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PubMed2006

[Current opinions on the treatment of androgen-independent prostate cancer].

Prostate cancer is a most common malignant neoplasm in males. In recent years, its incidence has been rising dramatically in China. Patients with recurrent prostate cancer may be treated with androgen deprivation strategies, but most cases will eventually develop into androgen-independent prostate cancer (AIPC). Until recently, chemotherapy has been shown to be effective in palliating the symptoms of the disease but not in improving survival. Current strategies for the treatment of AIPC have shown significant palliation, but no definitive increase in survival. Molecular mechanisms underlying the development of androgen-independent prostate cancer (AIPC) are poorly understood. However, there is growing evidence that different molecular profiles may result in the development of AIPC. In this paper, we not only review the molecular mechanism of AIPC, but also present some of the promising management principles and systemic chemotherapy options against AIPC.

Androgens↗

PubMed2005

Inhibition of the Akt, cyclooxygenase-2, and matrix metalloproteinase-9 pathways in combination with androgen deprivation therapy: potential therapeutic approaches for prostate cancer.

Prostate cancer cells are generally dependent on androgen stimulation mediated by the androgen receptor (AR) for growth and survival, and, therefore, hormonal manipulation, such as castration and/or the use of AR antagonists, results in a regression of the cancer. However, this treatment very rarely leads to the "cure" of advanced disease, and cancers eventually become androgen-independent. A number of genes/pathways have been reported to be activated in prostate cancer, most of which are possibly associated with disease progression. In this article, among them, we focus on Akt (also known as protein kinase B), cyclooxygenase (COX)-2, and matrix metalloproteinase (MMP)-9, whose activities or expressions have been found to be regulated by androgens/AR. Previous studies by us and others, with androgen-sensitive prostate cancer cell lines, have demonstrated that androgen deprivation results in activation/overexpression of Akt, COX-2, and MMP-9 in cells. This suggests that androgen deprivation in clinical settings activates the Akt, COX-2, and MMP-9 pathways in prostate cancer, which may increase cell growth and in turn promote the transition to the androgen-independent state. We hypothesize that androgen deprivation, in combination with inhibition of the Akt, COX-2, and MMP-9 pathways, delays the androgen-independent transition and has more beneficial effects than hormonal therapy alone.

Androgens↗

PubMed2001

Amplification of urokinase gene in prostate cancer.

Prostate cancer is the most common male malignancy in the United States as well as in many European countries. It is curable as long as it is localized, but the invasion of prostate cancer and formation of metastasis turn it into a life-threatening disease. Urokinase-type plasminogen activator (uPA) is believed to play a key role in tissue degradation and cell migration under various normal and pathological conditions, including cancer invasion and metastasis. Increased expression of uPA has been reported in various malignancies including prostate cancer. However, the mechanisms of the overexpression have remained poorly understood. Here, we report increased copy number of uPA gene in 3 of 13 hormone-refractory prostate carcinomas, including 1 high-level amplification. Real-time quantitative reverse transcription-PCR showed that the increased expression of uPA coincided with the amplification of the gene in these tumors. Matrigel invasion assay showed that prostate cancer cell line PC-3, containing amplification of the uPA gene, was more sensitive to the urokinase inhibitor, amiloride, than DU145 or LNCaP cell lines, which do not have the amplification. The findings suggest that one of the mechanisms underlying the overexpression of the uPA is the amplification of the gene, which is associated with the increased invasive potential of the cells.

Blotting, Northern↗

PubMed2005

Immune-based therapies for prostate cancer.

Prostate cancer is a leading cause of cancer morbidity and mortality in the United States. Animal and clinical studies performed four decades ago suggested that immunological approaches might be useful for the treatment of prostate cancer. The wealth of information that has been learned over the last two decades has suggested many new directions to the immune-based therapy of prostate cancer, including passive and active immunotherapy approaches. The findings from current trials, and the likely combination of current immunotherapy approaches with conventional therapies, portends a hopeful future for the treatment of prostate cancer.

Cancer Vaccines↗

PubMed1998

Infrequent genetic alterations of the PTEN gene in Japanese patients with sporadic prostate cancer.

Prostate cancer is a major cause of cancer death among elderly men in America, Europe, and Japan. However, the molecular mechanism of carcinogenesis is not yet well characterized. Frequent loss of heterozygosity (LOH) on chromosome 10q was reported in prostate cancer, and a candidate tumor suppressor gene, PTEN, was isolated on chromosome band 10q23.3. To investigate the genetic alterations of PTEN, we examined 45 primary prostate cancer specimens. LOH at the PTEN locus was observed in two (11.1%) of 18 tumors. However, no mutations were observed in any of the primary prostate cancers. These data suggest that mutation of the PTEN gene does not play a major role in prostate carcinogenesis of Japanese patients.

Aged↗

PubMed2003

Genetics of prostate cancer.

Prostate cancer is the most frequently diagnosed visceral cancer of men, responsible for approximately 40,000 deaths in adult males per year. To identify the genetic causes of prostate cancer, we performed a whole genome scan of affected sib pairs, using DNA markers spaced evenly across the human genome. We demonstrated that regions on chromosomes 1, 4, 5, 7, 8, 11, 16 and 19 might harbor genes that predispose individuals to prostate cancer and may affect tumor growth rate and tumor aggressiveness. Here we present DNA sequence analysis of KIAA 0872 and 17-beta hydroxysteroid dehydrogenase that are located on chromosome 16 within the mapped region, and we demonstrate that neither of these genes carries mutations in the protein coding region or their splice junction sites. These results suggest that these genes are less likely to be associated with the cause of familial prostate cancer.

17-Hydroxysteroid Dehydrogenases↗

PubMed2004

Is gene therapy the answer for prostate cancer?

Prostate cancer is the third most common cancer, accounting for one in 10 cancer diagnoses in men worldwide during 2000. Despite this high burden of morbidity, there is a lack of curative treatments for locally advanced and metastatic disease. Good anatomical accessibility of the prostate combined with substantial molecular understanding of the disease makes prostate cancer an attractive target for gene therapy. Considerable progress has been made in the development of suitable gene transfer vectors and prostate-targeting strategies. Therapeutic approaches being explored fall into two broad categories: corrective and cytoreductive/cytolytic. There are currently 63 prostate cancer gene therapy clinical trials based on these approaches registered in the United States and United Kingdom. Although significant hurdles remain to be overcome, early clinical trial results are encouraging, suggesting that gene therapy may become an important treatment option for prostate cancer.

Clinical Trials as Topic↗

PubMed2001

The use of Fas Ligand, TRAIL and Bax in gene therapy of prostate cancer.

Prostate cancer is the second leading cause of cancer death in the United States. Treatment options for confined disease are generally successful in prolonging life but long-term cures (10-15 years) are elusive for the majority of patients. The prognosis for advanced extra-capsular prostate cancer is grim. However, we are now entering the era of gene therapy options for treatment of prostate cancer. The human genome project coupled with genomics and protemics are providing information that will lead to selection of genes for treatment of prostate cancer. The problem is the science of delivery lags behind knowledge of gene function. Thus, it is important to develop therapies that do not require delivery to 100% of tumor cells but which nevertheless kills the entire cancer by virtue of the bystander effect or other means. This review covers the use, in gene therapy, of apoptotic inducing molecules such as Fas Ligand, and TRAIL which are believed to induce bystander killing activity and Bax which also may function in a similar way.

Adenoviridae↗

PubMed2006

Health-related quality of life in Dutch men with prostate cancer.

Prostate cancer is the most prevalent solid malignancy in men in the Netherlands. With regard to treatment, the focus of attention has shifted in the last decade from pure survival rates to health-related quality of life. HRQOL is affected differently by different treatments. The objective of this study is to assess the HRQOL related to treatment regime and time since diagnosis in Dutch men with prostate cancer. We conducted a cross-sectional study among 238 men with prostate cancer in a heterogeneous sample who filled in a general health-related quality-of-life measure (EORTC-QLQ-C30) and a prostate cancer specific quality-of-life instrument (the EORTC-QLQ-PR25) and a Joy-of-Life questionnaire. Men on hormonal treatment are doing worse compared with other treatments with respect to physical functioning, role functioning, fatigue, pain and sexual functioning. No differences were found between radical prostatectomy and radiation therapy on any of the HRQOL dimensions nor for time since diagnosis. In hormonal therapy, men who are diagnosed longer than two years ago report a worse cognitive functioning and more burdens from urinary problems.

Adult↗

PubMed2001

Bone marrow micrometastases in patients with stage I-II localised prostate cancer.

Prostate cancer commonly metastasises to the bones. Detection of bone marrow micrometastases (BMM) may give important information that helps define treatment strategies. This study was undertaken to analyse BMM in early prostate cancer patients and to determine the accuracy of immunohistochemical (IHC) and morphological methods in detecting cancerous cells. Preoperative core bone marrow biopsy (BMB) was performed in 103 patients with T1-2, N0, M0 prostate cancer after neoadjuvant androgen blockade. BMB were examined by IHC using monoclonal antibodies for cytokeratins (CK) (18, 19, PAN) and by cytomorphology of IHC-positive cells. In 103 patients, BMM were detected in 2 cases (2%) and an additional 3 cases (3%) were classified as suspicious. IHC alone revealed positive cells in 19 patients (18%). Cytomorphology disclosed IHC false-positive staining of some apparently normal bone marrow elements such as plasmocytes. The study shows a rather low rate of BMM in early prostate cancer. It also stresses the importance of cytomorphology as an adjunct to IHC as IHC alone may not be sufficient and appropriate for BMM detection.

Adult↗

PubMed2002

Shared decision-making strategies for early prostate cancer.

Prostate cancer remains one of the most prevalent and least understood of all human malignancies. Pathologic evidence suggests that neoplastic changes of the prostate epithelium begin early in a man's adult life, but do not become clinically evident or relevant until decades later. The natural history of this enigmatic disease is heterogeneous, ranging from a benign and indolent course to one that rapidly progresses, causing significant morbidity and mortality. The divergent aspects of prostate cancer are underscored by vast differences in incidence and mortality statistics, causing consternation among clinicians and patients regarding the relative value of early detection, screening, and treatment strategies. Competing risks and perceived benefits of proposed treatment options including surgery, radiation therapy, hormonal deprivation, watchful waiting, and newer technologies are complex. Given these uncertainties, how should patients integrate these data and what role must physicians play in the process? Here we present a summary of shared decision making for men with localized prostate cancer. We approach this task by using a clinical case scenario to discuss issues relating to incidence and mortality trends, uncertainty regarding natural history, biopsy techniques and concerns, relevant tumor and clinical data, patient information gathering through Web-based resources, as well as support and advocacy groups, outcomes implications, and methods patients use to approach treatment decisions. We present a unified platform for shared decision-making strategies regarding prostate cancer in clinical practice.

Decision Making↗

PubMed1999

DD3: a new prostate-specific gene, highly overexpressed in prostate cancer.

Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. Despite the tremendous efforts that have been made to improve the early detection of this disease and to design new treatment modalities, there is still an urgent need for new markers and therapeutic targets for the management of prostate cancer patients. Using differential display analysis to compare the mRNA expression patterns of normal versus tumor tissue of the human prostate, we identified a cDNA, DD3, which is highly overexpressed in 53 of 56 prostatic tumors in comparison to nonneoplastic prostatic tissue of the same patients. Reverse transcription-PCR analysis using DD3-specific primers indicated that the expression of DD3 is very prostate specific because no product could be amplified in 18 different normal human tissues studied. Also, in a sampling of other tumor types and a large number of cell lines, no expression of DD3 could be detected. Molecular characterization of the DD3 transcription unit revealed that alternative splicing and alternative polyadenylation occur. The fact that no extensive open reading frame could be found suggests that DD3 may function as a noncoding RNA. The DD3 gene was mapped to chromosome 9q21-22, and no homology of DD3 to any gene present in the computer databases was found. Our data indicate that DD3 is one of the most prostate cancer-specific genes yet described, and this makes DD3 a promising marker for the early diagnosis of prostate cancer and provides a powerful tool for the development of new treatment strategies for prostate cancer patients.

Base Sequence↗

PubMed2005

Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer.

Prostate cancer cells metastasize to the bone where their interaction with osteoclasts and osteoblasts can lead to alterations in the structure of the bone. We determined whether the systemic administration of the bisphosphonate, zoledronate, could prevent bone lysis and halt the proliferation of human prostate cancer cells injected into the tibia of nude mice. Zoledronate did not affect the in vitro proliferation of human prostate cancer PC-3MM2 cells. The in vivo administration of zoledronate produced significant bone preservation but did not inhibit the progressive growth of PC-3MM2 cells. The systemic administration of STI571 (imatinib mesylate, Gleevec), an inhibitor of phosphorylation of the platelet-derived growth factor receptor, in combination with paclitaxel, produced apoptosis of tumor cells and bone- and tumor-associated endothelial cells. The systemic administration of zoledronate with STI571 and paclitaxel produced a significant preservation of bone structure, a decrease in tumor incidence and weight, and a decrease in incidence of lymph node metastasis. This therapeutic activity was correlated with inhibition of osteoclast function, inhibition of tumor cell proliferation, and induction of apoptosis in tumor-associated endothelial cells and tumor cells. Cancer is a heterogeneous disease that requires multimodality therapy. The present data recommend the combination of a bisphosphonate agent with protein tyrosine kinase inhibitor and an anticycling drug for the treatment of prostate cancer bone metastasis.

Animals↗

PubMed1997

[Mutations of the androgen receptor gene a possible role in prostate cancer].

Prostate cancer is the second most frequent cancer in men, and the first after 75 years of age. It is androgen dependent and modifications of the androgen receptor (AR) could therefore be involved in its apparition, progression and evolution towards a stage of androgen independence which always occurs. Mutations of the AR have indeed been described. Some result in a more active receptor (constitutive mutations, amplification of the AR gene expression, prevalence of shorter alleles in exon 1) and could therefore be responsible for the progression of the disease in the absence of androgens or the increased cancer risk in some populations. Other mutations, in the ligand binding domain, modify the AR specificity resulting in its activation by weak androgens or even antiandrogens, progestagens or estradiol. These mutations could also explain why prostate cancer progresses in the absence of androgens. On the other hand, mutations resulting in androgen insensitivity could explain why a significant number of prostate cancer remain latent and never develop into an aggressive tumor. Finally, exon 1 polymorphism could be used as a prognostic marker, as it has been shown that the shorter alleles result in a more active AR and are predominant in populations at higher risk for prostate cancer. At any rate, even if AR mutations may be more frequent than initially thought, they remain rare and their significance remains to be determined.

Adenocarcinoma↗

PubMed1998

Prospects for gene therapy in human prostate cancer.

Prostate cancer is the most common neoplasm in men and a significant cause of mortality in affected patients. Despite significant advances, current methods of treatment are effective only in the absence of metastatic disease. Gene therapy offers a renewed hope of using the differential characteristics of normal and malignant tissue in constructing treatment strategies. Several clinical trials in prostate cancer gene therapy are currently under way, using immunomodulatory genes, anti-oncogenes, tumor suppressor genes and suicide genes. A continued understanding of the etiological mechanisms involved in the establishment and progression of prostate cancer, along with advances in gene therapy technology, should make gene therapy for prostate cancer therapeutically valuable in the future.

Cancer Vaccines↗

PubMed2002

MMAC/PTEN tumor suppressor gene regulates vascular endothelial growth factor-mediated angiogenesis in prostate cancer.

Prostate cancer presents with a broad spectrum of biologic behavior, ranging from being an indolent, incidental finding to an aggressively invasive and metastatic disease. An improved understanding of the events involved in prostate cancer progression is critically important to its diagnosis and staging, as well as to the development of new therapies. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of an angiogenic, gene-driven switch. In prostate cancer, one of the most powerful stimulators of angiogenesis is the vascular endothelial growth factor (VEGF). VEGF transcription can be induced by hypoxia through activation of the PI3 kinase pathway and hypoxia-inducible factor alpha. MMAC/PTEN (henceforth referred to as PTEN) is a recently identified tumor suppressor gene residing on chromosome 10q23, which is frequently inactivated in a wide range of human tumors, including advanced prostate cancer. The goal of this study was to determine whether PTEN inhibits angiogenesis by modulating VEGF activity. Our results showed that reintroduction of the PTEN gene into human prostate PC-3 and LNCaP cells decreased VEGF secretion, which was accompanied by various biologic activities, including inhibited endothelial cell growth and migration. PTEN expression also down-regulated VEGF mRNA levels, as detected by RT-PCR analysis. Concomitant with lessened VEGF expression was the reduction of VEGF promoter activity in PTEN-expressing cells. Our findings suggest that PTEN modulates angiogenesis by regulating VEGF expression.

Adenocarcinoma↗

PubMed1998

The expression of drug resistance gene products during the progression of human prostate cancer.

Prostate cancer progresses from a localized disease to a widely disseminated malignancy. Each step along this progression pathway involves multiple genetic alterations that impart a survival advantage to the tumor cell over its normal counterparts and may confer resistance to therapy. Because metastatic prostate cancer is one of the most therapy-resistant human neoplasms, we studied the expression of certain molecular determinants of drug resistance in the context of tumor progression. Paraffin-embedded formalin-fixed resected prostates were chosen based on Gleason grade and surgical stage. Immunohistochemistry was used to detect the expression of multidrug resistance protein (MRP), topoisomerase II alpha, p53, glutathione S-transferase pi, Bcl-2, and P-glycoprotein in these specimens. We found that all of the proteins were expressed in resected prostate except for P-glycoprotein. The expression of MRP, topoisomerase II alpha, p53, and Bcl-2 increased with the Gleason grade. In addition, the expression of MRP, topoisomerase II alpha, and p53 increased with the surgical stage. In contrast, the glutathione S-transferase pi and Bcl-2 expression decreased with the increasing surgical stage. Stage was the strongest indicator of protein expression. These results suggest that drug resistance gene products are expressed in prostate cancer at the time of surgical resection. Thus, although the emergence of the "pan-resistance" phenotype in prostate cancer may partly be a function of the selection pressure exerted by therapeutic interventions, certain determinants of chemoresistance may be caused by genetic changes accompanying tumorigenesis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Asymptomatic incidence and duration of prostate cancer.

Prostate cancer is known as a disease with an extremely high prevalence relative to its clinical incidence in the population. The combination of preclinical incidence and duration that could yield this phenomenon is of tremendous interest to researchers trying to understand the natural history of the disease and to develop efficient screening strategies. In this article, the authors present estimates of the age-specific asymptomatic incidence and average preclinical duration of prostate cancer. The methodological approach is to first estimate the age-specific incidence of new (stage AI) prostate cancers using preclinical prevalence data from autopsy studies performed between 1941 and 1964 and clinical incidence data for the years 1960-1986 from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. Then, the preclinical prevalence estimates are divided by the derived preclinical incidence estimates to yield estimates of the average duration of asymptomatic disease. The estimated mean duration among white men is between 11 and 12 years and appears to be approximately 1 year shorter for blacks than for whites. Comparison of the lifetime risks of preclinical and clinical disease suggests that approximately 75% of prostate cancers will never become diagnosed if clinical incidence remains at levels observed in 1984-1986, prior to the introduction of prostate-specific antigen (PSA) screening in the population.

Adult↗