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2.
Ann Oncol ; 31(9): 1186-1197, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32574722

RESUMO

BACKGROUND: A common polymorphism (1245A>C) in the HSD3B1 gene is associated with increased de novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy for metastatic castration-sensitive prostate cancer. The objective of the study was to determine whether this polymorphism is associated with outcomes for metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide. PATIENTS AND METHODS: A total of 547 patients treated with abiraterone or enzalutamide from two prospective cohorts were evaluated. The HSD3B1 genotype was determined by targeted sequencing and/or TaqMan single-nucleotide polymorphism genotyping. In cohort 1, patients were randomized to receive abiraterone + prednisone or enzalutamide. In cohort 2, patients received either agent according to investigator's choice. Prostate-specific antigen (PSA) response rate, time to PSA progression (TTPP), time to progression (TTP) and overall survival were determined. Associations between HSD3B1 genotypes and outcomes were evaluated via univariate Cox regression. Multivariable Cox model was used to determine the independent association of each covariate. RESULTS: The HSD3B1 variant genotype (CC) was present in 15% of patients and was associated with worse TTP [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.02-1.67, P = 0.032] and PSA response rates (48% for CC versus 62% and 65% for AA and AC, respectively [P = 0.019]), with no significant difference in TTPP (HR 1.28, 95% CI 0.99-1.66, P = 0.064). The effect of genotype was similar for treatment with abiraterone or enzalutamide with a negative test for interaction for TTPP (P = 0.997) and TTP (P = 0.749). Multivariable analysis did not show a significant association between genotype and TTP or TTPP. CONCLUSIONS: The HSD3B1 (CC) genotype was associated with shorter TTP and lower PSA response rate in patients with mCRPC treated with abiraterone or enzalutamide. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC.


Assuntos
Antagonistas de Androgênios , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Acetato de Abiraterona , Androstenos , Benzamidas , Células Germinativas , Humanos , Masculino , Complexos Multienzimáticos , Nitrilas , Feniltioidantoína/análogos & derivados , Estudos Prospectivos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Resultado do Tratamento
4.
Ann R Coll Surg Engl ; 100(2): 120-124, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29046095

RESUMO

Introduction Surgically inserted rectus sheath catheters (RSCs) are used increasingly for analgesia after cystectomy and other abdominal surgery. Currently, there is little information on the optimal positioning of RSCs to allow maximal spread of local anaesthetic. This study sought to assess the spread of dye injected via RSCs and to highlight the extent of its coverage in a fresh unembalmed cadaveric cystectomy model in order to confirm the nerve endings that are likely to be anaesthetised with RSCs. Methods Four cadavers underwent lower midline incision with limited bladder mobilisation. A RSC was inserted into the eight hemiabdomens. The RSCs were positioned either anterior (n=5) or posterior to the rectus muscle (n=3). Dye was injected down the RSCs to evaluate spread. The eight hemiabdomens were dissected anatomically to determine the surface area of dye spread and nerve root involvement. Results The mean surface area of dye spread with anteriorly placed RSCs was 30.6cm2 anterior and 25.9cm2 posterior to the rectus muscle. The mean surface area of dye spread with posteriorly placed RSCs was 11.3cm2 anterior and 37.3cm2 posterior to the rectus muscle. The mean number of nerve roots stained with anteriorly and posteriorly placed RSCs was 3.8 and 2.7 respectively. Subcutaneous spread of dye was seen with one anterior RSC insertion. Peritoneal spread was seen with one anteriorly positioned RSC. Conclusions This study has demonstrated efficient nerve root infiltration with anteriorly and posteriorly positioned RSCs. It appears that dye spreads between the fibres of the rectus muscle rather than out laterally to the nerve roots when spreading from its initial compartment.


Assuntos
Catéteres , Cistectomia/instrumentação , Cistectomia/métodos , Reto do Abdome/cirurgia , Idoso de 80 Anos ou mais , Cadáver , Corantes , Feminino , Humanos , Masculino , Modelos Biológicos
5.
Oncogene ; 36(24): 3417-3427, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28092670

RESUMO

Recent evidence has implicated the transmembrane co-receptor neuropilin-1 (NRP1) in cancer progression. Primarily known as a regulator of neuronal guidance and angiogenesis, NRP1 is also expressed in multiple human malignancies, where it promotes tumor angiogenesis. However, non-angiogenic roles of NRP1 in tumor progression remain poorly characterized. In this study, we define NRP1 as an androgen-repressed gene whose expression is elevated during the adaptation of prostate tumors to androgen-targeted therapies (ATTs), and subsequent progression to metastatic castration-resistant prostate cancer (mCRPC). Using short hairpin RNA (shRNA)-mediated suppression of NRP1, we demonstrate that NRP1 regulates the mesenchymal phenotype of mCRPC cell models and the invasive and metastatic dissemination of tumor cells in vivo. In patients, immunohistochemical staining of tissue microarrays and mRNA expression analyses revealed a positive association between NRP1 expression and increasing Gleason grade, pathological T score, positive lymph node status and primary therapy failure. Furthermore, multivariate analysis of several large clinical prostate cancer (PCa) cohorts identified NRP1 expression at radical prostatectomy as an independent prognostic biomarker of biochemical recurrence after radiation therapy, metastasis and cancer-specific mortality. This study identifies NRP1 for the first time as a novel androgen-suppressed gene upregulated during the adaptive response of prostate tumors to ATTs and a prognostic biomarker of clinical metastasis and lethal PCa.


Assuntos
Neuropilina-1/genética , Neuropilina-1/metabolismo , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias da Próstata/tratamento farmacológico , Regulação para Cima , Antagonistas de Androgênios/uso terapêutico , Linhagem Celular Tumoral , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Gradação de Tumores , Metástase Neoplásica , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Análise de Sobrevida
6.
Prostate Cancer Prostatic Dis ; 19(4): 390-394, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27431498

RESUMO

BACKGROUND: Obesity is a risk factor for incident prostate cancer (PC) as well as risk of disease progression and mortality. We hypothesized that men diagnosed with lower-risk PC and who elected active surveillance (AS) for their cancer management would likely initiate lifestyle changes that lead to weight loss. METHODS: Patients were enrolled in the Prostate Active Surveillance Study (PASS), a multicenter prospective biomarker discovery and validation study of men who have chosen AS for their PC. Data from 442 men diagnosed with PC within 1 year of study entry who completed a standard of care 12-month follow-up visit were analyzed. We examined the change in weight and body mass index (BMI) over the first year of study participation. RESULTS: After 1 year on AS, 7.5% (33/442) of patients had lost 5% or more of their on-study weight. The proportion of men who lost 5% or more weight was similar across categories of baseline BMI: normal/underweight (8%), overweight (6%) and obese (10%, χ2 test P=0.44). The results were similar for patients enrolled in the study 1 year or 6 months after diagnosis. By contrast, after 1 year, 7.7% (34/442) of patients had gained >5% of their weight. CONCLUSIONS: Only 7.5% of men with low-risk PC enrolled in AS lost a modest (⩾5%) amount of weight after diagnosis. Given that obesity is related to PC progression and mortality, targeted lifestyle interventions may be effective at this 'teachable moment', as men begin AS for low-risk PC.


Assuntos
Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Redução de Peso/fisiologia , Idoso , Índice de Massa Corporal , Peso Corporal/fisiologia , Progressão da Doença , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Estudos Prospectivos , Fatores de Risco
7.
Prostate Cancer Prostatic Dis ; 19(3): 264-70, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27136741

RESUMO

BACKGROUND: Expanding interest in and use of active surveillance for early state prostate cancer (PC) has increased need for prognostic biomarkers. Using a multi-institutional tissue microarray resource including over 1000 radical prostatectomy samples, we sought to correlate Ki67 expression captured by an automated image analysis system with clinicopathological features and validate its utility as a clinical grade test in predicting cancer-specific outcomes. METHODS: After immunostaining, the Ki67 proliferation index (PI) of tumor areas of each core (three cancer cores/case) was analyzed using a nuclear quantification algorithm (Aperio). We assessed whether Ki67 PI was associated with clinicopathological factors and recurrence-free survival (RFS) including biochemical recurrence, metastasis or PC death (7-year median follow-up). RESULTS: In 1004 PCs (∼4000 tissue cores) Ki67 PI showed significantly higher inter-tumor (0.68) than intra-tumor variation (0.39). Ki67 PI was associated with stage (P<0.0001), seminal vesicle invasion (SVI, P=0.02), extracapsular extension (ECE, P<0.0001) and Gleason score (GS, P<0.0001). Ki67 PI as a continuous variable significantly correlated with recurrence-free, overall and disease-specific survival by multivariable Cox proportional hazard model (hazards ratio (HR)=1.04-1.1, P=0.02-0.0008). High Ki67 score (defined as ⩾5%) was significantly associated with worse RFS (HR=1.47, P=0.0007) and worse overall survival (HR=2.03, P=0.03). CONCLUSIONS: In localized PC treated by radical prostatectomy, higher Ki67 PI assessed using a clinical grade automated algorithm is strongly associated with a higher GS, stage, SVI and ECE and greater probability of recurrence.


Assuntos
Antígeno Ki-67/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Proliferação de Células , Humanos , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Antígeno Prostático Específico , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Recidiva , Análise Serial de Tecidos
8.
Ann Oncol ; 27(6): 1116-1122, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27022067

RESUMO

BACKGROUND: Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. PATIENTS AND METHODS: Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. RESULTS: Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. CONCLUSIONS: Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. CLINICALTRIALSGOV ID: NCT00487786.


Assuntos
Diazepam/administração & dosagem , Proteínas de Choque Térmico HSP27/antagonistas & inibidores , Oligonucleotídeos Antissenso/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Diazepam/efeitos adversos , Diazepam/farmacocinética , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico , Humanos , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Oligonucleotídeos Antissenso/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia
9.
World J Urol ; 34(1): 41-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26621208

RESUMO

PURPOSE: The optimal extent of pelvic lymph node dissection (PLND) during radical cystectomy (RC) in patients with urothelial carcinoma of the bladder (UCB) is the subject of ongoing debate. In this study, we compared local recurrence-free and overall survival, in addition to complication rates, after extended PLND (ePLND) compared to standard PLND (sPLND). METHODS: We reviewed the charts of 314 patients who underwent RC for UCB between 2008 and 2013. ePLND was performed in 105 patients, and 105 matched patients who underwent standard PLND (sPLND) were selected based on clinical parameters. Local recurrence-free and overall survival rates were assessed using Kaplan-Meier survival analysis, and Cox proportional hazards models were used to assess potential determinants of these outcomes. Complications were assessed at 30 and 90 days using the Clavien-Dindo reporting system. RESULTS: More lymph nodes were removed by ePLND (median 21) compared to sPLND (median 9; P < 0.001), but the rate of nodal involvement was not different. In multivariable analysis, ePLND was associated with a better local recurrence-free survival (HR = 0.63, P = 0.005), but was not an independent predictor of overall survival (HR = 1.06, P = 0.84). Estimated blood loss was greater with ePLND (1047.3 vs. 584.5 ml P < 0.001), but there was no significant difference in complications. CONCLUSIONS: Extended PLND appears to reduce the risk of local recurrence, but was not an independent predictor of overall survival in this cohort. ePLND was associated with greater blood loss compared to sPLND, but not with other perioperative complications.


Assuntos
Carcinoma de Células de Transição/cirurgia , Cistectomia/métodos , Excisão de Linfonodo/métodos , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Perda Sanguínea Cirúrgica , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Estudos de Casos e Controles , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pelve , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
10.
Ann Oncol ; 26(8): 1589-604, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26041764

RESUMO

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.


Assuntos
Adenocarcinoma/terapia , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias da Próstata/terapia , Taxoides/uso terapêutico , Adenocarcinoma/patologia , Antineoplásicos/uso terapêutico , Docetaxel , Humanos , Masculino , Orquiectomia , Guias de Prática Clínica como Assunto , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/patologia , Radioterapia Adjuvante
11.
Clin Oncol (R Coll Radiol) ; 25(8): 506-13, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23660300

RESUMO

In the last decade, many systemic therapies have become available to improve survival in the setting of castration-resistant prostate cancer. Once effective treatments for advanced and incurable disease have been established, these agents are generally explored in the adjuvant and neoadjuvant settings to evaluate their role in increasing the chance of cure for localised disease. Clinical trials evaluating new therapies in high-risk prostate cancer can broadly be divided into two categories. Phase III (and some phase II) trials generally evaluate treatments that have already been shown to provide clinical benefit in the advanced disease setting; whereas smaller phase I (and some phase II) trials often serve as proof-of-principle assessments in the development of novel agents. The goal of this review is to provide an overview of present and ongoing clinical trials of both of these categories, evaluating the promise of systemic therapies in the setting of high-risk localised prostate cancer. We undertook a search of Ovid Medline, Embase and clinicaltrials.gov for prospective clinical studies assessing systemic therapy for early stage prostate cancer, either before or after definitive local treatment (surgery or radiation) from 2000 onwards. This resulted in 53 studies, of which 29 were deemed worthy of this overview and are presented herein, broadly divided by mechanism of action. Clearly, the arena evaluating the future of systemic therapies for localised prostate cancer will be a very active one.


Assuntos
Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias da Próstata/terapia , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Humanos , Masculino , Terapia Neoadjuvante/métodos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/cirurgia
12.
Prostate Cancer Prostatic Dis ; 16(3): 239-47, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23689346

RESUMO

BACKGROUND: Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth. METHODS: The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (lit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN-/-) mice. How suppressed GH/IGF-I levels impacted growth of PTEN-/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum. RESULTS: Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN-/- littermates. While the anterior lobes of lit/+ PTEN-/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20-week-old lit/lit and lit/+ PTEN-/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N-cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH. CONCLUSIONS: These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed.


Assuntos
Arrestinas/genética , Arrestinas/metabolismo , Hormônio do Crescimento/deficiência , Fator de Crescimento Insulin-Like I/deficiência , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Hiperplasia Prostática/metabolismo , Proteína de Ligação a Androgênios/genética , Proteína de Ligação a Androgênios/metabolismo , Animais , Peso Corporal/genética , Caderinas/genética , Caderinas/metabolismo , Transição Epitelial-Mesenquimal/genética , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PTEN Fosfo-Hidrolase/deficiência , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Secretadas pela Próstata/genética , Proteínas Secretadas pela Próstata/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas , Vimentina/genética , Vimentina/metabolismo , beta-Arrestinas
13.
Oncogene ; 32(15): 1933-42, 2013 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-22689054

RESUMO

Expression of clusterin (CLU) closely correlates with the regulation of apoptosis in cancer. Although endoplasmic reticulum (ER) stress-induced upregulation and retrotranslocation of cytoplasmic CLU (presecretory (psCLU) and secreted (sCLU) forms) has been linked to its anti-apoptotic properties, mechanisms mediating these processes remain undefined. Here, we show using human prostate cancer cells that GRP78 (Bip) associates with CLU under ER stress conditions to facilitate its retrotranslocation and redistribution to the mitochondria. Many ER stress inducers, including thapsigargin, MG132 or paclitaxel, increased expression levels of GRP78 and CLU, as well as post-translationally modified hypoglycosylated CLU forms. ER stress increased association between GRP78 and CLU, which led to increased cytoplasmic CLU levels, while reducing sCLU levels secreted into the culture media. GRP78 stabilized CLU protein and its hypoglycosylated forms, in particular after paclitaxel treatment. Moreover, subcellular fractionation and confocal microscopy with CLUGFP indicated that GRP78 increased stress-induced CLU retrotranslocation from the ER with co-localized redistribution to the mitochondria, thereby reducing stress-induced apoptosis by cooperatively stabilizing mitochondrial membrane integrity. GRP78 silencing reduced CLU protein, but not mRNA levels, and enhanced paclitaxel-induced cell apoptosis. Taken together, these findings reveal novel dynamic interactions between GRP78 and CLU under ER stress conditions that govern CLU trafficking and redistribution to the mitochondria, elucidating how GRP78 and CLU cooperatively promote survival during treatment stress in prostate cancer.


Assuntos
Clusterina/metabolismo , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico/metabolismo , Mitocôndrias/metabolismo , Neoplasias da Próstata/metabolismo , Apoptose , Linhagem Celular Tumoral , Clusterina/genética , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/genética , Humanos , Leupeptinas/farmacologia , Masculino , Potencial da Membrana Mitocondrial , Membranas Mitocondriais/metabolismo , Paclitaxel/farmacologia , Transporte Proteico , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Interferente Pequeno , Tapsigargina/farmacologia , Regulação para Cima
14.
Br J Cancer ; 107(9): 1467-73, 2012 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-23037714

RESUMO

BACKGROUND: The controversies concerning possible overtreatment of prostate cancer, highlighted by debate over PSA screening, have highlighted active surveillance (AS) as an alternative management option for appropriate men. Regional differences in the underlying prevalence of PSA testing may alter the pre-test probability for high-risk disease, which can potentially interfere with the performance of selection criteria for AS. In a multicentre study from three different countries, we examine men who were initially suitable for AS according to the Toronto and Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, that underwent radical prostatectomy (RP) in regards to:1.the proportion of pathological reclassification(Gleason score ≥7, ≥pT3 disease),2.predictors of high-risk disease,3.create a predictive model to assist with selection of men suitable for AS. METHODS: From three centres in the United Kingdom, Canada and Australia, data on men who underwent RP were retrospectively reviewed (n=2329). Multivariable logistic regression was performed to identify predictors of high-risk disease. A nomogram was generated by logistic regression analysis, and performance characterised by receiver operating characteristic curves. RESULTS: For men suitable for AS according to the Toronto (n=800) and PRIAS (410) criteria, the rates for upgrading were 50.6, 42.7%, and upstaging 17.6, 12.4%, respectively. Significant predictors of high-risk disease were:•Toronto criteria: increasing age, cT2 disease, centre of diagnosis and number of positive cores.•PRIAS criteria: increasing PSA and cT2 disease.Cambridge had a high pT3a rate (26 vs 12%). To assist selection of men in the United Kingdom for AS, from the Cambridge data, we generated a nomogram predicting high-risk features in patients who meet the Toronto criteria (AUC of 0.72). CONCLUSION: The proportion of pathological reclassification in our cohort was higher than previously reported. Care must be used when applying the AS criteria generated from one population to another. With more stringent selection criteria, there is less reclassification but also fewer men who may benefit from AS.


Assuntos
Prostatectomia/métodos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/cirurgia , Idoso , Detecção Precoce de Câncer/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Nomogramas , Estudos Prospectivos , Antígeno Prostático Específico/análise , Neoplasias da Próstata/patologia , Estudos Retrospectivos , Fatores de Risco
15.
Br J Cancer ; 106(12): 1945-52, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22588555

RESUMO

BACKGROUND: The objective of this study was to investigate whether the therapeutic activity of sorafenib could be enhanced by combining with OGX-011, an antisense oligodeoxynucleotide (ODN) targeting clusterin, in renal cell carcinoma (RCC). METHODS: We investigated the effects of combined treatment with OGX-011 and sorafenib on a human RCC ACHN model both in vitro and in vivo. RESULTS: Although clusterin expression was increased by sorafenib, additional treatment of ACHN with OGX-011 significantly blocked the upregulation of clusterin induced by sorafenib. Despite the lack of a significant effect on the growth of ACHN, OGX-011 synergistically enhanced the sensitivity to sorafenib, reducing the IC(50) by >50%. Apoptotic changes were intensively detected in ACHN after combined treatment with OGX-011 and a sublethal dose of sorafenib, but not either agent alone. Furthermore, this combined treatment resulted in the marked downregulation of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN compared with treatment with either agent alone. In vivo systemic administration of OGX-011 plus sorafenib significantly decreased the ACHN tumour volume compared with control ODN plus sorafenib. CONCLUSION: Combined use with OGX-011 may be useful in enhancing the cytotoxic effect of sorafenib on RCC by inducing apoptosis and inactivating major signal transduction pathways.


Assuntos
Benzenossulfonatos/farmacologia , Carcinoma de Células Renais/tratamento farmacológico , Clusterina/antagonistas & inibidores , Neoplasias Renais/tratamento farmacológico , Piridinas/farmacologia , Tionucleotídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Clusterina/metabolismo , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , Niacinamida/análogos & derivados , Oligonucleotídeos Antissenso/farmacologia , Compostos de Fenilureia , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Sorafenibe , Tionucleotídeos/administração & dosagem , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cell Death Differ ; 19(6): 990-1002, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22179576

RESUMO

Heat shock protein 27 (Hsp27) is emerging as a promising therapeutic target for treatment of various cancers. Although the role of Hsp27 in protection from stress-induced intrinsic cell death has been relatively well studied, its role in Fas (death domain containing member of the tumor necrosis factor receptor superfamily)-induced apoptosis and cell proliferation remains underappreciated. Here, we show that Hsp27 silencing induces dual coordinated effects, resulting in inhibition of cell proliferation and sensitization of cells to Fas-induced apoptosis through regulation of PEA-15 (15-kDa phospho-enriched protein in astrocytes). We demonstrate that Hsp27 silencing suppresses proliferation by causing PEA-15 to bind and sequester extracellular signal-regulated kinase (ERK), resulting in reduced translocation of ERK to the nucleus. Concurrently, Hsp27 silencing promotes Fas-induced apoptosis by inducing PEA-15 to release Fas-associating protein with a novel death domain (FADD), thus allowing FADD to participate in death receptor signaling. Conversely, Hsp27 overexpression promotes cell proliferation and suppresses Fas-induced apoptosis. Furthermore, we show that Hsp27 regulation of PEA-15 activity occurs in an Akt-dependent manner. Significantly, Hsp27 silencing in a panel of phosphatase and tensin homolog on chromosome 10 (PTEN) wild-type or null cell lines, and in LNCaP cells that inducibly express PTEN, resulted in selective growth inhibition of PTEN-deficient cancer cells. These data identify a dual coordinated role of Hsp27 in cell proliferation and Fas-induced apoptosis via Akt and PEA-15, and indicate that improved clinical responses to Hsp27-targeted therapy may be achieved by stratifying patient populations based on tumor PTEN expression.


Assuntos
Apoptose , Proliferação de Células , Proteínas de Choque Térmico HSP27/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfoproteínas/metabolismo , Receptor fas/metabolismo , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína de Domínio de Morte Associada a Fas/metabolismo , Proteínas de Choque Térmico HSP27/antagonistas & inibidores , Proteínas de Choque Térmico HSP27/genética , Humanos , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
17.
Curr Oncol ; 17 Suppl 2: S33-7, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20882130

RESUMO

Widespread use of testing for prostate-specific antigen (PSA) has led to a migration in the stage and grade of prostate cancer (PCa), with most men presenting with localized disease. However, 20%-35% of patients still present with high-risk disease (PSA > 20 ng/mL, biopsy Gleason score 8-10, or clinical stage T3). Despite advances in various treatment modalities, patients with high-risk disease have a significant chance of recurrence and death after surgery, often because of the presence of early occult metastasis at time of diagnosis. The optimal management of high-risk pca remains controversial. The present article aims to discuss the traditional approaches and the more recent evolution toward multimodal therapies.

18.
Br J Cancer ; 101(10): 1731-9, 2009 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-19844233

RESUMO

BACKGROUND: The objective of this study was to investigate the effects of interleukin-6 (IL-6) overexpression in androgen-dependent prostate cancer LNCaP cells on their phenotype under an androgen-deprived condition. METHODS: We established IL-6-overexpressing LNCaP (LNCaP/IL-6) by introducing the expression vector containing IL-6 cDNA. Changes in the phenotype in LNCaP/IL-6 were compared with that in LNCaP transfected with control vector alone (LNCaP/Co). RESULTS: In vitro, the growth of LNCaP/IL-6 was significantly inferior to that of LNCaP/Co under an androgen-deprived condition. Similarly, LNCaP/IL-6 tumour in nude mice rapidly regressed after castration; however, LNCaP/Co tumour growth was transiently inhibited after castration and then continuously accelerated. After androgen withdrawal, expression levels of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and Akt in LNCaP/IL-6 were markedly upregulated compared with those in LNCaP/Co; however, additional treatment with specific inhibitor of the MAPK or Akt signalling pathway significantly inhibited the growth of LNCaP/IL-6 compared with that of LNCaP/Co. Furthermore, gene microarray analyses showed that androgen deprivation resulted in differential expression of genes involved in growth, apoptotsis and tumorigenesis between LNCaP/Co and LNCaP/IL-6. CONCLUSION: Excessive secretion of IL-6 by LNCaP cells in an autocrine manner may have a suppressive function in their growth and acquisition of androgen-independent phenotype under an androgen-deprived condition.


Assuntos
Androgênios/deficiência , Interleucina-6/biossíntese , Neoplasias da Próstata/metabolismo , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucina-6/genética , Interleucina-6/farmacologia , Masculino , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Hormônio-Dependentes , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Antígeno Prostático Específico/biossíntese , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transfecção
19.
Urologe A ; 47(9): 1145-51, 2008 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-18670747

RESUMO

Patients with high-risk bladder cancer who do not respond to bacillus Calmette-Guerin (BCG) immunotherapy represent a significant therapeutic challenge. The addition of interferon to BCG has recently evolved as a second-line treatment option; however, many high-grade tumors are nonresponsive to interferon. Thus, replication-competent oncolytic vesicular stomatitis viruses (VSV) that selectively target interferon-refractory tumors are promising intravesical agents. In vitro, wild-type VSV as well as a mutant variant (AV3) that has an impaired ability to shut down innate immunity preferentially killed undifferentiated, interferon-nonresponsive bladder cancer cells. Testing of these viruses in an orthotopic murine model of high-grade bladder cancer, which we have recently validated, revealed that both AV3 and wild-type VSV significantly inhibited orthotopic tumor growth. Despite the use of immunocompromised nude mice, there was no evidence of toxicity. In conclusion, VSV instillation therapy demonstrated strong antitumor activity and safety in an orthotopic model of high-risk disease. These findings provide preclinical proof-of-principle for the intravesical use of VSV, especially in interferon-refractory patients.


Assuntos
Carcinoma de Células de Transição/terapia , Terapia Viral Oncolítica/métodos , Vírus da Estomatite Vesicular Indiana/genética , Administração Intravesical , Animais , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/patologia , Linhagem Celular Tumoral , Luciferina de Vaga-Lumes , Humanos , Interferons/metabolismo , Camundongos , Camundongos Nus , Mutação/genética , Invasividade Neoplásica , Transplante de Neoplasias , Carga Tumoral , Bexiga Urinária/imunologia , Bexiga Urinária/patologia , Vírus da Estomatite Vesicular Indiana/imunologia , Replicação Viral
20.
Urologe A ; 46(5): 516-20, 2007 May.
Artigo em Alemão | MEDLINE | ID: mdl-17372715

RESUMO

Therapeutic resistance is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress proteins, including heat shock proteins and clusterin. These molecular chaperones interact with various client proteins to assist in their folding and enhance cellular recovery from stress conditions. Cellular stress and cell death are linked, as the induction of chaperones appear to function at key regulatory points in the control of apoptosis. On this basis and on the role of stress proteins in the regulation of steroid receptors, kinases, caspases, and other protein remodeling events, it is not surprising that molecular chaperones have been implicated in resistance to anticancer treatments. Recently, several chaperones have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the events initiated by treatment-induced stress and discuss the potential role of chaperone inhibitors in prostate cancer treatment.


Assuntos
Proteínas de Choque Térmico/fisiologia , Neoplasias da Próstata/fisiopatologia , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Apoptose/fisiologia , Chaperoninas/antagonistas & inibidores , Chaperoninas/fisiologia , Clusterina/antagonistas & inibidores , Clusterina/fisiologia , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas de Choque Térmico/antagonistas & inibidores , Humanos , Masculino , Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico
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