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Advanced Prostate Cancer (advanced + prostate_cancer)
Selected AbstractsSIDE-EFFECTS OF TREATMENTS FOR LOCALLY ADVANCED PROSTATE CANCERBJU INTERNATIONAL, Issue 6 2006WILLIAM REID PITTS No abstract is available for this article. [source] Prolonging androgen sensitivity in prostate cancer , a role for COX inhibitors?ANZ JOURNAL OF SURGERY, Issue 9 2009Andrew Richards Abstract Background:, Advanced prostate cancer has long been known to respond to androgen deprivation, but disease inevitably progresses to become androgen independent. Lengthening the responsive period is an important, yet underinvestigated, clinical goal. This study aims to determine whether cyclooxygenase-2 (COX-2) inhibitors are potentially useful agents in prolonging androgen sensitivity. Methods:, The expression of COX-2 in human prostate surgical specimens, both benign and malignant, androgen dependent and independent, was determined by immunohistochemistry. Nude mice, in which prostate cancer xenografts had been established, were castrated and randomized to receive either COX-2 inhibitor or vehicle for 8 weeks. Time to androgen independence (AIPC), growth rate and rate of PSA rise were compared between groups. COX-2 expression, at the mRNA and protein level, was determined in the native xenograft cell line and in tissues of varying androgen sensitivity derived from the xenografts. Results:, In human tissues, COX-2 protein was expressed in prostate epithelium and was upregulated in prostate cancer and remained upregulated after androgen ablation and in the androgen-independent state. Tissue obtained from the LNCaP xenograft model showed variable COX-2 expression, with some evidence of downregulation in AIPC. The addition of a COX-2 inhibitor to castration does not lengthen the time to AIPC (P= 0.53), rate of tumour growth (P= 0.59) or rate of PSA rise (P= 0.34) in the LNCaP xenograft model. Conclusion:, This study does not support a role for COX-2 inhibitors in prolonging androgen responsiveness in prostate cancer. [source] Chromosome 18 suppresses tumorigenic properties of human prostate cancer cellsGENES, CHROMOSOMES AND CANCER, Issue 3 2006Audrey Gagnon Although prostate cancer is still the most diagnosed cancer in men, most genes implicated in its progression are yet to be identified. Chromosome abnormalities have been detected in human prostate tumors, many of them associated with prostate cancer progression. Indeed, alterations (including deletions or amplifications) of more than 15 human chromosomes have been reported in prostate cancer. We hypothesized that transferring normal human chromosomes into human prostate cancer cells would interfere with their tumorigenic and/or metastatic properties. We used microcell-mediated chromosome transfer to introduce human chromosomes 10, 12, 17, and 18 into highly tumorigenic (PC-3M-Pro4) and highly metastatic (PC-3M-LN4) PC-3-derived cell lines. We tested the in vitro and in vivo properties of these hybrids. Introducing chromosome 18 into the PC-3M-LN4 prostate cancer cell line greatly reduced its tumorigenic phenotype. We observed retarded growth in soft agar, decreased invasiveness through Matrigel, and delayed tumor growth into nude mice, both subcutaneously and orthotopically. This phenotype is associated with a marker in the 18q21 region. Combined with the loss of human chromosome 18 regions often seen in patients with advanced prostate cancer, our results show that chromosome 18 encodes one or more tumor-suppressor genes whose inactivation contributes to prostate cancer progression. © 2005 Wiley-Liss, Inc. [source] Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN-215) and a bombesin antagonist (RC-3095)INTERNATIONAL JOURNAL OF CANCER, Issue 8 2010Sandra Sotomayor Abstract Bombesin (BN) and gastrin-releasing peptide (GRP) have been shown to stimulate the growth of human prostate cancer in vivo and in vitro by mechanisms initiated by binding of the peptide to BN/GRP receptor (GRPR). GRPR is overexpressed in a variety of human cancers, including human prostatic carcinoma. This led us to evaluate the effectiveness of blocking GRPR and of chemotherapy targeted to GRPR in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cells, which exhibit different features of disease progression. Thus, we used a cytotoxic BN/GRP analog, AN-215, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to BN-like carrier peptide, and a BN/GRP receptor antagonist, RC-3095. Semiquantitative RT-PCR and Western blotting revealed that mRNA and protein levels for GRPR increased in prostate cancer cells as compared with nonneoplastic RWPE-1 cells. Immunofluorocytochemistry and Western blot assays revealed that AN-215 was the most effective analog decreasing both the expression of epidermal growth factor receptor family members and the activation of epidermal growth factor receptor and HER-2, which are associated to a poor prognosis. Furthermore, analogs targeted to BN/GRP receptors, AN-215 and RC-3095, blocked the effect of BN on cell growth in RWPE-1, LNCaP and PC-3 cells. These findings shed light on the mechanisms of action of these analogs and support the view that the use of AN-215 and RC-3095 for blocking BN/GRP receptors for targeted therapy may be of benefit for treatment of advanced prostate cancer. [source] Prostate cancer and PSA among statin users in the Finnish prostate cancer screening trialINTERNATIONAL JOURNAL OF CANCER, Issue 7 2010Teemu J. Murtola Abstract Decreased risk of advanced prostate cancer has been reported among men using statins. However, the evidence on overall prostate cancer risk is conflicting. We compared the relative risk between current users and non-users of statins or other cholesterol-lowering medications in a population undergoing systematical prostate cancer screening. The study cohort comprised of 23,320 men participating in the screening arm of the Finnish prostate cancer screening trial during 1996,2004. Information on medication use was obtained from a comprehensive national prescription database. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HRs) for prostate cancer. Serum prostate-specific antigen (PSA) level was compared between current users and non-users of cholesterol-lowering drugs. Compared with medication non-users, the overall prostate cancer incidence was decreased among statin users [HR 0.75, 95% confidence interval (CI) 0.63,0.89]. The inverse association was dose-dependent with cumulative amount of statin use, and strongest for low-grade and early stage tumors. The incidence was nonsignificantly lower also among users of other types of cholesterol-lowering drugs (HR 0.62, 95% CI 0.28,1.38), but without dose-dependence. Age-adjusted median serum PSA tended to be lower among users of cholesterol-lowering drugs, but the relative risk decrease among statin users was not related to decreased PSA. Overall incidence of prostate cancer was lowered among statin users when bias due to differential PSA testing between medication users and non-users was eliminated by systematical prostate cancer screening. Cholesterol-lowering with statins seems beneficial for prostate cancer prevention. [source] Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer riskINTERNATIONAL JOURNAL OF CANCER, Issue 11 2008Victoria L. Stevens Abstract Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29,38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations. © 2008 Wiley-Liss, Inc. [source] Necessity of re-evaluation of estramustine phosphate sodium (EMP) as a treatment option for first-line monotherapy in advanced prostate cancerINTERNATIONAL JOURNAL OF UROLOGY, Issue 2 2001Tadaichi Kitamura Abstract Estramustine phosphate sodium (EMP) was first introduced in the early 1970s for the treatment of prostate cancer, when EMP was supposed to have the dual effect of estrogenic activity and cytotoxicity. For the following decades, it was used mainly in hormone-refractory cases, with a conventional dosage of 4,9 capsules/day, which showed a 30,35% objective response rate. However, a very limited number of cases have been reported that used EMP as a first-line monotherapy in the conventional dosage. One study showed a response rate of 82%, which is at least as effective as conventional estrogen (diethylstilbestrol; DES) monotherapy. Nevertheless, EMP was almost abandoned for the treatment of prostate cancer because of severe adverse side-effects, especially in the cardiovascular system and gastrointestinal tract. Recently, two facts have become evident. First, EMP interferes with cellular microtubule dynamics but does not show alkylating effects. Second, EMP is able to produce a complex with calcium when dairy products are taken concomitantly with EMP, resulting in a decrease in the absorption rate of EMP from the gut. Many clinical trials have been undertaken without warning against concomitant dairy product intake since the introduction of EMP. This fact will jeopardize almost all the clinical trials performed before 1990. It is considered that response rates have been underestimated and better results could have been obtained because side-effects decrease dose-dependently. Low-dose EMP monotherapy (2 capsules/day) has been performed infrequently in previously untreated advanced prostate cancer. The only large trial by the European Organization for Research and Treatment of Cancer in 1984 was biased in selecting patients. Nevertheless, the response rate of EMP is comparable to that of DES. In this study, the adverse side-effects of EMP were less than that of DES. Recently, a study was conducted at the University of Tokyo of 11 patients with advanced prostate cancer on low-dose EMP as first-line monotherapy. The study found that the mean serum prostate-specific antigen level decreased to within the normal range by day 50; mean serum testosterone, leutinizing hormone and follicle-stimulating hormone reduced to undetectable levels by day 20; and mean serum estradiol increased to a very high level within 1 week. These data implicate that low-dose EMP can suppress quickly and adequately the pituitary,gonadal axis, although the antitumor effect has not as yet been elucidated. For these reasons, it is necessary to re-evaluate low-dose EMP monotherapy in previously untreated advanced prostate cancer. [source] Change in the ratio of free-to-total prostate-specific antigen during progression of advanced prostate cancerINTERNATIONAL JOURNAL OF UROLOGY, Issue 3 2000MASASHI TANAKA Abstract Background: The ratio of free-to-total prostate-specific antigen (PSA) is different in benign prostatic hyperplasia and in the early stage of prostate cancer. The present study was undertaken to examine the ratio of free-to-total PSA in the advanced stage of this cancer and its subsequent change during course of the disease. Methods: Free and total PSA were measured in sera collected from the following patients with benign and cancerous prostatic diseases: 47 cases of benign prostatic hypertrophy, nine in T1C with less than 10 ng/mL of total PSA, 11 in stage C, 16 in D2, 22 in remission under endocrine therapy, and 12 in relapse. In addition, PSA was measured sequentially in four other patients who were also in relapse. Results: The ratio of free-to-total PSA was similar in early and advanced stages of untreated prostate cancer and was lower than that in benign prostatic hyperplasia. The ratio increased to the level of benign prostatic hyperplasia during remission from stages C and D2 under endocrine therapy. There was no correlation with the intervals from the start of the therapy to examination. Following relapse, the ratio came down gradually to the level obtained in untreated prostate cancer. Conclusion: The ratio of free-to-total PSA was similar in all stages of untreated prostate cancer. Response and relapse to endocrine therapy were associated with increase and decrease in ratio, respectively. [source] Apoptosis evasion: The role of survival pathways in prostate cancer progression and therapeutic resistanceJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2006Shaun McKenzie Abstract The ability of a tumor cell population to grow exponentially represents an imbalance between cellular proliferation and cellular attrition. There is an overwhelming body of evidence suggesting the ability of tumor cells to avoid programmed cellular attrition, or apoptosis, is a major molecular force driving the progression of human tumors. Apoptotic evasion represents one of the true hallmarks of cancer and appears to be a vital component in the immunogenic, chemotherapeutic, and radiotherapeutic resistance that characterizes the most aggressive of human cancers [Hanahan and Weinberg, 2000]. The challenges in the development of effective treatment modalities for advanced prostate cancer represent a classic paradigm of the functional significance of anti-apoptotic pathways in the development of therapeutic resistance. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] Calpain-mediated androgen receptor breakdown in apoptotic prostate cancer cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2008Huanjie Yang Since androgen receptor (AR) plays an important role in prostate cancer development and progression, androgen-ablation has been the frontline therapy for treatment of advanced prostate cancer even though it is rarely curative. A curative strategy should involve functional and structural elimination of AR from prostate cancer cells. We have previously reported that apoptosis induced by medicinal proteasome-inhibitory compound celastrol is associated with a decrease in AR protein levels. However celastrol-stimulated events contributing to this AR decrease have not been elucidated. Here, we report that a variety of chemotherapeutic agents, including proteasome inhibitors, a topoisomerase inhibitor, DNA-damaging agents and docetaxel that cause cell death, decrease AR levels in LNCaP prostate cancer cells. This decrease in AR protein levels was not due to the suppression of AR mRNA expression in these cells. We observed that a proteolytic activity residing in cytosol of prostate cancer cells is responsible for AR breakdown and that this proteolytic activity was stimulated upon induction of apoptosis. Interestingly, proteasome inhibitor celastrol- and chemotherapeutic drug VP-16-stimulated AR breakdown was attenuated by calpain inhibitors calpastatin and N -acetyl- L -leucyl- L -leucyl- L -methioninal. Furthermore, AR proteolytic activity pulled down by calmodulin-agarose beads from celastrol-treated PC-3 cells showed immunoreactivity to a calpain antibody. Taken together, these results demonstrate calpain involvement in proteasome inhibitor-induced AR breakdown, and suggest that AR degradation is intrinsic to the induction of apoptosis in prostate cancer cells. J. Cell. Physiol. 217: 569,576, 2008. © 2008 Wiley-Liss, Inc. [source] A steroid fraction of chloroform extract from bee pollen of Brassica campestris induces apoptosis in human prostate cancer PC-3 cellsPHYTOTHERAPY RESEARCH, Issue 11 2007Yao-Dong Wu Abstract Bee pollen of Brassica campestris L. is widely used in China as a natural food supplement and an herbal medicine in strengthening the body's resistance against diseases including cancer. The present study was carried out to investigate the effect of a steroid fraction of chloroform extract from bee pollen of Brassica campestris L. on human cancer cell viability. Our studies show that among nine cancer cell lines of different origin (PC-3, LNCaP, MCF-7, Hela, BEL-7402, BCG-823, KB, A549 and HO8910), this steroid fraction displayed the strongest cytotoxicity in human prostate cancer PC-3 cells. The mode of cell death appeared to be apoptosis in PC-3 cells, as shown by flow-cytometric analysis and fluorescence microscopes. Caspase-3 activity was obviously enhanced after the cells were treated with the fraction. A time-dependent decrease in the expression of anti-apoptotic protein Bcl-2 was also observed by Western blot analysis. It is suggested that the steroid fraction could induce cytotoxicity in prostate cancer PC-3 cells by triggering apoptosis. The studies indicate that the steroid fraction of chloroform extract from bee pollen of Brassica campestris L. may be a promising candidate for the treatment of advanced prostate cancer. Copyright © 2007 John Wiley & Sons, Ltd. [source] Histrelin acetate: gonadorelin analogue given once a yearPRESCRIBER, Issue 3 2010MRPharmS, Steve Chaplin MSc Histrelin acetate (Vantas) is a gonadorelin analogue implant for the palliative treatment of advanced prostate cancer given once a year. In our New products review, Steve Chaplin presents the clinical data relating to its efficacy and adverse effects, and Mr Raj Persad considers its potential place in treatment. Copyright © 2010 Wiley Interface Ltd. [source] PSA and body composition by dual X-Ray absorptiometry (DXA) in NHANESTHE PROSTATE, Issue 2 2010Jay H. Fowke Abstract BACKGROUND Obese men are at higher risk for advanced prostate cancer and have a poorer prognosis following treatment. Several studies also report that obese men have lower blood PSA levels, suggesting that obesity may be interfering with the ability to detect early-stage prostate cancer. METHODS Dual X-ray absorptiometry (DXA) is considered a gold-standard measurement of body composition. We investigated the association between PSA levels and body composition measured by DXA among 1,360 men participating in NHANES (2001,2004), a representative sample of the U.S. male population. RESULTS After controlling for age, race, and other factors, PSA concentration was ,15% lower for men with the highest level of total mass, lean mass, fat mass, trunk lean mass, and trunk fat mass (all P for trend <0.05). We then multiplied PSA concentration by estimated plasma volume to calculate the amount of PSA in circulation (i.e., PSA mass). Total body fat mass and fat mass located in the body trunk were not significantly associated with PSA mass, however, PSA mass was ,10,15% higher across low versus high categories of total body lean mass and bone mineral content (all P -trend <0.05). CONCLUSION Our results using DXA to measure body composition confirm that a greater body mass, not just fat mass, is associated with a lower PSA concentration. This is consistent with PSA hemodilution within men with a higher body mass index. The separate associations between measured lean and fat mass on calculated PSA mass require further investigation. Prostate 70: 120,125, 2010. ©2009 Wiley-Liss, Inc. [source] A novel communication role for CYP17A1 in the progression of castration-resistant prostate cancerTHE PROSTATE, Issue 9 2009Jennifer A. Locke Abstract BACKGROUND CYP17A1 is currently a target for total androgen blockade in advanced prostate cancer (CaP) patients. After castration, or removal of testicular androgens, CYP17A1 can act as a rate-limiting enzyme in androgen synthesis from cholesterol or other adrenal precursors within the tumor microenvironment ultimately contributing to disease progression. Herein we provide evidence that CYP17A1 could also be a mediator of cell-to-cell communication within the CaP tumor microenvironment. METHODS CYP17A1 expression was evaluated by immunohistochemical analysis of human tumor sections and Western blot analysis of CaP patients' serum and exosome isolates. CYP17A1 activity assays were conducted in human serum (and positive control human liver and kidney microsomes) using progesterone as a precursor and an LC-MS endpoint. RESULTS These studies revealed that the expression pattern of CYP17A1 is typical of a secretory protein as it is localized to the luminal pole of the cells in exocrine secretory mode. CYP17A1 is expressed in human serum and in fact is elevated in the serum of CaP patients as compared to healthy controls. Serum CYP17A1 activity could not be confirmed, however, verification of CYP17A1 expression in exosomes suggests a role in cell-to-cell communication within the tumor microenvironment. CONCLUSIONS CYP17A1 is a crucial enzyme for de novo androgen synthesis within the tumor microenvironment after removal of testicular androgens by castration. We provide evidence for a novel role for CYP17A1 in serum and further reiterate the importance of targeting this enzyme in CaP progression. Prostate 69: 928,937, 2009. © 2009 Wiley-Liss, Inc. [source] The potential role of purine-rich element binding protein (PUR) , as a novel treatment target for hormone-refractory prostate cancer,THE PROSTATE, Issue 10 2008Takahiro Inoue Abstract BACKGROUND Hormonal therapy for advanced prostate cancer is typically effective at first, but almost all men suffer refractory disease which often is life threatening. The nuclear matrix comprises not only of the structural elements of the nucleus, but is associated with many components of the molecular machinery. Our aim is to find novel targets for the treatment of hormone-refractory prostate cancer (HRPC) by focusing on the composition of the nuclear matrix proteins (NMPs). METHODS LN96 cells were established at our Institution after long-term culturing of LNCaP cells under androgen deprived conditions. The composition of NMPs of LNCaP cells and LN96 cells were analyzed by two-dimensional (2D) electrophoresis and spots differentially expressed were investigated by mass spectrometry for identification. Among the spots identified, we analyzed the potential functional role of the identified proteins in prostate cancer cells by establishing stable overexpressed cells. RESULTS We found that purine-rich element binding protein (PUR), was significantly repressed not only in NMPs but also in total protein and mRNA levels of LN96 cells in comparison to LNCaP cells under the same steroid deprived conditions. Moreover, PUR, was decreased in its expression both at the protein and mRNA levels in the androgen-independent prostate cancer cell lines, PC3 and DU145 in comparison to LNCaP cells. Stably overexpressing PUR, in PC3 and DU145 cells negatively regulates cell proliferation, resulting in decreases in PCNA expression. CONCLUSION Further dissection of the role of PUR, in cell growth regulation may reveal a novel target for HRPC. Prostate 68:1048,1056, 2008. © 2008 Wiley-Liss, Inc. [source] RANKL inhibition is an effective adjuvant for docetaxel in a prostate cancer bone metastases modelTHE PROSTATE, Issue 8 2008K. M. Woods Ignatoski Abstract BACKGROUND Docetaxel induces an anti-tumor response in men with advanced prostate cancer (PCa); however, the side effects associated with docetaxel treatment can be severe, resulting in discontinuation of therapy. Thus, identification of an effective adjuvant therapy to allow lower doses of docetaxel is needed. Advanced PCa is typically accompanied by skeletal metastasis. Receptor activator of NFkB ligand (RANKL) is a key pro-osteoclastic factor. Targeting RANKL decreases establishment and progression of PCa growth in bone in murine models. METHODS The efficacy of inhibiting RANKL, using a recombinant soluble RANK extracellular domain fused with the immunoglobulin Fc domain (RANK-Fc), was tested as an adjuvant therapy with docetaxel for PCa bone metastasis in a murine intra-tibial model. RESULT The combination of RANK-Fc and docetaxel reduced tumor burden in bone greater than either treatment alone. CONCLUSION The combination of docetaxel with a RANKL-inhibiting agent merits further investigation for treatment of advance PCa. Prostate 68:820,829, 2008. © 2008 Wiley-Liss, Inc. [source] Ten-year survival and cardiovascular mortality in patients with advanced prostate cancer primarily treated by intramuscular polyestradiol phosphate or orchiectomyTHE PROSTATE, Issue 4 2007Arto Mikkola Abstract BACKROUND The aim of the study was to evaluate overall and prostate cancer (PCa) specific survival with special attention to cardiovascular (CV) mortality in patients primarily treated by parenteral polyestradiol phosphate (PEP) 240 mg/month or with orchiectomy (OE), taking into account the effect of pretreatment diseases and medication, and later PCa therapies. METHODS The present Finnprostate 6 study (10-year follow-up) consisted of 244 patients with locally advanced PCa (T3-4 M0) and 200 patients with metastatic PCa (T1-4 M1). Patients were randomized to OE or PEP therapy. The T3-4 M0 and T1-4 M1 patients were analyzed separately. RESULTS There was no difference in overall or PCa specific survival between the primary therapy groups in T3-4 M0 or T1-4 M1 patients. In the T3-4 M0 patients the primary treatment (PEP vs. OE) was statistically significantly associated with a risk of CV deaths (P,=,0.001). Such an association was not found in the T1-4 M1 patients. CONCLUSIONS The primary PEP and OE therapies are equal in terms of overall and PCa specific survival in patients with T3-4 M0 or T1-4 M1 disease. In T3-4 M0 patients PEP increases the risk of CV deaths compared to OE but not in T1-4 M1 patients. Prostate 67: 447,455, 2007. © 2007 Wiley-Liss, Inc. [source] Genistein-induced neuroendocrine differentiation of prostate cancer cellsTHE PROSTATE, Issue 11 2006Jacek Pinski MD Abstract BACKGROUND Neuroendocrine (NE) cells are present in normal prostate and their number appears to be increased in advanced prostate cancer (PCA). In this study, we studied the effect of the phytoestrogen, genistein, on NE differentiation of LNCaP cells in vitro. METHODS Neuroendocrine marker expression of LNCaP cells exposed to genistein was measured by immunohistochemistry, Western blot, and real-time PCR methods. Western blot analysis was used to study cell cycle and signaling pathways induced by genistein treatment. RESULTS Six days after continuous genistein treatment, the majority of genistein-surviving cancer cells underwent transdifferentiation into a NE-like phenotype overexpressing the NE markers chromogranin A, synaptophysin, serotonin, and beta-III tubulin. This NE differentiation process was associated with upregulation of the cell cycle modulators p21, p27, and p53, and activation of the MAPK and STAT3 pathways. CONCLUSION Our data indicate that genistein evokes not only apoptosis but also NE transdifferentiation of PCA cells. Prostate © 2006 Wiley-Liss, Inc. [source] Glutathione S -transferase pi is upregulated in the stromal compartment of hormone independent prostate cancerTHE PROSTATE, Issue 2 2003Ming Li Abstract Background Glutathione S -transferase (GST) pi is a detoxifying enzyme abundant in normal prostate basal cells but only rarely expressed in prostate cancer cells. The current studies are the first to focus on GST pi in the stromal compartment of prostate tumors. Methods We employed immunohistochemical, immunofluorescence, and Western blot analysis to measure GST pi expression and subcellular localization in 21 primary and metastatic tumors from patients with hormone independent prostate cancer, as well as seven lymph node metastases and six prostatectomy specimens. Results GST pi was detectable in stromal cells in 17 of the 21 hormone independent prostate tumors. GST pi tissue distribution in hormone independent tumors coincided with vimentin staining, suggesting that GST pi is expressed by reactive fibroblasts and/or myofibroblasts. Conclusions The current results suggest that prostate cancer cells induce an injury response in the stroma during progression to hormone independence, which results in GST pi expression. Stromal GST pi may contribute to chemoresistence of advanced prostate cancer. Prostate 56: 98,105, 2003. © 2003 Wiley-Liss, Inc. [source] Reduction of human prostate tumor vascularity by the ,1-adrenoceptor antagonist terazosinTHE PROSTATE, Issue 2 2001Kaspar Keledjian Abstract BACKGROUND We previously demonstrated that the quinazoline-derived a1-adrenoceptor antagonists doxazosin and terazosin suppress prostate cancer growth via apoptosis induction. The aim of this study was to determine the potential effect of a1-adrenoceptor antagonists on tumor vascularity of the human prostate. METHODS A total of 34 men with benign prostatic hyperplasia (BPH) who have been on terazosin treatment (for the obstructive symptoms) were pathologically diagnosed with prostate cancer following surgery. These patients were stratified according to the length of treatment periods with terazosin into two groups, 1 week,6 months, and 6,17 months. The control group consisted of prostatectomy specimens from 25 untreated prostate cancer patients undergoing surgery for localized disease. Formalin-fixed, paraffin-embedded prostate specimens were analyzed for apoptosis (TUNEL assay), cell proliferation (Ki-67), microvessel density (MVD) (von Willebrand factor/Factor VIII), vascular endothelial growth factor (VEGF) expression, and prostate specific antigen (PSA) immunoreactivity. RESULTS A significant induction of apoptosis was observed among cancerous prostatic epithelial cells in the terazosin-treated, as compared to the untreated prostate cancer specimens, while there was no significant change in the proliferative index of the same tumor cell populations after treatment. Furthermore, terazosin resulted in a significant decrease in prostate tissue MVD compared with the untreated group (P,<,0.01), that correlated with the increased apoptotic index of the cancerous areas. Tissue PSA expression in the prostatic tumor foci was also markedly reduced after terazosin treatment, while no significant changes in VEGF expression were detected. CONCLUSIONS These findings provide the first evidence that terazosin, a quinazoline-based a1-blocker decreases prostate tumor vascularity. Our study has significant clinical implications in identifying selected ,1-adrenoceptor antagonists as potential anti-tumor agents with apoptotic and anti-angiogenic effects in the human prostate that can be exploited for the treatment of advanced prostate cancer. Prostate 48:71,78, 2001. © 2001 Wiley-Liss, Inc. [source] On the invisibility of the emasculated (Respond to this article at http://www.therai.org.uk/at/debate)ANTHROPOLOGY TODAY, Issue 1 2010Richard Wassersug Castrating a male by destroying his testicles is a practice that most people assume ended a century or so ago with the collapse of the Chinese and Ottoman Empires and the death of the last castrato in the Vatican choir. However, because advanced prostate cancer is treated by either chemical or surgical castration, there are probably more castrated men alive today than ever before in history. Castration is also used in the western world as either a step in the sexual reassignment of male to female (MtF) transsexuals or rarely to treat recidivist sexual predators. In addition, some men desire emasculation who are neither cancer patients, MtF transsexuals, nor sexual predators. In this essay I argue that the public association of castration with sexual predators and deviant behaviour is so great that men, who require it as a medical treatment for cancer or who seek it for other reasons typically hide from public view. One consequence of the shame associated with castration is that those, who desire emasculation but do not have a diagnosis of cancer, too often subject themselves to risky and illegal amateur surgeries outside the medical system. I argue that for whatever reason a male seeks castration, the overall invisibility of the emasculated in modern society is a disservice. It minimizes the public's understanding of the magnitude of the impact of castration on cancer patients and it inhibits those in need of medical treatment from getting it in an appropriate and timely fashion. [source] Intraoperative radiotherapy during radical prostatectomy for intermediate-risk to locally advanced prostate cancer: treatment technique and evaluation of perioperative and functional outcome vs standard radical prostatectomy, in a matched-pair analysisBJU INTERNATIONAL, Issue 11 2009Bernardo Rocco OBJECTIVE To evaluate a novel approach with intraoperative radiotherapy (IORT) administered in the surgical field, after pelvic lymphadenectomy (PL) and before radical retropubic prostatectomy (RRP), evaluating acute and late toxicity, complications and biochemical progression-free survival (bPFS), as the adequate treatment of locally advanced prostate cancer is still a controversial issue. PATIENTS AND METHODS Between June 2005 and October 2007, 33 consecutive patients with intermediate-risk or locally advanced prostate cancer were selected for PL + IORT + RRP. IORT was delivered by a mobile linear accelerator in the operating room (electron beam, 12 Gy at 90% isodose). According to the pathological findings further adjuvant radio- or hormone therapy could be administered. The median follow-up was 16 months. This group was compared retrospectively with a historical group of 100 patients who had undergone RRP and further adjuvant therapy, selected with equivalent criteria. The comparison was conducted as a matched-pair analysis. The perioperative outcomes (surgical time, estimated blood loss, blood transfusions, days of catheterization, days of drainage, days of hospitalization), continence as the functional outcome, acute and late toxicity, rate of complications and bPFS were evaluated and compared. RESULTS The baseline characteristics of the two groups were equivalent but the node count and the number of positive lymph nodes was higher in the IORT group. The IORT group had longer surgery, and a shorter hospital stay and catheterization. There were no differences in continence rate, and no major complications in either group. The acute and late toxicity and bPFS were equivalent. A retrospective comparison and the short follow-up were the major limitations. CONCLUSIONS IORT administered before RRP seems a feasible approach, with little effect on the variables evaluated. [source] Locally advanced prostate cancer: the role of surgical managementBJU INTERNATIONAL, Issue 4 2009Kelly L. Stratton Among the heterogeneous population of patients with prostate cancer, a high-risk group with locally advanced prostate cancer (LAPC) present a diagnostic and therapeutic dilemma. Although the incidence of LAPC has decreased with screening since the introduction of prostate-specific antigen (PSA) testing, significantly many patients are still diagnosed with LAPC. These patients are by definition at higher risk of metastatic disease and worse outcomes. The role of radical prostatectomy (RP) in this population has been debated, as the combination of radiotherapy and hormonal therapy is becoming used more frequently for LAPC. Unfortunately, the clinical staging and evaluation of LAPC is a challenge that results in possibly understaging or overstaging these patients. This further complicates therapeutic decision-making, and as a result no established standard treatment has been proposed. Like other patients with prostate cancer, individualized therapeutic choices are essential and depend on a multitude of factors. Herein we examine the role of RP for managing LAPC and attempt to emphasize how the risk of distant disease and difficulty with clinical staging might favour incorporating a surgical approach as part of the therapy for patients with LAPC. [source] Systematic review of early vs deferred hormonal treatment of locally advanced prostate cancer: a meta-analysis of randomized controlled trialsBJU INTERNATIONAL, Issue 6 2007Gregory Boustead OBJECTIVE To compare the effectiveness of hormonal treatment (luteinizing hormone-releasing hormone agonists and/or antiandrogens) as an early or as a deferred intervention for patients with locally advanced prostate cancer (LAPC), as radiotherapy is currently the standard treatment for LAPC, with hormonal treatment considered a reserve option. METHODS We systematically reviewed randomized controlled trials (RCTs) in patients with LAPC treated with standard care (radical prostatectomy, radiotherapy, and/or watchful waiting) or standard care plus hormonal treatment. Outcomes assessed were mortality and objective disease progression. The meta-analysis used a fixed-effects model. RESULTS Of the 108 trials identified, seven met the inclusion criteria and were of sufficient quality to be included in the analysis. Early intervention with hormonal treatment significantly reduced all-cause mortality compared with deferred treatment (relative risk, RR, 0.86; 95% confidence interval, CI, 0.82,0.91; P < 0.001). Similarly, early vs deferred use of hormonal treatment significantly reduced: prostate cancer- specific mortality (RR 0.72; 95% CI 0.65,0.79); overall progression (RR 0.74; 0.69,0.78); local progression (RR 0.65; 0.57,0.73); and distant progression (RR 0.67; 0.61,0.74; all P < 0.001). Results were robust to changes in inclusion/exclusion criteria and use of a random-effects model for the meta-analyses. Heterogeneity and publication bias had no significant effect on the analyses. CONCLUSIONS Early intervention with hormonal treatment for patients with LAPC provides significantly lower mortality and objective disease progression than deferring their use until standard care has failed. [source] Preliminary evidence that the allogeneic response might trigger antitumour immunity in patients with advanced prostate cancerBJU INTERNATIONAL, Issue 5 2006Gordon Muir OBJECTIVE To explore the possibility that allogeneic responses might, by chance, encompass cross-reactive T cell clones specific for neo-antigenic tumour determinants, and thereby activate antitumour immunity; such cross-reactions are well documented for antiviral immunity, and genetic instability in developing cancers generates many neo-antigenic determinants as potential targets for immune responses, but the biology inevitably favours tumour progression. PATIENTS AND METHODS Fourteen patients with hormone-refractory prostate cancer received full-thickness skin allografts from different, unrelated donors (fellow patients) until each had received six grafts. Serum prostate-specific antigen (PSA) level was used as a surrogate for tumour mass. RESULTS One patient had a remarkable decline in PSA level, with levels at 1 year lower than before grafting. A second patient had stable PSA levels for almost 2 years. A third patient had stable PSA levels for 10,12 months before they resumed an exponential rise. Of four patients with PSA levels of >10 ng/mL, three required surgery or radiotherapy for obstructive symptoms during or shortly after grafting. CONCLUSION Transplant rejection involves mechanistically atypical T cell recognition of allogeneic major histocompatibility complex antigens, with massive polyclonal T cell activation. This unique aspect of T cell biology might represent a novel approach for initiating cross-reactive antitumour responses. [source] Side-effects of treatments for locally advanced prostate cancerBJU INTERNATIONAL, Issue 1 2006KEVIN M. O'CONNOR First page of article [source] A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancerBJU INTERNATIONAL, Issue 3 2005Mohd S. Ansari No abstract is available for this article. [source] Induction of potent antitumour natural-killer cells from peripheral blood of patients with advanced prostate cancerBJU INTERNATIONAL, Issue 9 2003T. Oikawa In this section there are four papers on a variety of topics. The subject of antitumour natural killer cells is addressed in patients with advanced prostate cancer. In another study, the authors describe their work into the effect of oestrogen and testosterone on the urethral seam of the developing male mouse genital tubercle. Another group of authors studied ion-channel currents of smooth muscle cells isolated from the prostate of the guinea pig, and the final paper describes how a novel pyrrole derivative, NS-8, suppresses the rat micturition reflex by inhibiting afferent pelvic nerve activity. OBJECTIVE To examine whether antitumour natural-killer (NK) cells can be induced from peripheral blood mononuclear cells (PBMCs) of patients with advanced prostate cancer, as cell therapy using antitumour immune cells is a promising candidate treatment but such patients generally have a suppressed immune response against cancer cells. PATIENTS AND METHODS PBMCs were obtained from 10 patients (four with stage D2 and six with stage B or C disease). For the NK cell expansion, PBMCs were co-cultured with irradiated HFWT cells, a cell line originating from Wilms' tumour, in RHAM , culture medium supplemented with 5% autologous plasma and interleukin-2 (200 U/mL) for 2 weeks. RESULTS When PBMCs were co-cultured with HFWT cells, lymphocytes from all patients had a 20- to 130-fold expansion after 2 weeks of culture. The CD16+ CD56+ cells constituted >,70% of the proliferated lymphocyte population. The induced NK cells had significantly greater cytotoxicity against a prostate cancer cell line (PC-3) than lymphocytes cultured with no HFWT cells. There was no significant difference in growth and phenotypes of lymphocytes and the induced NK cell activity between patients with stage D2, B or C. CONCLUSION NK cells with potent cytotoxic activity against prostate cancer cell lines from patients with advanced prostate cancer were selectively expanded. Further investigation is needed to determine whether this approach could be a candidate for cell therapy for advanced prostate cancer. [source] Outcome after radical prostatectomy with a pretreatment prostate biopsy Gleason score of ,8BJU INTERNATIONAL, Issue 6 2003M. Manoharan The use of radical prostatectomy to treat patients with high-grade prostate cancer is the subject of much discussion, and the authors from Miami present their considerable experience in this field. They show that patients with a pre-treatment biopsy of Gleason score of ,8 may benefit from radical prostatectomy, assuming a clinical stage of T1,T2, and particularly if their PSA level is <20 ng/mL. Authors from Palermo present data on the long-term outcome of antiandrogen monotherapy in advanced prostate cancer, with the 12-year results of a phase II study. This is a very interesting evaluation, showing that patients with an early objective response have a prolonged progression-free and overall survival. In a large series of superficial bladder tumours, urologists from Tokyo identify a group of patients with tumours of low malignant potential with a high recurrence rate, but a very low invasive property. They suggest that those tumours should be referred to as having a low malignant potential, rather than being called superficial bladder carcinoma. OBJECTIVE To determine the outcome and predictors of recurrence in patients with a pretreatment prostate biopsy Gleason score (GS) of ,,8 and treated with radical prostatectomy (RP). PATIENTS AND METHODS We retrospectively reviewed 1048 consecutive patients who underwent RP by one surgeon (M.S.S.); patients who had a pretreatment biopsy GS of ,,8 were identified. Information was recorded on patient age, initial prostate specific antigen (PSA) level, clinical stage, biopsy GS, pathology GS, extraprostatic extension (EPE), tumour volume, surgical margin status, seminal vesicle invasion (SVI), and lymph node involvement. The results were assessed statistically using the Kaplan-Meier method, univariate log-rank tests and multivariate analysis using Cox's proportional hazards regression. RESULTS In all, 123 patients met the initial selection criteria; 44 were excluded from further analyses (five salvage RP, 23 <,1 year follow-up and 16 adjuvant treatment). Thus 79 patients were included in the uni- and multivariate analyses; 25 (31%) patients had a GS of ,,7 in the RP specimen and 54 (69%) remained at GS ,,8. The mean follow-up was 55 months, the age of the patients 63 years and the mean (sd) initial PSA level 13 (12) ng/mL. The overall biochemical failure rate was 38% (41% if the final GS was , 8 and 32% if it was ,,7). For those with a GS of ,,8 in the RP specimen, 20% (11/54) were organ-confined; two patients (2.5%) in this group developed local recurrence. If the final GS was ,,7, 52% (13/25) were organ-confined. In the univariate analysis, significant risk factors for recurrence were PSA ,,20 ng/mL, EPE, SVI, a positive surgical margin and tumour volume. Cox's proportional regression indicated that a PSA of ,,20 ng/mL (hazard ratio 7.9, 95% confidence interval 2.6,24.2, P < 0.001), the presence of EPE (4.2, 1.6,10.9, P = 0.004) and a positive surgical margin (3.8, 1.5,9.7, P = 0.005) were significant independent predictors in a multivariate analysis. CONCLUSION RP is a reasonable treatment option for patients with a prostate biopsy GS of ,8 and clinical stage T1,2. These patients have a high chance of remaining disease-free if their PSA level is ,,20 ng/mL. Patients with a pretreatment biopsy GS of ,,8 should be counselled about the potential differences between the biopsy and the RP specimen GS. [source] Fluorodeoxyglucose positron emission tomography studies in the diagnosis and staging of clinically advanced prostate cancerBJU INTERNATIONAL, Issue 1 2003J. Sung OBJECTIVE To determine the value of 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography (PET) studies in evaluating patients with advanced prostate cancer. PATIENTS AND METHODS FDG-PET scans were taken in 30 patients with advanced prostate cancer 1 h after an injection with 555 MBq of FDG. Patients were scanned from the base of the skull to the inguinal region (including the pelvis). They were also assessed by computed tomography (CT) of the abdomen and pelvis, and bone scintigraphy, to evaluate them for metastases. RESULTS Thirteen patients had locally extensive prostate cancer and 17 had metastatic disease. Twenty of the 30 patients were positive for radioisotope uptake in the prostate or extraprostatically. The patients with PET-detected prostate cancer were untreated (seven), treated hormonally while they had rising PSA levels (eight), or treated hormonally with a detectable but stable PSA (five). The remaining 10 patients were negative for FDG uptake in the prostate or any metastatic sites; these 10 patients were receiving hormone therapy, with undetectable PSA levels. CONCLUSION FDG-PET imaging is not a useful test in evaluating advanced prostate cancer in patients being treated and who have an undetectable PSA level. Staging of advanced prostate cancer may be enhanced by FDG-PET imaging in patients who are untreated, who have had an incomplete response to therapy, or who have a rising PSA level despite treatment. [source] | ||||||||||||||||||||||||||||