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PubMed2002

An evaluation of bicalutamide in the treatment of prostate cancer.

Prostate cancer is a major health problem in men, causing significant morbidity and mortality. Although traditionally considered a disease of old age, improved diagnostic techniques have resulted in earlier diagnosis and many men are now treated while still physically and sexually active. Current therapies for prostate cancer, which include medical or surgical castration, have a significant impact on many aspects of quality of life. The non-steroidal antiandrogen bicalutamide (Casodex, AstraZeneca) has a favourable tolerability profile with demonstrated efficacy in several stages of prostate cancer and represents an alternative therapeutic strategy to castration. Mature survival data from men with previously untreated, locally-advanced disease reveal that bicalutamide monotherapy provides survival benefits that do not differ significantly from castration, while offering important advantages with respect to the maintenance of physical capacity and sexual interest. Recent data from a prospective randomised trial, the largest prostate cancer treatment study ever conducted, demonstrate that immediate therapy with bicalutamide (alone or as an adjuvant to therapy of curative intent) significantly reduces the risk of objective disease progression in patients with localised or locally-advanced prostate cancer. Antiandrogens are also used in combination with castration (combined androgen blockade) for advanced disease. Another large, randomised trial demonstrated that combined androgen blockade with bicalutamide is associated with a similar survival outcome to combined androgen blockade with flutamide and is better tolerated. The evidence reviewed demonstrates that bicalutamide currently has a favourable risk:benefit ratio in several stages of prostate cancer. The role of bicalutamide will be further defined by ongoing studies.

Anilides↗

PubMed2004

Understanding prostate cancer.

Prostate cancer is the second most common cancer affecting men in Europe and the USA. The incidence of prostate cancer has risen by 60-75% in the Western world in the last 15 years. One in twelve men over the age of 60 develop prostate cancer and this figure is expected to rise to three in twelve in the next 20 years. Early prostate cancer often does not cause symptoms. However, patients may present with lower urinary tract symptoms (LUTS) and therefore, such patients should be investigated. Effective treatment in the form of surgery and radiotherapy is availabLe for individuals with localised disease, and the effectiveness of different combination therapy is being assessed to improve the outcome further. Approximately 20% of the patients have metastatic disease on presentation. The mainstay of treatment for these patients is androgen ablation therapy; however patients on this regime eventually relapse and develop an androgen independent tumour. This aggressive stage of the disease carries a high morbidity and mortality. At present the treatment for such hormone refractory prostate cancer is inadequate and the desperate search for alternative forms of therapy continues.

Androgen Antagonists↗

PubMed2003

Prostate secretory protein PSP-94 decreases tumor growth and hypercalcemia of malignancy in a syngenic in vivo model of prostate cancer.

Prostate cancer is a common malignancy affecting men, which is often associated with skeletal metastases resulting in significant morbidity and mortality. In this hormone-dependent cancer, low levels of a prostate secretory protein of 94 amino acids (PSP-94) are associated with advanced disease stage. In the current study, we have examined the effect of PSP-94 on prostate cancer growth and experimental metastases to the skeleton. For these studies, MatLyLu rat prostate cancer cells were transfected with full-length cDNA encoding parathyroid hormone-related protein [PTHrP (MatLyLu-PTHrP cells)], which is known to be the major pathogenetic factor for malignancy-associated hypercalcemia. MatLyLu-PTHrP cells were inoculated s.c. into the right flank or via intracardiac route into the left ventricle of syngeneic male Copenhagen rats. Intracardiac inoculation of MatLyLu cells routinely results in the development of tumors in the lumbar vertebrae, resulting in hind-limb paralysis. Animals were infused with different doses of PSP-94 (0.1, 1.0, and 10.0 micro g/kg/day) starting on the day of tumor cell inoculation. Time of hind-limb paralysis and tumor volume were determined, and comparison was made between PSP-94-treated animals and control animals receiving vehicle alone. At the end of the study, animals were sacrificed, and plasma calcium, plasma PTHrP, and tumor PTHrP levels were determined. Whereas the highest dose of PSP-94 caused a modest but statistically significant delay in the development of hind-limb paralysis, a marked dose-dependent decrease in primary tumor volume was seen in experimental animals receiving PSP-94 due to its ability to promote tumor cell apoptosis. Furthermore, whereas control animals routinely developed hypercalcemia due to PTHrP production, treatment with PSP-94 led to a near normalization of plasma calcium and a marked reduction in PTHrP production as determined by radioimmunoassay and immunohistochemistry. Collectively, these results demonstrate the ability of PSP-94 to be an effective treatment modality for prostate cancer, where decrease in plasma PTHrP and calcium levels can serve as useful biochemical markers for monitoring the efficacy of this novel antitumor agent.

Animals↗

PubMed1993

An evaluation of prostate-specific antigen as a screening test for prostate cancer.

Prostate cancer is the second leading cause of cancer death in men. Recently, there has been increased interest in the use of prostate-specific antigen (PSA) as a screening test for prostate cancer. The PSA test offers the benefit of a reproducible, objective value that is independent of the examiner's skill; however, it does not seem to be effective alone as a screening test for prostate cancer. Additionally, the efficacy of treatment for prostate cancer with radiation therapy or radical prostatectomy remains to be demonstrated. Thus, further studies demonstrating an improved mortality in prostate cancer with PSA screening need to be performed before universal screening with PSA can be recommended. Meanwhile, education of the patient regarding the risks, benefits, and costs of PSA screening and subsequent treatment should be addressed before performing a PSA test.

Humans↗

PubMed1998

Antisense c-myc retroviral vector suppresses established human prostate cancer.

Prostate cancer eventually becomes androgen resistant, resumes growth, and kills the patient. Characterization of genetic events that lead to androgen refractory prostatic neoplasia has revealed the frequent overexpression of c-myc and uncontrolled prostate cancer proliferation. A novel strategy to combat advanced prostate cancer utilized a replication incompetent retrovirus that contained the mouse mammary tumor virus (MMTV) promoter within the retroviral vector to allow transcription of antisense c-myc gene within target prostate tumor cells. The transduction of cultured DU145 cells by XM6:MMTV-antisense c-myc RNA retrovirus did not affect cell proliferation in culture, yet a single direct injection of MMTV-antisense c-myc viral media into established DU145 tumors in nude mice produced a 94.5% reduction in tumor size compared to tumors treated with control virus MTMV sense fos and untreated tumor by 70 days. Two animals in the antisense c-myc-treated group had complete regression of their tumors. Histopathological examination of the tumors revealed that MMTV-antisense c-myc-transduced DU145 tumors had increased tumor cell differentiation, decreased invasion, and a marked stromal response. The mechanism for the antitumor effect of MMTV-antisense c-myc retrovirus appears to be suppression of c-myc mRNA and protein, and decreased bcl-2 protein. The in vivo transduction of prostate cancer cells with MMTV-antisense c-myc retroviruses reduced tumor growth by suppressing c-myc, resulting in the down-regulation of bcl-2 protein. Consequently, the MMTV-antisense c-myc retrovirus may be useful for gene therapy against advanced, hormone-refractory prostate cancer.

Animals↗

PubMed1999

Fluorescence in situ hybridization study of HER-2/neu oncogene amplification in prostate cancer.

Prostate cancer is a serious disease affecting men worldwide and treatment compromises the quality of life of prostate cancer patients. We conducted a study of 88 cases of prostate cancer in an attempt to identify prognostic biomarkers that can distinguish aggressive cases that must be treated immediately. HER-2/neu oncogene amplification was initially studied because amplification of this gene has been reported in many other cancers, including those studied in this laboratory. Fluorescence in situ hybridization (FISH) using a HER-2/neu gene probe with a chromosome 17 centromere control probe was performed on formalin-fixed, paraffin-embedded tissues. Of a total of 86 cases successfully analyzed, only 8 (9.3%) were found to be amplified. This frequency was lower than the frequency of amplification found in other cancers studied. Furthermore, no case was found where the level of amplification can be considered high. Only one case was found to have moderate amplification. The rest of the positive cases can all be classified as low amplification. Thus, while we have demonstrated that FISH is a sensitive technique for detecting oncogene amplification, the frequency and level of HER-2/neu amplification detected in prostate cancer seem to be lower than those in most cancers that we studied. In view of the fact that HER-2/neu amplification does not seem to play as significant a role, exploration of other biomarkers in prostate cancer is warranted.

Aged↗

PubMed2003

Drug-targeting strategies for prostate cancer.

Prostate cancer is the most frequently diagnosed cancer in North American men and accounts for 10% of cancer-related deaths in men. Despite advances in early detection and aggressive treatment of early disease, the overall mortality rate has not appear to have fallen, indicating that the current therapies are not beneficial for life expectancy and new strategies are required. Prostate cancer is a dynamic evolving process that develops in distinct steps, with each step liable to additional genetic hits that change the cancer cell phenotype and alter the patterns of gene expression. The molecular events in prostate cancer are beginning to be understood, including altered expression of tumor suppressor genes, pro- and anti-apoptotic genes, and oncogenes associated with the progression of the disease; and specific genes that are expressed predominantly or exclusively in prostate cells, prostate cancer cells, and prostate metastasis cells. These latter genes on the level of DNA, RNA and protein products are the targets of several new approaches to prostate cancer therapy and are the focus of this review.

Antisense Elements (Genetics)↗

PubMed2001

Insulin-like growth factors and prostate cancer.

Prostate cancer is one of the most common malignant tumors in Western countries. The etiology of prostate cancer is currently unknown, but it has been suggested that growth factor abnormalities may be involved in initiation and progression of this disease. Insulin-like growth factors (IGFs), including IGF-1 and IGF-2, are mitogenic peptides involved in the regulation of cell proliferation, differentiation and apoptosis. Studies have shown that IGFs are potent mitogens for a variety of cancer cells including prostate cancer since they stimulate cancer cell growth and suppress programmed cell death. This review outlines elements of IGF pathophysiology, reviews recent evidence that circulating IGF-1 levels are related to prostate cancer risk and discusses the clinical implications of these lines of research with respect to prevention and treatment.

Humans↗

PubMed2004

Molecular therapy intervention prospects in prostate cancer.

Prostate cancer is the most frequently diagnosed disease in American men today and the second leading cause of death among them. Transformation and progression towards malignancy in prostate cancer is dependant on the inability of the prostatic epithelial cells to undergo apoptosis rather than on the regulation of proliferation. Molecular targeting of inadequacies in this process of suppression of apoptosis could prove to be of great therapeutic importance for prostate cancer patients. Existence of tissue specific promoters to aid in the delivery of genes with therapeutic potential makes molecular therapy an attractive option. This review discusses salient features of molecules such as, Bcl-2, Bcl-(XL), NF-kappaB, Akt, PTEN and Par-4 that play a significant role in the regulation of prostate cancer and focuses on the prospects of effectively utilizing their potential for the therapy of hormone-sensitive and hormone-resistant prostate cancer.

Animals↗

PubMed2000

[Three-dimensional microstructural analysis of human lumbar vertebrae using microcomputed tomography in bone metastasis from prostate cancer].

Prostate cancer frequently metastasizes to bone, inducing osteosclerotic lesions. However, the morphological details of bone metastasis of prostate cancer have not been clarified. The trabecular bone structure of bone metastasis from prostate cancer was investigated in three dimensions using microcomputed tomography (micro-CT). A total of 17 cubes of the lumbar spine of a 77-year-old man with prostate cancer were excised post mortem: four of them from non-metastatic and the rest from metastatic sites. The samples were measured using micro-CT with a resolution of 23.2 microns and the standard structural indices and degree of anisotropy were computed. After micro-CT measurement, the samples were tested in a destructive manner for the assessment of mechanical properties. Samples from the metastatic sites showed significantly higher values than those from non-metastatic sites for bone volume (BV), bone surface (BS), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N) (p < 0.005). Bone surface density (BS/BV) and trabecular separation (Tb.Sp) were significantly higher in the samples from non-metastatic sites (p < 0.001). Samples from metastatic sites showed a more isotropic arrangement of trabecular bone than those from non-metastatic sites. Three-dimensionally reconstructed images depicted several different patterns of sclerotic bone metastasis, and osteolytic appearance was observed in all of them. Structural parameters such as BV/TV were well correlated with the mechanical properties (r = 0.899). The present study clarified the trabecular microstructure of bone metastasis from prostate cancer and suggests that both osteolysis and osteogenesis progress while interacting with each other in all phases of bone metastasis.

Aged↗

PubMed2005

Diet, lifestyle and risk of prostate cancer.

Prostate cancer has become a major public health problem worldwide. Yet, the etiology of prostate cancer remains largely unknown. Dietary factors, dietary supplements, and physical activity might be important in the prevention of the disease. In the majority of studies, it was observed that high consumption of meat and dairy products has been linked to a greater risk. In contrast, frequent consumption of fatty fish and tomato products has been associated with a reduced risk. It has been shown consistently that high levels of circulating insulin-like growth factor 1 (IGF-1) are associated with an increased risk of prostate cancer. Dietary factors are also recognized as determinants of circulating IGF-1, thus changes in diet may influence IGF-1 concentrations in serum. Furthermore, increased intake of vitamin E and selenium (from supplements) has been shown in intervention studies to decrease the risk. Possibly, high level of physical activity is also associated with decreased risk of prostate cancer. The accumulated scientific evidence concerning the associations between diet, lifestyle, and risk of prostate cancer development suggests that there are some identified modifiable risk factors that it might be recommended to change in order to decrease the risk for this common cancer site.

Antioxidants↗

PubMed2006

Involvement of the RNAse L gene in prostate cancer.

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Identification of genetic susceptibility loci for prostate cancer has however been extremely difficult, and only in 1996 was the first prostate cancer susceptibility locus HPC1 mapped to chromosome 1q24-25. Since, several additional putative loci have been identified by genetic linkage analysis on chromosome 1, 17, 20 and X (reviewed in). For three of these loci, family-based studies have identified three genes associated with inherited prostate cancer: the 3' processing endoribonuclease ELAC2/HPC2 gene, the macrophage scavenger receptor 1 gene (MSR1), and the endoribonuclease RNase L gene (RNAse L/HPC1). Here we will focus our review on the RNAse L gene and its involvement in prostate cancer and other diseases.

Chromosome Mapping↗

PubMed2004

[Molecular mechanisms involved in hormone resistance of prostate cancer].

Prostate cancer has an androgen-dependent growth mediated by the androgen receptor (AR). Androgen pathway blockage is the standard therapy for the treatment of prostate cancers at an advanced stage. In spite of an initial sensitivity, prostate cancers become more or less quickly towards androgen-independent. Hormone refractory can be due to amplification of AR gene, AR mutations and the increase in co-activator protein expression or in the 5alpha-reductase activity. These induce an agonist activity with the anti-androgens or others steroid hormones like estrogens on AR and allow AR activation with weak concentrations of androgens. Growth factors and cytokines can induce AR phosphorylation independently of the ligand fixation. In condition of androgenic deprivation, AR remains actively involved in the growth of the cancerous cells prostate. Nevertheless, there are others partial AR-independent pathways as neuroendocrine differentiation. The comprehension of these various mechanisms is the key of the development of more effective therapies on hormono-refractory prostate cancers.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2000

Unanswered questions in screening for prostate cancer.

Prostate cancer fulfils some of the conditions required of a disease that might be managed by population screening. In a cohort of 50- to 60-year-old men, carrying out a rectal examination and prostate specific antigen (PSA) test will detect clinically suspicious areas within the prostate in approximately 5%, and approximately 10% will have a raised PSA. We are however unsure which of the prostate cancers that are known to be present in approximately 30-40% of men aged over 60 years will be detected. Eventually after such screening, around 4% of men with an otherwise normal prostate will be found to have prostate cancers. The use of rectal examination may increase the number of tumours found, but will reduce compliance. The use of free/total PSA ratios will reduce the number of unnecessary biopsies at the expense of missing some tumours. Of more concern, we remain uncertain how effective aggressive local treatment is in altering the natural history of the disease. The risk of a 50-year-old man with a 25 year life expectancy of having microscopic cancer is 42%, of having clinically evident cancer is 9.5%, and of dying of prostate cancer 2.9%. Only a small proportion of cancers known to be present become clinically evident: more men die with prostate cancer than of it. Screening will identify some men with cancer who will not benefit from treatment. It is unclear whether screening would be followed by a reduction in morbidity and mortality. Recent data suggest a screening effect has been observed in the USA with: an increase in incidence, a decrease in men with distant metastases. The small decrease in mortality recently observed (many times smaller than the increase in incidence) may be confounded by inappropriate 'attribution' of cause of death, the detection of men with better prognosis distant metastatic disease responsive to hormonal ablation and changes in social factors such as diet. Future changes may incorporate molecular markers that might aid identification of men best treated aggressively because of a risk of progression. Tests to identify genetic pre-disposition may also allow targeted screening. New treatments and early chemoprevention or dietary strategies will again shift the ground on which these arguments are being rehearsed. The most urgent evidence required concerns the effectiveness of treatment strategies.

Cost of Illness↗

PubMed2000

Tumor vaccines for the management of prostate cancer.

Prostate cancer is a significant health problem and one of the leading causes of cancer-related death among men. Given the typically long natural history of the disease, there is considerable interest in developing new therapies to treat or prevent metastatic disease, and cancer vaccines are a particularly attractive immune-based approach. Early clinical studies using non-specific immunomodulatory treatments have met with limited success, but also suggest that improved immunologic approaches might be useful in treating human prostate cancer. Over the last decade, the identification of immune cells responsible for actual destruction of prostate tissue and advances in immunologic and molecular techniques have led to a variety of vaccination approaches that are currently being evaluated in human clinical trials. The present article discusses the rationale in animal models for particular immunization strategies and describes the vaccines currently being used in patients with prostate cancer. The ongoing identification of tumor antigens and proteins involved in prostate cancer progression and the development of better immunologic animal models suggest a hopeful future for the design of effective prostate cancer vaccines.

Acid Phosphatase↗

PubMed1987

An evaluation of prostate specific antigen in prostatic cancer.

Prostate specific antigen levels were measured in 118 patients with prostatic cancer and 138 control individuals. Prostate specific antigen was sensitive in detecting prostatic cancer. The levels of prostate specific antigen were elevated in 10 per cent of the patients with stage A, 24 per cent with stage B, 53 per cent with stage C and 92 per cent with stage D disease. However, prostate specific antigen levels also were elevated in 9 per cent of the patients with benign prostatic hypertrophy. This lack of specificity in the presence of benign prostatic hypertrophy probably precludes prostate specific antigen from being recommended as a screening test for prostatic cancer. The ultimate role of prostate specific antigen might be as the marker of choice to monitor therapy for prostatic carcinoma.

Antigens↗

PubMed2003

Probasin promoter (ARR(2)PB)-driven, prostate-specific expression of the human sodium iodide symporter (h-NIS) for targeted radioiodine therapy of prostate cancer.

Prostate cancer is one of the most promising candidates for sodium iodide symporter (NIS)-mediated gene therapy. Adenovirus-mediated expression of NIS that is driven by prostate-specific promoters induces generous radioiodine accumulation in prostate cancer cells that may be used for therapy with (131)I. We have recently developed a replication-deficient adenovirus carrying the human NIS cDNA linked to a composite probasin promoter, ARR(2)PB, aiming toward specific expression of the human NIS gene (h-NIS) in prostate tissue for targeted radioactive iodide therapy of prostate cancer (Ad-ARR(2)PB/hNIS). The ability of Ad-ARR(2)PB/hNIS to cause NIS expression in tumor cells was characterized by iodide uptake assay and compared with Ad-CMV/hNIS in which the h-NIS expression is driven by the cytomegalovirus (CMV) promoter. Androgen-dependent prostate cancer cell lines (LNCaP) and non-prostate origin tumor cell lines (SNU449, MCF-7, HCT116, OVCAR-3, and Panc-1) were infected with the viral constructs, and perchlorate-sensitive (125)I uptake and NIS protein expression were measured. Ad-ARR(2)PB/hNIS-infected LNCaP cells showed androgen-dependent and perchlorate-sensitive iodide uptake. Iodide accumulation in LNCaP cells infected with Ad-ARR(2)PB/hNIS, followed by incubation with synthetic androgen, was 5.3-fold increased compared with those coincubated with perchlorate (15,184 +/- 1,173 cpm versus 2,837 +/- 187 cpm). Ad-ARR(2)PB/hNIS-infected LNCaP cells revealed a 3.2-fold increase of iodide accumulation compared with those infected with Ad-CMV/hNIS (multiplicity of infection = 30). Iodide uptake in a panel of non-prostate tumor cell lines infected with Ad-ARR(2)PB/hNIS was no more than 2,500 cpm, demonstrating the tissue specificity of this construct. These results indicate that Ad-ARR(2)PB/hNIS can be used to achieve high-magnitude and tissue-specific expression of h-NIS in prostate tissue and is a promising candidate for cancer gene therapy of prostate cancer.

Adenoviruses, Human↗

PubMed1995

Screening for prostate cancer.

Prostate cancer is a serious health care problem in the United States. Whether or not to screen for it has become a timely issue. Although a large number of men have clinically important, asymptomatic, undetected prostate cancer, an even larger number have clinically unimportant cancer. To justify screening programs, not only must we avoid detecting biologically unimportant cancers, we must also detect and effectively treat that subset of tumors that, if undiagnosed, would progress, produce symptoms, and reduce life expectancy. Serum prostate-specific antigen (PSA) assay, or its variations such as PSA density, PSA velocity, and age-specific reference ranges, and the digital rectal examination are the best tests for detecting clinically important, asymptomatic, curable tumors. Recent data suggest that using serum PSA levels does not result in an overdetection of unimportant tumors. Highly effective, curative treatment of localized prostate cancer is available. These factors promote optimism that screening for prostate cancer will ultimately prove beneficial. Nonetheless, men should be informed regarding the benefits and possible risks before being screened for prostate cancer.

Humans↗