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Hormone-refractory Prostate Cancer (hormone-refractory + prostate_cancer)
Selected AbstractsThe gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is amplified in late-stage prostate cancerGENES, CHROMOSOMES AND CANCER, Issue 7 2006Outi R. Saramäki Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) has been found in several malignancies, including prostate cancer, with an aggressive phenotype. Amplification of the gene has previously been demonstrated in several malignancies, but not in prostate cancer. Our goal was to evaluate the gene copy number and expression alterations of EZH2 in prostate cancer. The copy number of EZH2 in cell lines (LNCaP, DU145, PC-3, 22Rv1), xenografts (n = 10), and clinical tumors (n = 191) was studied with fluorescence in situ hybridization. All cell lines had a gain of EZH2. Eight of the ten xenografts showed an increased copy number of the gene, including one case of high-level amplification (,5 copies of the gene and EZH2/centromere ratio ,2). 34/125 (27%) of untreated prostate carcinomas showed increased copy number, but only one case of low-level amplification (,5 copies of the gene and EZH2/centromere ratio <2), whereas half (25/46) of the hormone-refractory carcinomas showed increased copy number, including seven cases of low-level amplification and three cases of high-level amplification (P < 0.0001). Expression of EZH2 was significantly (P = 0.0009) higher in hormone-refractory prostate cancer compared with that in benign prostatic hyperplasia or untreated cancer, according to quantitative real-time RT-PCR assay. Also, the expression of EZH2 protein was found to be higher in hormone-refractory tumors than in hormone-naïve tumors by immunohistochemistry. The EZH2 gene amplification was significantly (P < 0.05) associated with increased EZH2 protein expression. The data show that amplification of the EZH2 gene is rare in early prostate cancer, whereas a fraction of late-stage tumors contains the gene amplification leading to the overexpression of the gene, thus indicating the importance of EZH2 in the progression of prostate cancer. © 2006 Wiley-Liss, Inc. [source] ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2003Stanislav Zelivianski Abstract Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone-refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine- and docetaxel-induced cell growth suppression of androgen-independent prostate cancer cells. In androgen-independent C-81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl-2 by increasing phosphorylated Bcl-2 by more than 6-fold and Bax expression by 3-fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl-2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl-2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel-induced growth suppression in PC-3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone-refractory prostate cancer. © 2003 Wiley-Liss, Inc. [source] Safety and efficacy of docetaxel, estramustine phosphate and hydrocortisone in hormone-refractory prostate cancer patientsINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2010Yoshihiro Nakagami Objective: To assess the combination of docetaxel (DTX), estramustine phosphate (EMP) and hydrocortisone for patients with hormone-refractory prostate cancer (HRPC). Methods: A total of 63 patients with HRPC were treated with a chemotherapeutic regimen including DTX, EMP, and hydrocortisone. Clinical and pathological features were correlated to serum prostate-specific antigen (PSA) recurrence and survival rates. Incidence and degree of toxicities were also retrospectively reviewed. Results: A median of 11 courses of chemotherapy was administered per patient. PSA levels decreased by >50% in 32 (51%) patients and >90% in 18 (29%) patients. Median time to PSA progression was 6 months (range from 1 to 41 months) and median time of overall survival was 14 months (range from 1 to 56 months). In a univariate analysis to predict overall survival, PSA, hemoglobin, alkaliphosphatase, and performance status prior to the chemotherapy were significant factors. Despite grade 3,4 neutropenia in 87% of patients, grade 5 interstitial pneumonia in one patient and grade 4,5 myocardial infarction in two patients were recognized, the regimen seemed to be relatively safe. Conclusions: Combination chemotherapy with DTX, EMP and hydrocortisone provides survival benefits for patients with HRPC with an acceptable toxicity profile. We need to further evaluate who might benefit most from this regimen. [source] Association of circulating tumor cells with tumor-related methylated DNA in patients with hormone-refractory prostate cancerINTERNATIONAL JOURNAL OF UROLOGY, Issue 5 2010Takatsugu Okegawa Objectives: To assess whether circulating tumor cells with tumor-related methylated DNA can be used to predict survival in patients with hormone-refractory prostate cancer. Methods: Blood samples from 76 patients with hormone-refractory prostate cancer were analyzed. Circulating tumor cells were enumerated with the CellSearch System in whole blood. This system was developed using an epithelial cell adhesion molecule antibody-based immunomagnetic capture and automated staining methodology. Hypermethylation at adenomatosis polyposis coli, glutathione-S-transferase-,, prostaglandin-endoperoxide synthase 2, multidrug resistance 1 and Ras association domain family 1 isoform A was analyzed using a sensitive SYBR green methylation-specific polymerase chain reaction. Patient charts were retrospectively examined. Results: Median overall survival time was 19.3 months (range 11,48). Of the 76 patients, 47 (62%) had five or more circulating tumor cells, with a median overall survival of 12.0 months compared with 26.0 months for patients with fewer than five circulating tumor cells (P < 0.001). Circulating tumor cells were detected in 36 of 39 (92%) patients with tumor-related methylated DNA but only 11 of 37 (30%) patients without methylated DNA (P < 0.001). Thirty-nine (51%) patients had one or more methylated marker. Their median overall survival time was 12.0 months compared with 48.0 months or more for patients without methylated DNA (P < 0.001). Prostate-specific antigen-doubling time, circulating tumor cells and methylated DNA were independent predictors of overall survival time. Conclusions: Hormone refractory prostate cancer patients with circulating tumor cells and/or tumor-related methylated DNA show a significantly poorer outcome than those without these blood markers. [source] Oral estramustine phosphate and oral etoposide for the treatment of hormone-refractory prostate cancerINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2000Yoshiteru Sumiyoshi Abstract Background: The purpose of the present study was to evaluate the antitumor activity and toxicity of oral estramustine phosphate (EMP) in combination with oral etoposide in patients with hormone-refractory prostate cancer. Methods: Twenty patients with adenocarcinoma of the prostate that progressed after one or more regimens of androgen-deprivation therapy were enrolled into this trial. Oral EMP was administered twice daily, for a total daily dose of 560 mg, and oral etoposide (50 mg/bodyweight per day) was given on days 1,21 and was stopped on days 22,35. Treatment was continued until evidence of disease progression appeared or two consecutive rises in the prostate-specific antigen (PSA) value were observed. Results: Ten of 20 patients showed a decrease of 50% or greater in the PSA value from initially elevated PSA levels after therapy. The median progression-free duration and 2 year cause-specific survival rate of these 10 patients were 208 days (range 71,693 days) and 67.5%, respectively. There were no significant differences in age, pretreatment PSA value, duration from initial treatment to relapse, prior therapy or survival between patients who had a decrease of 50% or greater in PSA values after this combination therapy and those who did not. The main toxicities (, grade 2) were anemia, leukocytopenia, thrombocytopenia, gastrointestinal and hepatic disorders, which occurred in 40, 15, 10, 15 and 5% of patients, respectively. Conclusions: The combination of oral EMP and etoposide is considered to be a well-tolerated outpatient treatment regimen for patients with hormone-refractory prostate cancer and the therapy deserves further investigation. [source] MiR-34a attenuates paclitaxel-resistance of hormone-refractory prostate cancer PC3 cells through direct and indirect mechanismsTHE PROSTATE, Issue 14 2010Keitaro Kojima Abstract BACKGROUND Patients with hormone-refractory prostate cancer are treated with taxane drugs, but eventually become drug resistant. We aimed to elucidate the molecular mechanisms underlying paclitaxel resistance of hormone-refractory prostate cancer with a special focus on the roles of miR-34a and SIRT1. METHODS Paclitaxel-resistant cells (PC3PR) were generated from hormone-refractory PC3 cells. The expression levels of mRNA and miRNA were determined by reverse transcriptase PCR and those of protein were by Western blot analysis. Transfection of miRNA precursor or siRNA was performed using the liposome-mediated method. RESULTS MiR-34a over-expression and SIRT1 knockdown attenuated paclitaxel resistance of PC3PR cells. MiR-34a expression was reduced in PC3PR cells compared with PC3 cells, while the expression levels of HuR and Bcl2 as well as SIRT1 were elevated in PC3PR cells. Luciferase reporter assays revealed that both SIRT1 3,-UTR and promoter activities were higher in PC3PR cells than in PC3 cells. Introduction of miR-34a precursor into PC3PR cells resulted in decreases in HuR, Bcl2, and SIRT1 expression and inhibition of the SIRT1 3,-UTR activity. HuR knockdown reduced SIRT1 and Bcl2 expression. These results suggest that miR-34a not only directly but also indirectly via regulating HuR expression acts on the 3,-UTR of SIRT1 and Bcl2 mRNAs, thereby controlling their expression. Thus, in PC3PR cells, reduced expression of miR-34a confers paclitaxel resistance via up-regulating SIRT1 and Bcl2 expression. CONCLUSIONS MiR-34a and its downstream targets SIRT1 and Bcl2 play important roles in the development of paclitaxel resistance, all of which can be useful biomarkers and promising therapeutic targets for the drug resistance in hormone-refractory prostate cancer. Prostate 70: 1501,1512, 2010. © 2010 Wiley-Liss, Inc. [source] Docetaxel,ST1481 sequence exerts a potent cytotoxic activity on hormone-resistant prostate cancer cells by reducing drug resistance-related gene expressionTHE PROSTATE, Issue 2 2010Francesco Fabbri Abstract BACKGROUND The efficacy of current therapy for hormone-refractory prostate cancer is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different antitumor drug combinations in hormone-resistant prostate cancer (HRPC) cell lines. METHODS The activity of docetaxel (Doc), cisplatin (Cis), oxaliplatin (Oxa), SN-38 and ST1481, singly or in combination, was assessed in different HRPC cell lines (PC3, parental DU145 and taxane-resistant DU145-R) by SRB test. Apoptosis was evaluated by TUNEL and ANN-V assays. Extrusion pump activity was studied by Hoechst 33342 assay, while gene expression related to drug efflux mechanisms and DNA damage repair was analyzed by RT-PCR. RESULTS Doc induced a high cytocidal effect in the HRPC cells, whereas Cis, Oxa, SN-38 and ST1481 exerted prevalently cytostatic activity. Doc followed by ST1481 proved to be the most effective drug sequence among those investigated, producing an important synergistic effect (R.I. from 2.0 to 5.2) in all the tested cell lines. Moreover, this sequence induced a significant downregulation of xenobiotic extrusion pump and DNA damage repair gene expression. ST1481 synergistically increased the cytocidal effect of Doc, probably through a downregulation of extrusion pump activity and DNA damage repair-related genes. CONCLUSIONS Our results show that the Doc,,,ST1481 sequence effectively reduces the cancer cell population and restores Doc activity in taxane-resistant HRPC, indicating its potential usefulness as first- or second-line treatment of hormone-refractory prostate cancer. Prostate 70: 219,227, 2010. ©2009 Wiley-Liss, Inc. [source] Liposomal gemcitabine (GemLip),efficient drug against hormone-refractory Du145 and PC-3 prostate cancer xenograftsTHE PROSTATE, Issue 11 2009Peter Jantscheff Abstract BACKGROUND Gemcitabine (Gemc) is an efficient chemotherapeutic drug in various cancer types (e.g., pancreas) but has only limited effects on hormone-refractory prostate cancer (HRPCa). Since HRPCa cells are highly sensitive to even low doses of Gemc in vitro, the lack of clinical effects might be due to rapid degradation of Gemc by deaminases combined with impaired accumulation in tumor tissue and PCa cells. Liposomal formulation (GemLip) is expected to protect the entrapped cytotoxic substance from enzymatic degradation and furthermore augment its accumulation within tumor tissues due to an enhanced permeability of the tumor vessels. METHODS Anti-tumoral and anti-metastatic activity of GemLip and Gemc were investigated in two luciferase-expressing, human hormone-refractory PC-3 and Du145 HRPCa xenograft models in immunodeficient mice. Tumor growth was monitored by in vivo luminescence imaging (orthotopic) or callipering (subcutaneous). Anti-metastatic effects of treatment were determined by in vitro luciferase assay of the tissues. RESULTS Tumor growth of subcutaneous Du145 xenografts was significantly inhibited only by GemLip (8 mg/kg: P,=,0.014 and 6 mg/kg: P,=,0.011) but not by conventional Gemc (360 mg/kg). In contrast, growth of orthotopic PC-3 xenografts was significantly inhibited by both, GemLip (P,=,0.041) and Gemc (P,=,0.002). The drugs furthermore strongly reduced spleen and liver metastases in this model. CONCLUSIONS As shown by the very low efficient concentration of GemLip, liposomal entrapment of Gemc greatly enhances its activity. GemLip has, even at very low doses, a significant anti-tumoral and anti-metastatic therapeutic effect in HRPCa xenografts in vivo and was beneficial even when the conventional Gemc failed. Prostate 69:1151,1163, 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] Evaluation of the safety, pharmacokinetics and treatment effects of an ,,,3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer and bone metastasesASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 1 2010Mark A ROSENTHAL Abstract Aim: This study aimed to evaluate the safety, pharmacokinetics and treatment effects of an ,,,3 integrin inhibitor on bone turnover and disease activity in men with hormone-refractory prostate cancer (HRPC) and bone metastases. Methods: A total of 21 patients with bone metastases and HRPC were randomized to receive MK-0429 200 mg b.i.d. or 1600 mg b.i.d. for 4 weeks. Toxicity, pharmacokinetics and markers of bone turnover and tumor activity were examined. Results: Nausea was the most common adverse event: one (200-mg group) and 11 (1600-mg group) patients. At 4 weeks, mean AUC0,12 h was 210 mmol*h (200-mg group) and 673 mmol*h (1600-mg group); mean Cmax values were 42 mmol/L (200-mg group) and 154 mmol/L (1600-mg group). Urinary cross-linked N-telopeptides of type I collagen to creatinine ratio (uNTx), a bone turnover biomarker, showed a change from baseline of ,43.4 percent (200-mg group) and ,34.1 percent (1600-mg group). There was an increase in serum prostate specific antigen (PSA), a marker for disease activity, of 54.1 percent (200-mg group) and 44.5 percent (1600-mg group). Conclusion: MK-0429 was generally well tolerated, with the most common side-effect being nausea. There was some evidence of an early reduction of bone turnover, indicating a potential for clinical use in the treatment of MBD although serum PSA was unexpectedly increased during the study. [source] Effects of sphingosine-1-phosphate and sphingosylphosphorylcholine on intracellular Ca2+ and cell death in prostate cancer cell linesAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2007A. C. M. Mulders Summary The sphingolipid metabolites sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) can be involved in cellular growth and apoptosis, by both receptor-dependent and -independent mechanisms. We investigated the role of S1P and SPC in intracellular Ca2+ elevation, cell proliferation and cell death in DU 145 and PC3 hormone-refractory prostate cancer cell lines. S1P and SPC increased intracellular Ca2+ levels, most likely in a receptor-independent manner. Surprisingly, both S1P and SPC did not stimulate but rather reduced cell growth through induction of apoptosis. Therefore, antagonists targeted against S1P, SPC and their receptors do not appear to be promising new approaches in the treatment of hormone-refractory prostate cancer. [source] Characterization of calcium-independent purinergic receptor-mediated apoptosis in hormone-refractory prostate cancerBJU INTERNATIONAL, Issue 3 2008Majid Shabbir OBJECTIVE To investigate the nature of purinergic signalling in hormone-refractory prostate cancer (HRPC) cells in vitro, as extracellular ATP inhibits the growth of HRPC in vitro via the activation of P2 purinergic receptors, and to characterize which P2 receptors subtypes and secondary mechanisms are involved. MATERIALS AND METHODS The effect of extracellular ATP on HRPC cell lines PC-3 and DU-145, and the normal prostate cell line PNT-2, were investigated. Reverse-transcription polymerase chain reaction was used to assess P2 purinergic receptors, which were pharmacologically characterized using various receptor agonists and antagonists. The effect of ATP on intracellular Ca2+ concentration ([Ca2+]i) was examined to asses its role in growth inhibition. The effect of combining ATP with the chemotherapeutic drug mitoxantrone was also assessed. RESULTS PC-3 cells expressed mRNA for P2X4,5,7, P2Y1,2,4,6; DU-145 cells expressed mRNA for P2X4,5, P2Y1,2,4,6,11; PNT-2 cells expressed mRNA for P2X4,5,7 and P2Y1,2,4,6,11. ATP (10,4m) inhibited HRPC PC-3 cell growth by ,,90%, an effect partially inhibited by the nonselective P2 receptor antagonists pyridoxal-5,-phosphate-6-azophenyl-2,,4, disulphonic acid (PPADS) and suramin. The order of potency of agonists was: adenosine 5,-O-(3 thiotriphosphate) > ATP > benzoyl benzoyl ATP >> 2-methylthio ATP. DU-145 cells responded similarly. Pharmacological profiling implicated P2X5 and/or P2Y11 receptors in the antineoplastic response in HRPC. ATP induced apoptosis in a [Ca2+]i -independent mechanism. ATP was significantly less effective on PNT-2 cells, which also had a different order of agonist potency. ATP combined with mitoxantrone in an additive manner in HRPC. CONCLUSIONS ATP effectively reduces growth of HRPC cells via calcium-independent apoptosis. Pharmacological profiling indicates P2X5 and/or P2Y11 receptors in this process, with a different functional purinergic receptor profile and sensitivity in normal vs cancer cells. [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] A randomized study of docetaxel and dexamethasone with low- or high-dose estramustine for patients with advanced hormone-refractory prostate cancerBJU INTERNATIONAL, Issue 3 2006THOMAS NELIUS OBJECTIVE To test the combination of docetaxel with two different doses of estramustine in patients with hormone-refractory prostate cancer (HRPC), to improve response rates and to lower side-effects, as docetaxel-based chemotherapy is an increasing option for men with advanced HRPC, and alone or combined with estramustine, docetaxel improves median survival. PATIENTS AND METHODS In all, 72 patients with metastatic HRPC were randomly assigned to receive docetaxel (70 mg/m2 intravenously, on day 2 every 21 days) and estramustine (3 × 280 mg/day oral starting 1 day before docetaxel, for 5 consecutive days) for arm A, or estramustine (3 × 140 mg/day oral starting 1 day before docetaxel, for 3 consecutive days) for arm B. Premedication with oral dexamethasone at a total daily dose of 16 mg, in divided doses twice a day was administered in arm A on day 1,5 and in arm B on day 1,3. Initially, six cycles were administered. Chemotherapy was restarted after a significant increase in prostate-specific antigen (PSA) level. Patients were monitored for any measurable PSA response and toxicity. RESULTS Between the arms there was no statistically significant difference in time to progression and overall survival. However, treatment B had less treatment-related toxicity than A. Independent prognostic variables were baseline factors like PSA level, haemoglobin level, Eastern Cooperative Oncology Group performance status, and bone pain at presentation. CONCLUSIONS In this randomized phase II study the combination of docetaxel and estramustine had substantial activity in HRPC, with a significant incidence of severe toxicity, both haematological and not. Nevertheless, treatment-related toxicity was predictable and manageable. There was no better effect with a higher dose of estramustine with docetaxel than for a lower dose. There was a slight tendency to higher toxicity for high-dose estramustine but this was not statistically significant. The present results support the assertion that estramustine is not necessary in docetaxel-based treatment regimens. [source] The use of flutamide as a single antiandrogen treatment for hormone-refractory prostate cancerBJU INTERNATIONAL, Issue 4 2004D. Fawcett No abstract is available for this article. [source] PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancerBJU INTERNATIONAL, Issue 4 2000B.L. Pfeifer Objective To assess the effectiveness of PC-SPES, a dietary supplement containing eight herbal extracts, which is a popular alternative therapy among patients with hormone-refractory prostate cancer; anecdotal reports claim that this agent provides relief of metastatic pain, improvements in quality of life and reduction of prostatic specific antigen (PSA) level. Patients and methods Sixteen men treated for advanced metastatic prostate cancer (stage D3) with either orchidectomy or a luteinizing-hormone releasing hormone agonist, with or without anti-androgen, were enrolled into a prospective clinical trial to evaluate the possible toxic and beneficial effects of PC-SPES. After hormone-ablative therapy had failed, and with established disease progression, all patients received supplemental treatment with PC-SPES (2.88 g daily) for 5 months. Hormonal therapy was continued throughout the trial to avoid the known withdrawal effect of anti-androgen on PSA levels. Results The supplemental intake of PC-SPES was associated with significant (P < 0.05,0.01) improvements in quality-of-life measures, reductions in patient's pain ratings (P < 0.05,0.01), and a decline in PSA levels (P < 0.01), with no major side-effects. Conclusions These results support the anecdotal reports of the beneficial effects of PC-SPES as a comparable alternative to current management regimens in hormone-refractory prostate cancer. However, no conclusions can be drawn about the long-term effects of this new herbal therapy. [source] Phase 1/2 dose-escalation study of a GM-CSF-secreting, allogeneic, cellular immunotherapy for metastatic hormone-refractory prostate cancer,CANCER, Issue 5 2008Celestia S. Higano MD Abstract BACKGROUND This open-label, multicenter, dose-escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete granulocyte-macrophage-colony-stimulating factor (GM-CSF). METHODS Dose levels ranged from 100 × 106 cells q28d × 6 to 500 × 106 cells prime/300 × 106 cells boost q14d × 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, prostate-specific antigen (PSA) kinetics, and serum GM-CSF pharmacokinetics. RESULTS Eighty men, median age 69 years (range, 49-90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. PSA stabilization occurred in 15 (19%) patients, and a >50% decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43%) in the low-dose group, 13 of 18 (72%) in the mid-dose group, and 16 of 18 (89%) in the high-dose group (P = .002; Cochran-Armitage trend test). CONCLUSIONS This immunotherapy was well tolerated. Immunogenicity and overall survival varied by dose. Two phase 3 trials in patients with metastatic HRPC are underway. Cancer 2008. © 2008 American Cancer Society. [source] The risk of renal impairment in hormone-refractory prostate cancer patients with bone metastases treated with zoledronic acid,CANCER, Issue 6 2007William K. Oh MD Abstract BACKGROUND Bisphosphonates have been used to treat bone metastases in hormone-refractory prostate cancer (HRPC), but certain agents have been associated with renal toxicity. For this observational study, the authors assessed the risk of renal impairment in patients with HRPC who received zoledronic acid from December 1999 to April 2005. METHODS A comprehensive medical records review was performed in a major tertiary oncology center (n = 122 patients). The primary outcome of renal impairment was defined as an increase ,0.5 mg/dL or ,1.0 mg/dL over baseline creatinine value if the baseline value was <1.4 mg/dL or ,1.4 mg/dL, respectively. A risk factor analysis was conducted using the Andersen-Gill extension to the Cox proportional hazards model. RESULTS Renal impairment was observed in 23.8% of patients. The risk of renal impairment increased with an extended duration of zoledronic acid therapy (<6 months, 11.1%; ,24 months, 26.3%) and previous pamidronate treatment (45.5% vs 19.0% for patients with no prior pamidronate). A significantly greater risk of renal impairment was associated with increasing age at zoledronic acid initiation, prior pamidronate use, and a history of renal disease, hypertension, or smoking (P , 0.05). CONCLUSIONS In an outpatient clinic setting, the risk of renal impairment among patients with HRPC who received zoledronic acid was greater than the risk reported previously in clinical trials. Cancer 2007 © 2007 American Cancer Society. [source] | ||||||||||||||||||||||