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[Prostatic specific antigen for detection and monitoring of prostatic cancer].

Prostatic specific antigen (PSA) can be detected in normal and benign hypertrophic prostates, as well as in prostatic cancer and its metastases. Since it appears in the serum, this glycoprotein has become an established marker for the detection and monitoring of prostate cancer. Using a radioimmunoassay (CIS--Biointernational, France), we found serum PSA levels higher than 4 ng/ml in 55 of 58 patients with prostatic cancer. The concentrations were proportional to tumor stage: significantly higher in stages C and D than in stages A and B (p less than 0.002). In all 6 cases with occult prostatic carcinoma (stage A), levels were higher than 15 ng/ml. PSA was found to be a good indicator of response to therapy, as well as a marker of tumor progression during follow-up. After radical prostatectomy serum PSA levels decreased to below 1 ng/ml. Following radiotherapy levels returned to normal within 1-6 months in 8 of 11 patients. In 21 of 23 with metastases serum PSA decreased during hormonal treatment. In 3 who responded initially to hormonal therapy, levels increased before clinical manifestation of tumor progression. We conclude that PSA is a sensitive serum marker for the diagnosis of prostatic cancer in cases of metastatic disease of unknown origin, as well as for monitoring the response to treatment of prostatic carcinoma. The use of PSA serum levels for screening for prostatic cancer is still controversial.

Antigens, Neoplasm↗

Active surveillance: towards a new paradigm in the management of early prostate cancer.

Prostate cancer is the only human cancer that is curable but which commonly does not need to be cured. Active surveillance is a new strategy that aims to individualise therapy by selecting only those men with significant cancers for curative therapy. Patients with favourable tumour characteristics are closely monitored using serum prostate specific antigen (PSA) concentrations and repeat prostate biopsies. The choice between radical treatment and continued observation is based on evidence of disease progression, defined in terms of the PSA doubling time, and "upgrading" at repeat biopsy. Active surveillance provides an excellent opportunity for studies to identify markers of prostate-cancer behaviour. Knowledge of prostate cancer biomarkers would have an immediate effect on clinical decision-making and would also identify targets for the development of novel therapeutic strategies. In the longer term, active surveillance may accelerate progress towards a new treatment paradigm for early prostate cancer based on the selective use of therapies designed, not to eradicate the disease, but to alter its natural history.

Disease Progression↗

Cell-cycle dysregulation and the molecular mechanisms of prostate cancer.

Prostate cancer is the most common cause of non-cutaneous cancer in men and although frequently latent is the second commonest cause of death. Screening for the disease was historically based on symptoms of urethral obstruction, clinical examination of the prostate gland and serum measurements of prostate specific antigen. As prostate cancer growth in the early stages is enhanced by androgens, the mainstay of therapy has been androgen ablation by pharmaco-therapeutic or surgical means. The subsequent development of androgen therapy resistant prostate cancer in many patients, for whom therapeutic options remain limited, has led researchers to focus attention on understanding the molecular genetics of prostate cancer. The array of genetic abnormalities observed in prostate tumors, which include changes in components of the cell cycle, suggest the disease is quite heterogeneous and may require further sub-classification based on genetic markers. Such analyses may lead to identification of relevant new prognostic and therapeutic indicators. The advent of transgenic mouse models of prostate cancer may provide a critical tool for the implementation of rational genetic based therapeutics and alternate drug design.

Animals↗

The Gordon Wilson Lecture. Natural history and treatment of early stage prostate cancer.

Prostate cancer poses a challenge to society and to physicians. It is a remarkably prevalent tumor, perhaps the most common cancer in the world in its histologic manifestation. In its clinically apparent form, it is notably heterogeneous. Some patients live out their lives with a prostate cancer that remains stable for decades without treatment. In other cases, the cancer grows aggressively, responds poorly to therapy, and causes death within a few years. The median loss-of-life expectancy for men diagnosed with prostate cancer has been estimated at 9 years. Important advances have been made in the past two decades in the treatment of prostate cancer. Further progress will require more accurate characterization of the primary tumor in each individual patient to tailor treatment--whether conservative or aggressive, surgery or radiation--more accurately to the nature of the individual cancer. Imaging studies in particular must be improved if we are to have better, noninvasive ways to identify the presence of a cancer and to define its volume, location, and extent. Substantial progress against this disease will require major breakthroughs in our understanding of the etiology of prostate cancer, the development of effective chemopreventive agents, more accurate ways to assess the biological potential of the tumor, and more effective systemic agents to treat metastatic cancer.

Combined Modality Therapy↗

Endocrine therapy for prostate cancer.

Prostate cancer consists of epithelial and stromal elements that are heterogeneous with regard to androgen dependence. Nearly 80% of patients with symptomatic metastatic prostate cancer obtain prompt objective and subjective response to androgen deprivation. Surgical castration remains an effective form of therapy, has low morbidity, and obviates compliance problems with medical regimens. New LH-RH analogs offer complete medical androgen deprivation, appear as effective as estrogen therapy at 2-year follow-up, and have significantly lower cardiovascular side effects. Thus, LH-RH analogs may replace estrogen therapy for the medical management of metastatic prostate cancer. Androgen deprivation therapy has not been proved to prolong the survival of patients with prostate cancer. The optimal timing for initiation of endocrine therapy in these patients remains controversial. Techniques for predicting androgen dependence of prostate cancer are still evolving and are not yet applicable on a widespread clinical basis.

Adrenal Glands↗

Primary radiation therapy for localized prostate cancer.

Prostate cancer in men is similar to breast cancer in women; both cancers rank first, respectively, in incidence and are normally responsive to radiation therapy. In addition, advances in mammography help detect earlier breast cancers, and the development and refinement of prostatic specific antigen (PSA) has resulted in early detection of low-stage localized prostate cancers. This has generated debate over the proper management of localized prostate cancer. While there have not been any controlled, prospective, randomized trials of sufficient power to compare the various local therapies, based on the current available data, the three commonly used local modalities, surgery, and external beam radiation therapy and brachytherapy (radioactive seed implant), have similar efficacy controlling the disease up to 10 years in many patients. Technological advances in treatment delivery and planning have improved the treatment of prostate cancer with external-beam radiotherapy using three-dimensional conformal radiotherapy (3DCRT), ultrasound-guided transperineal implant, or intensity-modulated radiotherapy (IMRT), as well as proton or neutron beam based therapies.

Humans↗

Has ultrasonography a role in screening for prostatic cancer?

Prostate specific antigen (PSA) is widely used as the first line test for the diagnosis of prostate cancer in asymptomatic men. The role of transrectal ultrasound is now predominantly accepted as a means of accurate biopsy of the prostate, but there is confusion about the best biopsy protocols for the diagnosis of prostate cancer. Optimum diagnosis of prostate cancer is obtained using a combination of digital palpation of the prostate, serum PSA measurements and transrectal sonography. The role of colour Doppler imaging in the diagnosis of prostate cancer is still under assessment.

Biopsy, Needle↗

Immune monitoring in a phase 1 trial of a PSA DNA vaccine in patients with hormone-refractory prostate cancer.

Prostate cancer remains a leading cause of cancer illness and death among men in Europe. No curative treatment exists when the disease has spread beyond the prostate. Immunotherapy with DNA vaccines has emerged as a potential therapeutic approach for the induction of antitumor specific cytotoxic T lymphocytes. In this study six patients with hormone-refractory prostate cancer were monitored for their ability to mount PSA-specific cellular responses after receiving a pVAX/PSA DNA vaccine (patients 1-3, 100 microg; patients 7-9, 900 microg) with recombinant GM-CSF and IL-2 as adjuvants. IFNgamma ELISPOT showed that naturally processed PSA protein and PSA peptides are recognized by T cells in the blood of some prostate cancer patients after a PSA DNA vaccine. Analysis of other cytokines showed the production of IL-4 and IL-6 but importantly did not show an increase in the number of IL-10-producing cells after vaccination in any of the patients. The authors conclude that a pVAX/PSA DNA vaccine can induce PSA-specific cellular immune responses in patients with hormone-refractory prostate cancer, thus emphasizing the potential for PSA as a target molecule for the immunotherapy of prostate cancer.

Antigen Presentation↗

Par-4 for molecular therapy of prostate cancer.

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer deaths in American men. Although many treatment measures such as androgen deprivation, radiation therapy, and cryoablation exist for primary prostate cancer, there is currently no effective treatment for patients presenting advanced or metastatic stages of the disease. Molecular therapy offers an attractive approach to the treatment of primary prostate cancer because the prostate is not a life-sustaining organ, and a number of tissue specific promoters can be used for prostatic gene expression following relatively straightforward delivery routes. This review discusses the general molecular therapy applications in the context of prostate cancer, and most importantly, identifies the prostate apoptosis response-4 (Par-4) gene, which exclusively induces apoptosis in cancer cells and not normal cells, as a prospective molecule for therapy of the disease.

Adenoviridae↗

Screening and early detection for prostate cancer.

Prostate cancer is the most common malignancy in men. Mortality due to prostate cancer has continued to increase over the past five decades despite all the different options of treatment at the disposal of the urologist, such as, surgery, radiotherapy, chemotherapy and biotherapy. Presently, effective therapy for prostate cancer is only possible with early diagnosis of the disease still localised within the prostate. Recent studies have demonstrated that the present screening techniques including Digital Rectal Examination (DRE), Serum Prostate Specific Antigen (PSA) concentration, Transrectal Ultrasound (TRUS) and Random Ultrasonically guided multiple prostatic biopsies can detect some potentially curable asymptomatic localised cancers. The main goal of a cancer screening test is to help reduce mortality. To date, it has been established that screening increases early detection and survival but there is no evidence that screening reduces mortality. If in future early detection and intervention is proved to provide real benefit apart from the overdiagnosis of latent non aggressive tumours, then the mortality from prostate cancer could begin to decline in the next decade. However, if our current armamenteria of therapies continue to be ineffective in treating men with prostate cancer, the current emphasis on screening and early detection will decline.

Biopsy↗

Gene-based therapy in prostate cancer.

Prostate cancer is one of the commonest causes of illness and death from cancer. Radical prostatectomy, radiotherapy, and hormonal therapy are the main conventional treatments. However, gene therapy is emerging as a promising adjuvant to conventional strategies, and several clinical trials are in progress. Here, we outline several approaches to gene therapy for prostate cancer that have been investigated. Methods of gene delivery are described, particularly those that have commonly been used in research on prostate cancer. We discuss efforts to achieve tissue-specific gene delivery, focusing on the use of tissue-specific gene promoters. Finally, the present use of gene therapy for prostate cancer is evaluated. The ability to deliver gene-therapy vectors directly to prostate tissue, and to regulate gene expression in a tissue-specific manner, offers promise for the use of gene therapy in prostate cancer.

Gene Expression Regulation, Neoplastic↗

Molecular cytogenetics of prostate cancer.

Prostate cancer is the most common malignancy among men in Western industrialized countries. The molecular pathogenesis of the disease is poorly known. Over the past 10 years, chromosomal aberrations in prostate cancer have been studied with several techniques, such as loss of heterozygosity (LOH), classical cytogenetics, and molecular cytogenetics, namely with fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). These analyses, especially those performed by CGH, have enabled the distinction of the predominant chromosomal regions of involvement in prostate cancer. Studies have shown that the most common chromosomal alterations in prostate cancer are losses at 1p, 6q, 8p, 10q, 13q, 16q, and 18q and gains at 1q, 2p, 7, 8q, 18q, and Xq. Fluorescence in situ hybridization (FISH) has been used to identify the target genes for some of these chromosomal alterations. For example, amplifications of AR (at Xq12), MYC (8q24), and EIF3S3 (8q23) have been found in a large fraction of hormone-refractory prostate cancer by FISH. However, many of the critical oncogenes and tumor suppressor genes located in the altered chromosomal regions have not yet been identified.

Chromosome Aberrations↗

Molecular and genetic prognostic factors of prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in Western males, responsible for 3% of all deaths in men over 55 years of age and second only to lung cancer as a cause of cancer death. Biomarkers have become an important diagnostic tool in prostate cancer. The discovery of the serum marker prostate-specific antigen (PSA) significantly facilitated the detection and management of prostate cancer. As we enter into the post-genomics era, novel biomarkers of prostate cancer of therapeutic significance will invariably emerge. Here we review a series of existing and emerging molecular-based prognostic markers particularly with radiotherapy.

Genetic Markers↗

A review of epidemiologic studies of tomatoes, lycopene, and prostate cancer.

Prostate cancer is the most common cancer in American men. Preventable measures for this malignancy are not well established. Among potentially beneficial natural compounds is the carotenoid lycopene, which is derived largely from tomato-based products. Recent epidemiologic studies have suggested a potential benefit of this carotenoid against the risk of prostate cancer, particularly the more lethal forms of this cancer. Five studies support a 30% to 40% reduction in risk associated with high tomato or lycopene consumption, three are consistent with a 30% reduction in risk, but the results were not statistically significant, and seven were not supportive of an association. The largest relevant dietary study, a prospective study in male health professionals found that consumption of two to four servings of tomato sauce per week was associated with about a 35% risk reduction of total prostate cancer and a 50% reduction of advanced (extraprostatic) prostate cancer. Tomato sauce was by far the strongest predictor of plasma lycopene levels in this study. In the largest plasma-based study, very similar risk reductions were observed for total and advanced prostate cancer for the highest versus lowest quintile of lycopene. Other studies, mostly dietary case-control studies, have not been as supportive of this hypothesis. The reasons for these inconsistencies are unclear, but in three of the seven null studies, tomato consumption or serum lycopene level may have been too low to observe an effect. Because the concentration and bioavailability of lycopene vary greatly across the various food items, dietary questionnaires vary markedly in their usefulness of estimating the true variation in tissue lycopene concentrations across individuals. To optimize the interpretation of future findings, the usefulness of the questionnaire to measure lycopene levels in a population should be directly assessed. Although not definitive, the available data suggest that increased consumption of tomatoes and tomato-based products may be prudent.

Anticarcinogenic Agents↗

Death receptor-induced cell death in prostate cancer.

Prostate cancer mortality results from metastasis and is often coupled with progression from androgen-dependent to androgen-independent growth. Unfortunately, no effective treatment for metastatic prostate cancer increasing patient survival is available. The absence of effective therapies reflects in part a lack of knowledge about the molecular mechanisms involved in the development and progression of this disease. Apoptosis, or programmed cell death, is a cell suicide mechanism that enables multicellular organisms to regulate cell number in tissues. Inhibition of apoptosis appears to be a critical pathophysiological factor contributing to the development and progression of prostate cancer. Understanding the mechanism(s) of apoptosis inhibition may be the basis for developing more effective therapeutic approaches. Our understanding of apoptosis in prostate cancer is relatively limited when compared to other malignancies, in particular, hematopoietic tumors. Thus, a clear need for a better understanding of apoptosis in this malignancy remains. In this review we have focused on what is known about apoptosis in prostate cancer and, more specifically, the receptor/ligand-mediated pathways of apoptosis as potential therapeutic targets.

Apoptosis↗

In vivo and in vitro approaches to study metastasis in human prostatic cancer.

Prostate cancer is the most common malignancy in American males and is second only to lung cancer as a cause of death in the United States. Clinically, radical prostatectomy offers a patient with locally contained disease an excellent chance for cure. For patients with metastatic disease, the current therapies are merely palliative. Understanding the biology of prostate cancer metastasis should facilitate the development of novel and effective therapeutic modalities. Crucial to this objective is the availability of human tumor systems in which the biology of metastasis can be studied. The present chapter will briefly assess various in vivo and in vitro approaches to study metastasis in human prostate cancer. Utilization of athymic nude mice has played an important role in maintaining human prostatic cancer cells as xenografts and has provided an opportunity to establish site-specific subpopulations of the parental cell lines for further characterization and investigation. At present, a few established cell lines have been useful for this purpose. Fresh tumor specimens, unfortunately, have shown limited ability to grow in nude mice. The recent development of novel approaches to permit the maintenance of freshly harvested prostate cancers has been encouraging. The use of reconstituted basement membrane (Matrigel) for co-injection with cancer cells into the subcutaneous tissues has supported growth of biologically indolent tumors. Another approach is to administer tumor cells orthotopically into the prostate of recipient nude mice. Bone marrow metastases in nude mice have been rare in the past. Recently, three approaches have been shown to be successful in accomplishing bony metastasis with PC-3 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Prostate-specific antigen: the new early detection test for prostate cancer.

Prostate cancer is the second leading cause of cancer deaths in men, affecting one in 11 men in the United States. Early detection in the preclinical stage offers the best chance of increased survival, decreased morbidity and possible cure. Prostate-specific-antigen assay is rapidly joining the digital rectal exam as the standard early detection test for prostate cancer because digital rectal exam alone is no longer considered adequate. The American Cancer Society now recommends an annual serum prostate-specific-antigen test for every man age 50 or older, and current evidence strongly suggests that combining the serum prostate-specific-antigen test with the digital rectal exam increases the early detection rate for prostate cancer. This article describes prostate-cancer screening guidelines, serum prostate-specific-antigen test interpretation and an algorithm for abnormal serum prostate-specific-antigen test follow-up.

Adult↗

Prognostic and predictive factors in prostate cancer.

Prostate cancer is a major public health problem in the Western world, and the second most common male malignancies in the European Union. Detection of the disease is possible at an early stage, using serum prostate specific antigen measurement and prostatic biopsies. To date, however, screening for prostate cancer has not been shown to be of benefit to patients in improving outcome. This is compounded by uncertainties surrounding treatment efficacy, as more men appear to die with prostate cancer than from it. Studies addressing these issues are underway in Europe and the U.S.A. Clinicians are currently unable to advise their patients with any degree of certainty as to the appropriateness of treatment for prostate cancer, because of their inability to differentiate tumours that will progress from those that will remain quiescent. This article reviews the various clinical, pathological and experimental markers available, and their value in providing prognostic information, which may assist clinicians and patients in making management decisions. Further research is still required to understand the biological behaviour of prostate cancer and to assess the value of screening and treatment efficacy in order to advise patients, clinicians and health care systems accordingly.

Apoptosis↗