RESUMEN
Histone lysine demethylase 4 (KDM4) is an epigenetic regulator that facilitates the transition between transcriptionally silent and active chromatin states by catalyzing the removal of methyl groups on histones H3K9, H3K36, and H1.4K26. KDM4 overamplification or dysregulation has been reported in various cancers and has been shown to drive key processes linked to tumorigenesis, such as replicative immortality, evasion of apoptosis, metastasis, DNA repair deficiency, and genomic instability. KDM4 also plays a role in epigenetic regulation of cancer stem cell renewal and has been linked to more aggressive disease and poorer clinical outcomes. The KDM4 family is composed of four main isoforms (KDM4A-D) that demonstrate functional redundancy and cross-activity; thus, selective inhibition of one isoform appears to be ineffective and pan-inhibition targeting multiple KDM4 isoforms is required. Here, we describe TACH101, a novel, small-molecule pan-inhibitor of KDM4 that selectively targets KDM4A-D with no effect on other KDM families. TACH101 demonstrated potent antiproliferative activity in cancer cell lines and organoid models derived from various histologies, including colorectal, esophageal, gastric, breast, pancreatic, and hematological malignancies. In vivo , potent inhibition of KDM4 led to efficient tumor growth inhibition and regression in several xenograft models. A reduction in the population of tumor-initiating cells was observed following TACH101 treatment. Overall, these observations demonstrate the broad applicability of TACH101 as a potential anticancer agent and support its advancement into clinical trials.
Asunto(s)
Histona Demetilasas , Neoplasias , Humanos , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/uso terapéutico , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Epigénesis Genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapéuticoRESUMEN
BACKGROUND: EPI-506 is the first of a new class of drugs targeting the N-terminal domain (NTD) of the androgen receptor (AR), potentially overcoming known resistance mechanisms to androgen receptor pathway inhibitors (ARPIs) among men with metastatic castration resistant prostate cancer (mCRPC). METHODS: Patients with mCRPC who had progressed on prior ARPI were enrolled in this phase 1 open-label, adaptive 3 + 3 dose escalation study. The primary outcome was safety and tolerability of oral EPI-506. Secondary objectives included determination of the maximal tolerated dose (MTD), pharmacokinetic profile, and antitumor efficacy. RESULTS: 28 mCRPC patients were enrolled into 7 dose cohorts of EPI-506 ranging from 80-3600 mg given once daily and 1800 mg given twice daily. Six DLTs occurred in 4 patients; Grade 4 elevated amylase; Grade 3 abdominal pain; Grade 3 elevated ALT and Grade 3 elevated AST; Grade 2 nausea and Grade 1 vomiting which resulted in study drug intake of < 75% of the expected dose during the DLT assessment period. The most common drug-related adverse events included diarrhea, nausea and fatigue. Six patients had a PSA decline not meeting PSA response criteria. The study was terminated prior to reaching the MTD due to poor oral bioavailability. CONCLUSIONS: This phase 1 trial established the safety of EPI-506 and provides proof of concept for targeting the AR NTD. Next generation compounds with improved bioavailability and potency are in clinical development.
Asunto(s)
Antagonistas de Receptores Androgénicos , Compuestos de Bencidrilo , Clorhidrinas , Neoplasias de la Próstata Resistentes a la Castración , Antagonistas de Receptores Androgénicos/efectos adversos , Compuestos de Bencidrilo/efectos adversos , Clorhidrinas/efectos adversos , Humanos , Masculino , Náusea/inducido químicamente , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos , Resultado del TratamientoRESUMEN
BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Administración Oral , Antagonistas de Receptores Androgénicos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Benzamidas , Progresión de la Enfermedad , Método Doble Ciego , Humanos , Masculino , Metástasis de la Neoplasia/diagnóstico por imagen , Nitrilos , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Radiografía , Receptores Androgénicos , Análisis de SupervivenciaRESUMEN
: Despite the recent approval and widespread use of abiraterone acetate and enzalutamide for the treatment of castration-resistant prostate cancer (CRPC), this disease still poses significant management challenges because of various tumor escape mechanisms, including those that allow androgen receptor (AR) signaling to remain active. These AR-related resistance mechanisms include AR gene amplification or overexpression, constitutively active ligand-independent AR splice variants, and gain-of-function mutations involving the AR ligand-binding domain (LBD), among others. Therefore, the development of AR-targeted therapies that function independently of the LBD represents an unmet medical need and has the potential to overcome many of these resistance mechanisms. This article discusses N-terminal domain (NTD) inhibition as a novel concept in the field of AR-directed therapies for prostate cancer. AR NTD-targeting agents have the potential to overcome shortcomings of current hormonal therapies by inhibiting all forms of AR-mediated transcriptional activity, and as a result, may affect a broader AR population including mutational and splice variant ARs. Indeed, the first clinical trial of an AR NTD inhibitor is now underway. IMPLICATIONS FOR PRACTICE: Because of emerging resistance mechanisms that involve the ligand-binding domain of the androgen receptor (AR), there is currently no effective treatment addressing tumor escape mechanisms related to current AR-targeted therapies. Many patients still demonstrate limited clinical response to current hormonal agents, and castration-resistant prostate cancer remains a lethal disease. Intense research efforts are under way to develop therapies to target resistance mechanisms, including those directed at other parts of the AR molecule. A novel small-molecule agent, EPI-506, represents a new pharmaceutical class, AR N-terminal domain inhibitors, and shows preclinical promise to overcome many known resistance mechanisms related to novel hormonal therapies.
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Antagonistas de Andrógenos/uso terapéutico , Compuestos de Bencidrilo/uso terapéutico , Clorhidrinas/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/química , Humanos , Masculino , Dominios Proteicos , Receptores Androgénicos/fisiología , Estudios Retrospectivos , Transducción de Señal , Esteroide 17-alfa-Hidroxilasa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. METHODS: In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. FINDINGS: Median treatment duration was 16·6 months (IQR 10·1-21·1) in the enzalutamide group and 4·6 months (2·8-9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1-13·9) in the enzalutamide group and 5·6 months (5·5-5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54-0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6-5·7) in the enzalutamide group and 5·6 months (5·4-5·6) in the placebo group (HR 0·62 [95% CI 0·53-0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5-not reached) and 31·3 months (95% CI 23·9-not reached) in the placebo group (HR 0·72 [95% CI 0·61-0·84]; p<0·0001). INTERPRETATION: In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer. FUNDING: Astellas Pharma and Medivation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Dolor/tratamiento farmacológico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Supervivencia sin Enfermedad , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Nitrilos , Dolor/patología , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/patología , Calidad de VidaRESUMEN
BACKGROUND: The open-label, single-arm enzalutamide expanded access program (EAP) in the United States and Canada evaluated the safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received docetaxel. METHODS: Patients (n = 507) received enzalutamide 160 mg/day until disease progression, intolerable adverse events (AEs), or commercial availability occurred. AEs and other safety variables were assessed on day 1, weeks 4 and 12, and every 12 weeks thereafter. Data following transition to commercial drug were not collected. RESULTS: Median age was 71 years (range 43-97); 426 patients (83.9%) had a baseline ECOG score of ≤1. In addition to docetaxel, the majority of patients had received prior prostate cancer treatments such as abiraterone (76.1%) or cabazitaxel (28.6%). Median study treatment duration was 2.6 months (range 0.03-9.07). The most frequently reported reasons for discontinuation were commercial availability of enzalutamide (46.7%) and progressive disease (33.7%). A total of 88.2% of patients experienced AEs; 45.4% experienced AEs with a maximum grade of 1 or 2. Fatigue (39.1%), nausea (22.7%), and anorexia (14.8%) were the most commonly reported AEs. Seizure was reported in four patients (0.8%). The most commonly reported event leading to death was progression of metastatic prostate cancer (7.7%). CONCLUSION: In this heavily pretreated EAP population with progressive mCRPC, enzalutamide was well tolerated and the safety profile was consistent with that of the AFFIRM trial.
Asunto(s)
Antineoplásicos/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/epidemiología , Taxoides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Benzamidas , Docetaxel , Resistencia a Antineoplásicos/efectos de los fármacos , Fatiga/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Nitrilos , América del Norte/epidemiología , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. METHODS: This trial is an ongoing open-label, single-arm, phase 2 study, done across 12 European sites. Men aged over 18 years, with hormone-naive prostate cancer for whom hormone therapy was indicated, and who had non-castration levels of testosterone and prostate-specific antigen (PSA) of 2 ng/mL or greater at screening, and an Eastern Cooperative Oncology Group score of 0, received oral enzalutamide 160 mg/day. The primary outcome was the proportion of patients with an 80% or greater decline in PSA at week 25. All analyses included all patients who had received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT01302041. FINDINGS: 67 men were enrolled into the study. 62 patients (92.5%, 95% CI 86.2-98.8) had a decline in PSA of 80% or greater at week 25. The most commonly reported treatment-emergent adverse events up to week 25 were gynaecomastia (n=24), fatigue (n=23), nipple pain (n=13), and hot flush (n=12), all of which were of mild to moderate severity. Nine patients had a treatment-emergent adverse event of grade 3 or higher, most of which were reported in one patient each, except for pneumonia (grade 3, two patients) and hypertension (grade 3, four patients). Five patients reported serious adverse events, none of which were deemed to be treatment related. INTERPRETATION: Our findings suggest that enzalutamide monotherapy in men with hormone-naive prostate cancer of varying severity provides a level of disease suppression, and was generally well tolerated. These findings provide a rationale for further investigation of clinical response and outcomes with enzalutamide in non-castrate men with prostate cancer.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/sangre , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Benzamidas , Humanos , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Resultado del TratamientoRESUMEN
PURPOSE: Increased levels of cell-free circulating DNA have been described in various malignancies as a diagnostic and prognostic biomarker. We analyzed the significance of cell-free DNA in patients with testicular cancer. MATERIALS AND METHODS: Cell-free DNA was isolated from the serum of 74 patients with testicular cancer, including 39 with seminoma and 35 with nonseminoma, and 35 healthy individuals. Real-time polymerase chain reaction was used to quantify a 106, a 193 and a 384 actin-beta DNA fragment. DNA integrity is expressed as the ratio of large (193 or 384 bp) to short (106 bp) DNA fragments. RESULTS: Actin-beta-106/193/384 fragment levels were significantly increased in patients with cancer compared to those in healthy individuals (each p <0.001). DNA integrity was significantly decreased in patients with cancer (p <0.001). Cell-free DNA fragment levels were not different when comparing patients with nonseminoma and seminoma (p >0.24). ROC analysis demonstrated that cell-free DNA levels distinguished patients with cancer from healthy individuals with 87% sensitivity and 97% specificity. Even in 31 patients in whom the established serum tumor markers alpha-fetoprotein, human chorionic gonadotropin, placental alkaline phosphatase and lactate dehydrogenase were normal cell-free DNA levels allowed us to distinguish between patients with cancer and healthy individuals with 84% sensitivity and 97% specificity. Cell-free DNA levels were more frequently increased in patients with clinical stage 3 than in patients with stage 1 or 2 disease (p <0.046). CONCLUSIONS: Cell-free DNA levels are increased in patients with testicular cancer and they allow the accurate discrimination of healthy individuals. The high sensitivity of cell-free DNA could facilitate the management of testicular cancer, especially in patients with conventional tumor markers that are not increased.
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ADN/sangre , Neoplasias de Células Germinales y Embrionarias/sangre , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias Testiculares/sangre , Neoplasias Testiculares/diagnóstico , Adolescente , Adulto , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: DNA hypermethylation is a common cancer associated alteration. We analyzed methylation patterns of cell-free serum DNA in patients with testicular cancer. MATERIALS AND METHODS: Hypermethylation at APC, GSTP1, PTGS2, p14(ARF), p16(INK) and RASSF1A was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment in 73 patients with testicular cancer and 35 healthy individuals. RESULTS: Hypermethylation was more common in patients with testicular cancer than in healthy individuals, including APC 57% and 6%, p16(INK) 53% and 17%, p14(ARF) 53% and 0%, RASSF1A 47% and 0%, PTGS2 45% and 0%, and GSTP1 25% and 0%, respectively (each p <0.01). Methylation frequencies at the investigated gene sites were similar in nonseminoma and seminoma cases (p >0.05). Diagnostic information was increased when multiple gene sites were analyzed in combination (ROC AUC 0.834, 67% sensitivity and 97% specificity). Diagnostic information was superior to the analysis of AFP/HCG/PLAP/LDH (combined sensitivity 58% and AUC 0.791). The sensitivity of hypermethylation in patients with unsuspicious conventional tumor markers was 71% (AUC 0.871, 97% specificity). Hypermethylation at PTGS2 was more common in patients with pT1 stage tumors (p = 0.011). CONCLUSIONS: The detection of hypermethylated cell-free serum DNA has the potential of a useful additional diagnostic parameter in patients with testicular germ cell cancer. Furthermore, in cases without conventional tumor marker increases testing CpG island hypermethylation in cell-free circulation DNA may improve the ability to detect early and/or recurrent testicular cancer.
Asunto(s)
Biomarcadores de Tumor/sangre , Islas de CpG/genética , Metilación de ADN/genética , Neoplasias de Células Germinales y Embrionarias/sangre , Neoplasias Testiculares/sangre , Adolescente , Adulto , Biomarcadores de Tumor/genética , Biopsia con Aguja , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , ADN/sangre , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/cirugía , Orquiectomía/métodos , Probabilidad , Pronóstico , Curva ROC , Valores de Referencia , Sensibilidad y Especificidad , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Adulto JovenRESUMEN
PURPOSE: CpG island hypermethylation is a frequent event in bladder carcinogenesis and progression. We investigated the diagnostic and prognostic value of hypermethylation in cell-free serum DNA of patients with bladder cancer. MATERIALS AND METHODS: The study cohort consisted of 45 patients with bladder cancer undergoing cystectomy and 45 with histologically confirmed benign prostatic hyperplasia serving as controls. Hypermethylation at APC, DAPK, GSTP1, PTGS2, TIG1 and Reprimo was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment. RESULTS: Hypermethylation at the APC and GSTP1 promoter was detected in 59% of cases, whereas TIG1 (32%), PTGS2 (24%) and DAPK (2%) were less frequently hypermethylated. In the benign prostatic hyperplasia group 3 patients also harbored methylated GSTP1 DNA, whereas none of the other gene sites was methylated. Hypermethylation at APC, GSTP1 or TIG1 distinguished patients with bladder cancer and controls most accurately with 80% sensitivity and 93% specificity. Hypermethylation significantly correlated with prognostic unfavorable clinicopathological parameters, including APC with pT stage, GSTP1, or GSTP1 or TIG1 with multifocal bladder cancer and APC, or APC or TIG1 with surgical margin positivity. Bladder cancer specific mortality was significantly increased in patients with APC hypermethylation. CONCLUSIONS: The detection of hypermethylation in cell-free serum DNA provides valuable diagnostic and prognostic information that can still be improved by combining the results of 3 gene sites (APC, GSTP1 and TIG1). The presence of hypermethylated DNA in the serum of patients with bladder cancer is associated with a worse outcome. Our results suggest that measuring hypermethylation in the serum of patients with bladder cancer is a useful biomarker.
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Metilación de ADN , ADN/sangre , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , ADN/genética , ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Vejiga Urinaria/mortalidadRESUMEN
Patients with malignancies often possess increased concentrations of cell-free serum DNA. In this study, we investigated serum DNA levels in each 45 patients with bladder cancer (BCA) undergoing radical cystectomy and with benign prostate hyperplasia. A quantitative real-time PCR was used to amplify a 124 bp (PTGS2; mostly apoptotic origin) and a 271 bp (Reprimo; mostly necrotic origin) DNA fragment. Changes in the origin of DNA fragments were specified as the Apoptosis Index (AI, ratio of 124 bp/271 bp fragments). Small and large fragments were increased (p<0.001 and p=0.041) in BCA patients. The AI increase suggests that DNA fragmentation was mostly (p<0.001) caused by apoptosis. High levels of small DNA fragments distinguished between BCA and BPH with high sensitivity (96%) and moderate specificity (62%). DNA levels and the AI were not correlated with clinicopathological parameters. However, an increased AI was correlated with BCA-specific mortality in a multivariate analysis (p=0.011) indicating that the AI is an independent prognostic factor. Thus, cell-free DNA seems to be a useful prognostic marker in patients with BCA.
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Apoptosis/fisiología , Biomarcadores de Tumor/sangre , Fragmentación del ADN , ADN/sangre , Neoplasias de la Vejiga Urinaria/sangre , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Hiperplasia Prostática/sangre , Curva ROC , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y Especificidad , SueroRESUMEN
The objective of this work was to substantially review all preclinical and clinical data on phytochemicals, such as genistein, lycopene, curcumin, epigallocatechin-gallate, and resveratrol, in terms of their effects as a potential treatment of prostate cancer. It is known, that prostate cancer patients increasingly use complementary and alternative medicines in the hope of preventing or curing cancer. The preclinical data for the phytochemicals presented in this review show a remarkable efficacy against prostate cancer cells in vitro, with molecular targets ranging from cell cycle regulation to induction of apoptosis. In addition, well-conducted animal experiments support the belief that these substances might have a clinical activity on human cancer. However, it is impossible to make definite statements or conclusions on the clinical efficacy in cancer patients because of the great variability and differences of the study designs, small patient numbers, short treatment duration and lack of a standardised drug formulation. Although some results from these clinical studies seem encouraging, reliable or long-term data on tumor recurrence, disease progression and survival are unknown. At present, there is no convincing clinical proof or evidence that the cited phythochemicals might be used in an attempt to cure cancer of the prostate.
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Fitoterapia/métodos , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Carotenoides/uso terapéutico , Catequina/análogos & derivados , Catequina/uso terapéutico , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Curcumina/uso terapéutico , Flavonoides/uso terapéutico , Genisteína/uso terapéutico , Humanos , Masculino , Fenoles/uso terapéutico , Fitoestrógenos/uso terapéutico , Preparaciones de Plantas/uso terapéutico , Polifenoles , Quercetina/uso terapéutico , Resveratrol , Estilbenos/uso terapéuticoRESUMEN
In traditional Chinese Medicine, the preparation Danggui Longhui Wan has been used for years in the treatment of chronic myelocytic leukemia. The compound indirubin has been shown to be the active constituent. A cell permeable derivative, indirubin-3'-monoxime, is a selective and potent inhibitor of cyclin-dependent kinases (cdk). The ability of indirubin-3'-monoxime to induce apoptosis and tumor cell death in transitional cell cancer cell lines was investigated here. The growth-inhibitory properties were evaluated by EZ4U, a cytotoxic assay; apoptosis induction was determined by immunoblotting of cleaved PARP and flow cytometry of Annexin-V/PI staining during treatment. To evaluate further the underlying molecular action of indirubin-3'-monoxime on the cell cycle, the levels of cdk-1 and survivin, a mitotic spindle checkpoint and apoptosis-regulating protein, respectively, were additionally determined by flow cytometry and immunoblotting. The results indicated that indirubin-3'-monoxime induced reversible growth arrest in all four cell lines and an increase of apoptosis in two of them. The treatment with indirubin-3'-monoxime increased the expression of survivin almost four times in the RT4 cells and more than doubled it in the RT112 and T24 cells. In the SUP cells, the expression of survivin increased more than seven-fold after 72-h incubation. No clear correlation between the low apoptosis induction rate and extent of survivin expression was found. Cdk expression was not significantly altered by indirubin-3'-monoxime. In summary, indirubin-3'-monoxime might be a promising candidate for targeted cancer therapy, however, its molecular action remains to be further evaluated.
Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Células Transicionales/tratamiento farmacológico , Indoles/farmacología , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas de Neoplasias/biosíntesis , Oximas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Apoptosis/fisiología , Proteína Quinasa CDC2/biosíntesis , Proteína Quinasa CDC2/genética , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Proteínas Inhibidoras de la Apoptosis , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias/genética , Survivin , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. OBJECTIVE: To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. DESIGN, SETTING, AND PARTICIPANTS: One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (<4 bone metastases; n=867), high-volume bone disease (≥4 bone metastases; n=850), lymph node only disease (n=195). INTERVENTION: Oral enzalutamide (160mg) or placebo once daily while continuing androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Coprimary endpoints (rPFS, OS) were prospectively evaluated in nonvisceral and visceral subgroups. All other efficacy analyses were post hoc. RESULTS AND LIMITATIONS: Enzalutamide improved rPFS versus placebo in patients with nonvisceral disease (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.14-0.22), visceral disease (HR, 0.28; 95% CI, 0.16-0.49), low- or high-volume bone disease (HR, 0.16; 95% CI, 0.11-0.22; HR, 0.22; 95% CI, 0.16-0.29, respectively), and lymph node only disease (HR, 0.09; 95% CI, 0.04-0.19). For OS, HRs favored enzalutamide (<1) across all disease subgroups, although 95% CI was >1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease. CONCLUSIONS: Enzalutamide provided clinically significant benefits in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos/efectos adversos , Benzamidas , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Supervivencia sin Enfermedad , Método Doble Ciego , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Metástasis Linfática , Masculino , Nitrilos , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Estudios Prospectivos , Tasa de Supervivencia , Carga TumoralRESUMEN
Carboxyamido-triazole (CAI) is an orally bioavailable calcium influx and signal transduction inhibitor that has been shown to be anti-invasive, anti-angiogenic and anti-metastatic in different human tumors including transitional cell carcinoma. This study was undertaken to further evaluate the activity of CAI in a rat bladder cancer model. A transitional cell carcinoma (TCC) was chemically induced by intravesical installation of methyl-nitrosurea (MNU) in the bladder of female Fischer 344 rats. First, a toxicity study was performed which revealed no side-effects of CAI in the animals up to a dose of 250 mg/kg CAI. For treatment, a dose of 100 mg/kg CAI dissolved in PEG-400 vehicle was chosen. Oral administration of CAI continuously daily for 4 weeks (group A), 3 days/week over 6 weeks (group B), or intravesically twice a week for 6 weeks (group C) caused a reduction of spontaneous development of TCC. Lower stage and grade of tumors were seen in all CAI-treated animals. Under CAI treatment, the apoptotic rate in tumors increased, whereas the proliferation rate decreased, as shown by TUNEL assay and KI-67-immunhistochemistry, respectively. The highest efficacy was seen in group B, with 5 out of 10 animals tumor-free. Intravesical application (group C) resulted in 3 out of 10 animals tumor-free. Normal urothelium was not affected by CAI. This animal model confirms the anti-tumor effect of CAI and shows induction of apoptosis and growth inhibition in bladder cancer by the drug.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Triazoles/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Animales , Antineoplásicos/toxicidad , Carcinógenos , Carcinoma de Células Transicionales/inducido químicamente , Proliferación Celular/efectos de los fármacos , Femenino , Metilnitrosourea , Ratas , Ratas Endogámicas F344 , Triazoles/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamenteRESUMEN
BACKGROUND: Superantigens are among the most potent T-cell mitogens known. Since T-cell activation and T-cell-derived cytokines play a role in the immune response associated with intravesical Bacillus Calmette-Guerin (BCG) application, this study was initiated to explore the fundamental aspects of a potential new immunomodulatory therapy for superficial bladder cancer. Since Superantigen-induced cytotoxicity is mediated by apoptosis, the effects of SEB (staphylococcal enterotoxin B)-Superantigen-activated PBMC (peripheral blood mononuclear cells) on bladder cancer cells were evaluated with regard to Fas/Fas-ligand-based interactions. MATERIALS AND METHODS: Whether SEB can induce Fas-ligand expression on PBMC and the extent of cytokine secretion were examined by flow cytometry and specific ELISA. In addition, whether the SEB-activated PBMC are able to induce apoptosis in transitional cell carcinoma cells (TCC) was evaluated in co-culture experiments. RESULTS: It was shown that SEB induced pronounced time- but not dose-dependent specific Fas-ligand expression on PBMC, lasting 1 h to 7 h after initiation of the experiment. Cleaved soluble Fas-ligand was detected in the culture supernatants 24 h after stimulation, but not earlier. Further, a strong time-dependent secretion of cytokines IL-2, IFN-gamma and TNF-alpha released from the SEB-stimulated PBMC was shown. In co-culture experiments, it was demonstrated that SEB-activated PBMC significantly induced apoptosis in TCC cells. The released cytokines from SEB-treated PBMC demonstrated only a minor, not significant, apoptotic response in TCC cells. CONCLUSION: This first evaluation of the possible mode of action of a Superantigen opens the door for extended studies of this interesting approach to the treatment of bladder cancer.
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Apoptosis/inmunología , Carcinoma de Células Transicionales/inmunología , Enterotoxinas/inmunología , Leucocitos Mononucleares/inmunología , Superantígenos/inmunología , Neoplasias de la Vejiga Urinaria/inmunología , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/terapia , Línea Celular Tumoral , Citocinas/inmunología , Citocinas/metabolismo , Enterotoxinas/farmacología , Proteína Ligando Fas , Humanos , Factores Inmunológicos/inmunología , Factores Inmunológicos/farmacología , Inmunoterapia/métodos , Leucocitos Mononucleares/metabolismo , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/inmunología , Superantígenos/farmacología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/terapia , Receptor fas/biosíntesis , Receptor fas/inmunologíaRESUMEN
Flavopiridol is a semi-synthetic flavone analog of the alkaloid, rohitukine, a compound from an Indian tree, Dysoxylum binectariferum. It has been shown to inhibit cyclin-dependent kinases (CDKs), causing cell cycle arrest and growth inhibition. Flavopiridol is reported to have cytotoxic activity against a wide range of cancer cell lines and has demonstrated its efficacy in several clinical trials. Flavopiridol seems a well-suited potential new agent for the treatment of bladder cancer. We, therefore, evaluated whether flavopiridol inhibits growth and induces apoptosis in bladder cancer cells and additionally examined the toxicity and efficacy of this drug in vivo in a rat bladder cancer model. The in vitro experiments showed an IC20 of 50-100 nM in all cell lines tested. However, there was a difference in the response with regard to the grading of the tumor cells at higher doses. The IC50 was found to be 150-350 nM in the well-differentiated RT4 and RTI12 cell lines after treatment with flavopiridol, in comparison to a IC50 of 1000 nMfor the poorly-differentiated cell lines T24 and SUP. After exposure to flavopiridol, all tumor cell lines underwent significant apoptosis in comparison to untreated cells, beginning at a dose of 50 nM flavopiridol. At high concentrations (500 nM) of flavopiridol, 80-90% of all cells showed severe apoptotic alterations. The treatment of rat urinary bladder cancer with flavopiridol demonstrated the best efficacy with an intermittent treatment of 0.1 mg/kg, 3 times weekly over a total of 3 weeks, resulting in 7/12 animals tumor-free and a trend for the remaining tumors to have lower stage and grade. There seems to be a small advantage in intermittent versus daily application of flavopiridol. In summary, our results indicated that flavopiridol could be a useful therapeutic agent for bladder cancer, inhibiting tumor growth, malignant progression and inducing apoptosis.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Transicionales/tratamiento farmacológico , Flavonoides/farmacología , Piperidinas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Carcinoma de Células Transicionales/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Endogámicas F344 , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Enzalutamide is an androgen receptor inhibitor with a demonstrated overall survival benefit in metastatic castration-resistant prostate cancer. A phase 2 study of enzalutamide monotherapy in patients with hormone-naïve prostate cancer (HNPC) showed a high response rate for the prespecified primary endpoint (ie, prostate-specific antigen [PSA] response at week 25), regardless of metastases at baseline, and favorable tolerability. OBJECTIVE: To determine the long-term efficacy and safety of enzalutamide monotherapy at 1 and 2 yr. DESIGN, SETTING, AND PARTICIPANTS: Open-label, single-arm study in patients with HNPC and noncastrate testosterone (≥230 ng/dl). INTERVENTION: Oral enzalutamide 160mg/d until disease progression or unacceptable toxicity. OUTCOME MEASUREMENTS AND ANALYSIS: PSA response (≥80% decline from baseline) assessed at 1 yr (49 wk) and 2 yr (97 wk). RESULTS AND LIMITATIONS: The median (range) age was 73 (48-86) yr and 26 patients (39%) presented with metastases at study entry. Of 67 patients enrolled, 45 (67%) remained on enzalutamide at week 97. For patients remaining on therapy, the PSA response rate at week 97 was 100% (95% confidence interval 92-100%). Of 26 patients with metastases at baseline, 13 (50%) had a complete and four (15.4%) had a partial response as best overall tumor response up to 97 wk on treatment. There was overall maintenance of total-body bone mineral density (BMD) and moderate changes in lean and fat body mass at 49 and 97 wk. The most common adverse events were gynecomastia, nipple pain, fatigue, and hot flushes. The study limitations include lack of a control group and of endocrine, glycemic, and lipid data at 97 wk. CONCLUSIONS: Long-term enzalutamide monotherapy in men with noncastrate HNPC is associated with large sustained reductions in PSA, signals indicating a favorable tumor response, and favorable safety/tolerability profile, with relatively small negative effects on total-body BMD. PATIENT SUMMARY: In this long-term follow-up of the efficacy and safety of enzalutamide monotherapy in patients with hormone-naïve prostate cancer, enzalutamide maintained long-term reductions in prostate-specific antigen, with a minimal impact on total-body bone mineral density. TRIAL REGISTRATION: NCT01302041.
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Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Recurrencia Local de Neoplasia/sangre , Feniltiohidantoína/análogos & derivados , Prostatectomía , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Benzamidas , Quimioterapia Adyuvante , Estudios de Seguimiento , Humanos , Calicreínas/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/patología , Resultado del TratamientoRESUMEN
Pro- and anti-apoptotic factors and intracellular signaling pathways are targets for therapeutic development of anticancer agents. Carboxyamido-triazole (CAI) is an inhibitor of transmembrane calcium influx and intracellular calcium-requiring signal transduction pathways. The present study investigates the effects of CAI on human transitional cancer cell (TCC) viability and apoptosis, and evaluates whether apoptotic resistance may be overcome pharmacologically. Both well-differentiated (RT4, RT112/grade 1) and poorly-differentiated (T24/grade 3; SUP/grade 4) human TCC lines were shown to express Fas. Upon exposure to agonistic monoclonal Fas antibody, only well-differentiated TCC lines underwent apoptotic cell death. CAI exposure reduced cell viability and caused an at least additive anti-apoptotic effect in combination with the Fas antibody in the Fas-insensitive TCC lines. Under the same conditions under which CAI treatment augmented Fas-mediated apoptosis, it was shown to reduce intracellular bcl-2 quantity. This response to CAI indicates that apoptotic cell death is enhanced by the reduction of bcl-2 protein expression. We suggest that the antitumor effect of CAI is at least partially based on restoring a pathway of apoptosis. It may cause transformation of cell homeostasis that leads to the alteration of apoptotic mechanisms, thus allowing highly malignant tumor cells to re-enter the physiological course of cell elimination.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carcinoma de Células Transicionales/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Triazoles/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Calcio/metabolismo , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Transducción de Señal/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Receptor fas/biosíntesis , Receptor fas/inmunologíaRESUMEN
BACKGROUND: Gemcitabine and paclitaxel are currently co-administered in clinical studies for bladder cancer as this drug combination may offer better tumor responses. However, the drugs may antagonize the cytotoxic capacity of each other due to cell cycle perturbations. In this study, we evaluated different application schedules to determine the efficacy of the combination and its potential interactions. MATERIALS AND METHODS: Bladder cancer cell lines were exposed to either gemcitabine or paclitaxel, in concentrations ranging from 1-1000 nM. The inhibition concentrations (IC) 20, 50 and 70 were assessed by MTT assay after 24, 48 and 72 hours. Then, the cytotoxic activity and apoptosis induction abilities of the combined agents using the IC20 concentration were analyzed by MTT and Annexin-V/PI staining, respectively. The effects on the cell cycle were assessed by flow cytometry of bromodeoxyuridine (BrdU) and propidium iodide (PI). RESULTS: Gemcitabine and paclitaxel dose-dependently inhibited cell proliferation. Simultaneous application of gemcitabine/paclitaxel yielded superior cytotoxicity rates after 48 and 72 hours. Sequential treatment of cells showed similar results when gemcitabine was given 24 hours before paclitaxel. However, when paclitaxel was given before gemcitabine, the cell kill was less. Gemcitabine as well as paclitaxel have potent apoptosis inducing abilities. Cell cycle evaluation demonstrated a shift towards the S-phase after gemcitabine and a progressive G2/M block after paclitaxel treatment. CONCLUSION: The combination of gemcitabine and paclitaxel in vitro yields superior cytotoxic efficacy, if given simultaneously or with gemcitabine first. While in vitro cell models may not necessarily predict clinical outcome, they do provide a basis for rational scheduling of drugs in clinical trials.