therefore, must be selectively targeted to cancer sites. The cytotoxicity of thapsigargin can be attenuated, however by coupling to a targeting peptide to produce an inactive prodrug that is only activated by prostate cancer specific proteases such as the serine protease prostate-specific antigen (PSA). PSA-activated thapsigargin prodrugs have been characterized that are selectively toxic to PSA-producing prostate cancer cells in vitro and in vivo. These prodrugs are currently undergoing preclinical evaluation as potential targeted therapy for prostate cancer.

Apoptosis↗

PubMed2003

Advances in immunotherapy for prostate cancer.

Prostate cancer is the most common malignancy in American men. Metastatic prostate cancer is incurable, with the currently best treatment, androgen ablation, being only palliative. Therefore, there is a need to develop new, more effective therapies against this disease. Multiple immunotherapeutic strategies are being explored for the treatment of prostate cancer, with the hope that such treatment will be more effective and have fewer side effects than current treatment options. Several immunotherapy strategies have been shown to be effective against prostate tumors in animal models, and many of these strategies are beginning to be tested in clinical trials for their efficacy against human prostate cancer. It is likely that effective treatment of prostate cancer will require the use of both immunotherapeutic and traditional approaches in multimodality treatments. In addition, for immunotherapy to be effective against prostate cancer, ways to overcome immune evasion and immunosuppression by the tumor cells will need to be developed.

Adoptive Transfer↗

PubMed1993

Early diagnosis of prostate cancer.

Prostate cancer continues to be a leading cause of cancer death in American men. Since no studies have yet been reported that demonstrate a reduction in prostate cancer mortality, widespread prostate cancer screening by any modality must be considered experimental. Although, for an individual patient, screening may appear to have great potential benefit, when applied on a large scale, both the expense and potential morbidity could have a substantially negative impact on health care. These issues are too often ignored by enthusiasts of screening, but inevitably they will need to be addressed. Can society afford the expense of screening even if it does lead to reduced mortality? In addition, if health care resources are limited, is prostate cancer screening the best use of these funds? Finally, until the efficacy of prostate cancer screening is demonstrated by properly performed studies, it is essential that patients be told of both the potential risks and benefits of screening so that a fully informed decision can be made. Alternatively, should patients only be told that screening is clearly in their best interest? Currently, these questions have not been adequately addressed.

Biomarkers, Tumor↗

PubMed2004

[Genetic susceptibility to prostate cancer].

Prostate cancer is the most frequent malignant tumor among men over 50 years old. Its incidence varies according to countries and ethnic group. Known risk factors are race and positive family history of the disease. Familial aggregation (at least 2 cases in the family) is observed in about 20% of cases and an hereditary form of prostate cancer in 5%. This proportion increases with younger age at diagnosis. Six putative loci are already identified but undoubtedly, others will be found in forthcoming studies. The genetic heterogeneity observed in hereditary prostate cancer reflects variety of origins of the studied families. In some families, aggregation of prostate cancer and other cancers suggests the involvement of common predisposing genes. In other familial and in sporadic cases, the genetic component should be polygenic: prostate cancer wouldn't result to segregation of a major gene mutations transmitted according to a monogenic inheritance, but rather to sharing of alleles at many loci, each contributing to a small increase in cancer risk. Indeed, several genetic polymorphism were associated with an increased risk of developing prostate cancer and could explain the variations of prostate cancer incidence observed between populations.

Female↗

PubMed2004

Seeking help for erectile dysfunction after treatment for prostate cancer.

Prostate cancer survivors appear to have higher rates of seeking medical help for erectile dysfunction (ED) than other cohorts of sexually dysfunctional men; however, factors associated with help-seeking for ED after prostate cancer have not been investigated. A group of 1,188 men with ED after prostate cancer responded to a postal survey about their sexuality, including a new questionnaire developed to measure traditional masculine attitudes about sex that could inhibit help-seeking. Respondents had a mean age of 68 years and were an average of 4.3 years postdiagnosis of cancer. At the time of the survey, 46% had sought medical help for ED since their cancer treatment and 44% intended to seek help in the next year. A hierarchical backward selection logistic regression analysis was performed to determine factors correlated with seeking help for ED after prostate cancer. Blocks of factors were entered in to the analysis in order. Factors significant within each step were retained when calculating a final model. Out of 37 factors entered into the model, three retained significance: Men who sought help for ED were more likely to have had a prostate cancer treatment designed to spare sexual function and reported higher distress about postcancer ED. Even with all other factors taken into account, men who had more positive attitudes on the Help-Seeking Questionnaire were significantly more likely to have sought help for ED. A second logistic regression analysis examined correlates of intent to seek help for ED within the next year. Out of 38 factors entered into the analysis, six retained significance in the final model: Men intending to seek help had been treated more recently for their prostate cancer, were more dissatisfied with their sexual function, had higher levels of distress about postcancer ED and loss of sexual desire, and were more likely to have sought help for ED even before their prostate cancer was diagnosed. Even with these factors taken into account, positive attitudes on the Help-Seeking Questionnaire were significantly associated with help-seeking intentions. These results suggest that cognitive-behavioral interventions designed to challenge men's negative beliefs about seeking help for ED could potentially increase help-seeking behavior.

Adult↗

PubMedDate not supplied

Glutathione S-transferase M1 gene but not insulin-like growth factor-2 gene or epidermal growth factor gene is associated with prostate cancer.

Prostate cancer is the most common urologic malignancy involving multiple factors. There is evidence that suggests that detoxification enzymes and growth factors may play a role in the formation of prostate cancer. Our aim was to investigate whether polymorphisms of glutathione S-transferase M1 (GST M1), insulin-like growth factor-2 (IGF-2), and epidermal growth factor (EGFR) genes could be used as genetic markers for risk of prostate cancer. In this study, we compared the frequency of the polymorphisms of GST M1, IGF-2, and EGFR genes among 96 patients with prostate cancer and 121 healthy male volunteers from the same geographic area (age, older than 60 years). There was significant difference in the GST M1 genotype between the prostate cancer group and the control group (P=0.042). The GST M1 null genotype was significantly higher in the cancer group (59.4%) than in the control group (45.5%). However, our study did not reveal a significant association between prostate cancer and the distribution of the IGF-2 or EGFR genotypes. This study suggests that the GST M1 gene, but not the IGF-2 or the EGFR genes, may be a risk factor of developing prostate cancer in Taiwan.

Aged↗

PubMed2003

[Prostate specific antigen and diagnosis of prostate cancer].

Prostate cancer had a development predominantly at peripheral gland and stay for a long time asymptomatic without clinical symptoms. When the cancer is symptomatic, it is often translate an advanced stage. The symptoms of prostate cancer are not specifics: urinary troubles, compression of iliac vessels or bone metastases pain. The digital rectal examination highlight an induration nodule, irregular and painless. The probability to have a cancer increase with the rate of the prostate specific antigen (PSA). Some others situations can increase the rate of PSA: benign prostatic hyperplasia, prostatitis, bladder catheterisation, urinary retention, endoscopic examination. The ratio of free-PSA/total-PSA (fPSA/tPSA) permits a best discrimination between benign prostatic hyperplasia and prostate cancer The more fPSA/tPSA ratio is low, the more the risk of prostate cancer is high. Prostate cancer is suspected with the digital rectal examination and the rate of PSA but the diagnosis is made by histological examination (the tissue samples are took by transrectal ultrasound-guided biopsies). The staging of disease must be realised according to the risk of metastasis appreciated by clinical stage, rate of PSA and Gleason score.

Age Factors↗

PubMed2004

Telomerase as a new target for the treatment of hormone-refractory prostate cancer.

Prostate cancer is the leading cause of cancer-related deaths in men. Androgen ablation is the mainstay of treatment for advanced prostate cancer. This therapy is very effective in androgen-dependent cancer; however, these cancers eventually become androgen independent, rendering anti-androgen therapy ineffective. The exploration of novel modalities of treatment is therefore essential to improve the prognosis of this neoplasia. Telomeres are specialized heterochromatin structures that act as protective caps at the ends of chromosomes. Telomere maintenance in the majority of tumor cells is achieved by telomerase, a reverse transcriptase enzyme that catalyzes the synthesis of further telomeric DNA. Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue. Moreover, the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of telomerase, is regulated by androgens as well as by different oncogenes including Her-2, Ras, c-Myc and Bcl-2, which seem to play an important role in prostate cancer progression. Thus, telomerase may represent a very good candidate for targeted therapy in prostate tumors. To inhibit telomere maintenance by telomerase, approaches that directly target either telomerase and telomeres or the telomerase regulatory mechanisms have been used. Moreover, strategies targeting telomerase-positive cells as a means to directly kill the tumor cells have been tested. This review summarizes the most promising results achieved by anti-telomerase strategy in different solid tumors. Most of the telomerase-associated therapies described here have proved very promising for the treatment of prostate cancer. On the basis of the good results obtained and considering the multigenic defects of human tumors, including prostate cancer, the combination of anti-telomerase strategies with conventional drugs and/or molecules capable of interfering with oncogenic pathways could efficiently improve the response of this neoplasia.

Humans↗

PubMed2002

Gene therapy for prostate cancer.

Prostate cancer is the most common noncutaneous cancer in man. When confined to the prostate it can be cured by radical prostatectomy or irradiation therapy. However, there are no curative therapies for locally advanced, recurrent or metastatic disease. Prostate cancer gene therapy has recently transition from preclinical studies to clinical trials with the goal of developing novel treatments for prostate cancer. The greatest challenge in treating advanced prostate cancer is therapeutic access to and the elimination of metastases. This review details two aspects of prostate cancer gene therapy, the types of delivery systems under development and specific categories of therapeutic genes available with an emphasis on the mechanism of action of specific gene therapy strategies.

Adjuvants, Immunologic↗

PubMed2002

The prospects of retinoids in the treatment of prostate cancer.

Prostate cancer is the most prevalent cancer amongst males and accounts for 13% of cancer deaths in this population in the US. Aggressive, androgen-independent, metastatic prostate cancer is incurable, and the search for new therapies has been directed towards identifying agents that block proliferation and induce differentiation and/or apoptosis of prostate cancer cells. Retinoid receptor agonists, such as all- retinoic acid, can induce apoptosis of prostate cancer cells, but clinical studies have demonstrated only mild to moderate efficacy. Retinoic acid receptor antagonists are a new class of retinoids, and pre-clinical studies have shown that they potently inhibit the growth of prostate cancer cells and induce apoptosis. Here, we review whether retinoids have a role in the fight against prostate cancer.

Animals↗

PubMed2005

The chromogranin-A (CgA) in prostate cancer.

Prostate cancer is one of the most frequent tumors in men. The neuroendocrine differentiation in prostate cancer has become more widely recognized and has attracted considerable attention as a potentially new finding with major diagnostic, prognostic and therapeutic implications. We investigated the role of the serum concentrations of CgA in a group of 57 patients with prostate cancer and in 61 elderly subjects with benign prostate hyperplasia (BPH). Neuron-specific enolase (NSE) is the most frequently employed marker to detect neuroendocrine features. Serum prostate-specific antigen (PSA), CgA and NSE levels were determined. Comparing prostate cancer group versus BPH group, the CgA level difference was 63.00 ng/ml (p<0.0001) and the PSA level difference was 50.86 mcg/ml (p<0.0001). Between prostate cancer group and control group the CgA level difference was 94.3 ng/ml (p<0.0001), the PSA level difference was 52.91 mcg/ml (p<0.0001), and the NSE level difference was 1.34 microg/l (p<0.0001). Patients with higher CgA levels had poorer prognosis and survival, compared to those with lower CgA levels. These results support the concept that serum CgA level determination before treatment is a potential prognostic factor for prostate cancer.

Adenocarcinoma↗

PubMed2003

Epidemiology of prostate cancer.

Prostate cancer incidence and mortality rates vary worldwide. In the United States, prostate cancer is the most common malignancy affecting men and is the second-leading cause of cancer death. Risk of developing prostate cancer is associated with advancing age, African American ethnicity, and a positive family history, and may be influenced by diet and other factors. The incidence of prostate cancer increased sharply after the introduction of widespread screening for prostate-specific antigen (PSA), although rates have now returned to levels seen before that time. PSA screening has been associated with a shift toward diagnosis of earlier-stage disease, but this has not been accompanied by a shift toward a lower histologic grade. Although overall prostate cancer mortality rates decreased during the 1990s, it was largely because of reductions in deaths among men diagnosed with distant disease. In contrast, mortality rates for men diagnosed with localized or regional disease increased gradually during most of the 1990s before decreasing slightly among white men and reaching plateaus among African Americans.

Black or African American↗

PubMed2006

Should finasteride be used to prevent prostate cancer?

Prostate cancer is an important public health problem. Chemoprevention offers an attractive solution because it may lead to decreased disease-specific mortality. Furthermore, because many men are treated radically for prostate cancers that pose little or no threat to life, chemoprevention may also provide an excellent strategy for diminishing treatment-related costs and adverse effects such as erectile and urinary dysfunction. The Prostate Cancer Prevention Trial was a 7-year randomized study of finasteride versus placebo among men aged older than 55 years. All men were intended to have a prostate biopsy at study conclusion. At trial's end, there was a 25% reduction in period prevalence in all prostate cancers (24.4% for placebo vs 18.4% for finasteride). This represents a 6% absolute risk reduction. A larger number of higher-grade cancers were noted among men randomized to finasteride, which post hoc analyses and studies suggest are almost certainly related to previously unrecognized biases in trial design. There continues to be great debate as to the clinical significance of the cancers prevented. It is our opinion that among men who warrant 5-alpha reductase inhibitors (5ARIs) as part of their benign prostatic hyperplasia regimen, cancer prevention should be recognized as an additional benefit of treatment. Furthermore, men with high risk of clinically significant prostate cancer, such as significant family history, abnormal prostate biopsy histologies, and African descent, should be made aware of these findings. Men with significant anxiety or concern about prostate cancer should also be made aware of the risks and benefits of this therapy. Additional trials of antiestrogens, micronutrients, and other 5ARIs, which will mature over the next 2 to 5 years, will better define the role of 5ARIs in prostate cancer chemoprevention.

Clinical Trials as Topic↗

PubMed2004

p42/p44 Mitogen-activated protein kinase signal transduction pathway: a novel target for the treatment of hormone-resistant prostate cancer?

Prostate cancer is the second leading cause of cancer deaths in men. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate. Androgen withdrawal remains the only treatment for these men with clinically advanced disease; however, most of these men, who initially respond to hormone ablation therapy, fail and the disease progresses. There is at present no effective treatment for hormone-independent prostate cancer. Several lines of evidence suggest a role of p42/p44 mitogen-activated protein kinase (p42/p44 MAP kinase) signal transduction pathways in prostate cancer. At the molecular level, a variety of genetic alterations lead to an epigenetic mechanism by which a feedback autocrine loop between membrane receptors and associated ligands serves as an essential component of the growth, proliferation, and metastasis of prostate cancer at an advanced and androgen-independent stage. Peptide growth factors are known to exert their effects by a complex array of mechanisms primarily mediated by the p42/p44 MAP kinase signal transduction pathway. Thus, we hypothesized that MAP kinase signal transduction pathways could serve as new and novel targets in prostate cancer therapy. In this article we provide an overview of the role played by MAP kinase signal transduction in the prostate.

Humans↗

PubMed1994

Clinical and economic considerations in the treatment of prostate cancer.

Prostate cancer is a growing health problem with considerable economic consequences. Despite progress in the management of this disease, few areas in medicine generate greater disagreement. The larger part of healthcare resources are allocated to 'halfway technologies' aimed at palliative intervention to prolong life, while a relatively small part goes to measures aimed at preventing or curing the disease. The aetiology of this cancer is multifactorial and no practical measures for primary prevention are known. The number of patients diagnosed with prostate cancer is increasing steadily. The age-adjusted mortality, however, has increased only slightly. In its early stages, prostate cancer is often asymptomatic and is usually not diagnosed until it has advanced. Programmes for the early detection of prostate cancer (screening) claimed to reduce morbidity and mortality are a matter of controversy. Furthermore, there has been much debate regarding optimal treatment in the early stages of the disease. Economic considerations have not as yet been integrated into studies concerning localised prostate cancer. The routine first-line treatment of advanced prostate cancer usually involves some type of endocrine treatment. The most straightforward technique is surgical castration. Oral estrogens are as effective as castration, but have significant cardiovascular adverse effects. These may possibly be prevented if estrogens are given parenterally. A third principal endocrine treatment is the administration of antiandrogens. Medical castration can be attained by the administration of recently developed synthetic peptides, gonadotrophin-releasing hormone {luteinising hormone-releasing hormone (LHRH)} (GnRH) analogue agonists which are given parenterally. The advantage of this type of medical castration is that the trauma of surgical castration and the adverse effects of oral estrogens are avoided. In an attempt to improve the results obtained with endocrine treatment, the concept of combining surgical or medical castration with antiandrogens was introduced. This combination could offer improved response rates and survival in a significant number of patients. However, this advantage must be weighed against the tolerability profiles and the high costs of antiandrogens and GnRH analogues. When using expensive drugs, the duration of treatment is a crucial factor in the total cost. As the length of treatment varies greatly between patients it is difficult to decide the most cost-effective alternative for a single individual. The patient's preference is an important factor when selecting treatment. When there is little or no difference in the effect of different regimens the total lifetime cost is important.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen Antagonists↗

PubMed1999

A review of quality-of-life evaluations in prostate cancer.

Prostate cancer is a highly prevalent malignancy in older men. Because the disease and its treatments have the potential to cause substantial morbidity in affected individuals, prostate cancer has been the subject of great interest for quality-of-life (QOL) researchers. In this article, we review published QOL studies that have focused on individuals with prostate cancer. Generic survey instruments have generally been found to be insensitive to changes in health-related quality of life (HR-QOL) related to prostate cancer and its treatments. Domain-specific survey instruments (such as those focusing on sexual function) have been more sensitive, but fail to capture all relevant impacts. At least 9 disease-specific instruments have been developed to measure the HR-QOL impact of prostate cancer. These instruments generally focus on specific symptoms related to the disease and its treatment--urinary function, bowel function, sexual function, physical function, psychological function and pain--however, the domains covered are not consistent from instrument to instrument, and the domains of emphasis within each instrument are rarely the same. In addition, no single instrument has been applied to all major therapies for prostate cancer across men at different ages and stages of disease. Finally, HR-QOL evaluations in some patient groups, such as those with advanced disease, have received relatively little attention to date. As a result of the proliferation of prostate cancer-specific survey instruments and inconsistencies in their design and application, decision-makers face great difficulties evaluating HR-QOL across disease stages and comparing the HR-QOL impacts of alternative therapies, including conservative management ('watchful waiting'). In order for these tools to be useful for patient management and policy-making, coordination of instrument development efforts with the goal of consolidating the number of measures used is urgently needed.

Humans↗