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1.
Zhonghua Zhong Liu Za Zhi ; 42(2): 133-138, 2020 Feb 23.
Artigo em Chinês | MEDLINE | ID: mdl-32135648

RESUMO

Objective: To evaluate the long-term effect and safety of chrono-chemotherapy combined with intensity modulated radiotherapy (IMRT) in locally advanced nasopharyngeal carcinoma (NPC). Methods: 160 patients with locally advanced NPC were randomly divided into a chrono group and conventional group according to random number table. In the first stage, all patients underwent two cycles of induced chemotherapy, consisting of docetaxel, cisplatin and 5-Fu every 21 days. Notably, patients received chrono-moduated chemotherapy according to circadian rhythm in the chrono group, and conventional chemotherapy in the conventional group. Then, 21 days after the completion of first stage, three cycles of concurrent cisplatin chemotherapy every 21 days were given to all patients during IMRT. The median follow-up after the completion of radiotherapy was 31 months. Long-term side effects and the survival of patients were observed. Results: Patients in the chrono group had significantly lower rates of hearing loss (22.72%), dysphagia (0) and neck fibrosis (4.54%) compared with those in the conventional group (39.13%、8.69%, 15.94%, respectively, all P<0.05). Meanwhile, the 1- year overall survival rates (97.0% vs 92.8%), 3-year overall survival rates (80.3% vs 81.2%), 1-year progression free survival rates (95.5% vs 87.0%), 3-year progression free survival rates (71.2% vs 73.9%), 1-year locoregional relapse-free survival rates (97.0% vs 95.7%), 1-year locoregional relapse-free survival rates (92.4% vs 92.8%), 1-year distant metastasis-free survival rates (97.0% vs 98.6%) and 3-year distant metastasis-free survival rates (90.9% vs 91.3%) between the chrono group and the conventional group were not statistically significant (all P>0.05). Conclusions: Compared with conventional chemotherapy, chrono-chemotherapy combined with IMRT didn't affect long-term survival, but reducing the incidence of adverse events in patients with locally advanced NPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Terapia Combinada , Docetaxel/administração & dosagem , Cronoterapia Farmacológica , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Radioterapia de Intensidade Modulada/métodos , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(10): e19360, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150078

RESUMO

BACKGROUND: A systemic review and meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy, toxicity and safety of concurrent chemoradiotherapy (CCRT) with or without induction chemotherapy (IC) for locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: Research searching was performed in Web of Science, PubMed, The Cochrane Library, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chongqing VIP Database for Chinese Technical Periodicals and Wanfang Database. RCTs including patients diagnosed with locoregionally advanced NPC without metastasis and randomly treated with IC plus CCRT and CCRT alone were included. Survival and outcome data were extracted and meta-analysis was performed using the Revman 5.3.0 software. RESULTS: Ten RCTs (2280 patients) were selected and used for pooled meta-analysis. In comparison with CCRT, IC plus CCRT treatment significantly improved the overall survival (OS; HR = 0.70, 95%CI 0.56-0.87, P = .002), progression-free survival (PFS; HR = 0.75, 95%CI 0.65-0.87, P < .0001), distant metastasis failure-free survival (DMFS; HR = 0.71, 95%CI 0.58-0.85, P = .0003) and loco-regional failure-free survival (LFES; HR = 0.72, 95%CI 0.59-0.88, P = .002) of patients with locoregionally advanced NPC. Patients treated with IC and CCRT had higher incidence of grade 3-4 leucopenia and thrombocytopenia than patients treated with CCRT alone (P < .0001). No significant difference in other grade 3-4 adverse events and radiation toxicity was observed between the two groups. IC combined with CCRT improved the survival of patients with locoregionally advanced NPC. CONCLUSIONS: Combined IC and CCRT therapy was an efficacy treatment regimen for locoregionally advanced NPC.


Assuntos
Quimiorradioterapia/métodos , Quimioterapia de Indução/normas , Neoplasias Nasofaríngeas/tratamento farmacológico , Terapia Combinada , Humanos , Quimioterapia de Indução/métodos , Quimioterapia de Indução/tendências , Neoplasias Nasofaríngeas/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Resultado do Tratamento
3.
Int J Cancer ; 146(8): 2305-2314, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31950498

RESUMO

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated "risk of bias" tool to assess study quality. Four separate Phase I-II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5-34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I-III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Antígeno CTLA-4/imunologia , Quimiorradioterapia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/imunologia , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia
4.
Pediatr Blood Cancer ; 67(4): e28162, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31925925

RESUMO

Juvenile nasopharyngeal angiofibroma (JNA) is a pathologically benign yet locally aggressive and destructive tumor that develops in the choana and nasopharynx. Historical treatment of JNA has included embolization, surgical resection, and radiation. Here, we describe three patients who received therapy with the mTOR inhibitor sirolimus with improvement in clinical symptoms, imaging, and overall well-being.


Assuntos
Angiofibroma/tratamento farmacológico , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Nasofaríngeas/tratamento farmacológico , Sirolimo/uso terapêutico , Adolescente , Angiofibroma/patologia , Criança , Humanos , Masculino , Neoplasias Nasofaríngeas/patologia , Resultado do Tratamento
5.
J Cancer Res Clin Oncol ; 146(2): 429-439, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31677113

RESUMO

PURPOSE: To compare the clinical results and functional outcomes between two-dimensional conventional radiation therapy (2DRT) and intensity-modulated radiation therapy (IMRT) in nasopharyngeal carcinoma (NPC) with skull-base invasion. METHODS: A total of 1258 patients were subclassified into two groups: mild skull-base invasion group (792; 63%) and severe skull-base invasion group (466; 37%). Patients were pair matched (1:1 ratio) using six clinical factors into 2DRT or IMRT groups. The Kaplan-Meier method and Cox regression model were performed to assess overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS). Toxicities were evaluated. RESULTS: IMRT significantly improved four-year OS compared with 2DRT (65.6% vs. 81.8%, P = 0.000), DFS (57.3% vs. 73.3%, P = 0.000) and LRRFS (76.5% vs. 87.5%, P = 0.003) in NPC with severe skull-base invasion, but similar results were observed in patients with mild skull-base invasion (P > 0.05). In patients with severe invasion, radiation therapy techniques were found to be an independent prognostic factor for OS (HR = 0.457, P = 0.000), DFS (HR = 0.547, P = 0.000) and LRRFS (HR = 0.503, P = 0.004). IMRT was associated with better OS. In subgroups analysis, IMRT group also had a better survival in OS, DFS (P < 0.05 for all rates) for patients received concurrent chemotherapy and sequential chemotherapy compared to 2DRT in the severe invasion group. The IMRT group displayed lower incidence of mucositis, xerostomia, trismus (< 1 cm) and temporal lobe necrosis than the 2DRT group. CONCLUSIONS: IMRT significantly improved patient survival compared with 2DRT in NPC patients with severe skull-base invasion, but a similar survival rate was noted in mild invasion patients. Chemotherapy can improve survival in NPC patients with severe invasion. Among the two therapies, IMRT significantly decreased therapy-related toxicity.


Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Quimiorradioterapia , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/patologia , Radioterapia de Intensidade Modulada , Estudos Retrospectivos , Base do Crânio/patologia , Adulto Jovem
6.
Eur Radiol ; 30(1): 537-546, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31372781

RESUMO

OBJECTIVES: To establish and validate a radiomics nomogram for prediction of induction chemotherapy (IC) response and survival in nasopharyngeal carcinoma (NPC) patients. METHODS: One hundred twenty-three NPC patients (100 in training and 23 in validation cohort) with multi-MR images were enrolled. A radiomics nomogram was established by integrating the clinical data and radiomics signature generated by support vector machine. RESULTS: The radiomics signature consisting of 19 selected features from the joint T1-weighted (T1-WI), T2-weighted (T2-WI), and contrast-enhanced T1-weighted MRI images (T1-C) showed good prognostic performance in terms of evaluating IC response in two cohorts. The radiomics nomogram established by integrating the radiomics signature with clinical data outperformed clinical nomogram alone (C-index in validation cohort, 0.863 vs 0.549; p < 0.01). Decision curve analysis demonstrated the clinical utility of the radiomics nomogram. Survival analysis showed that IC responders had significant better PFS (progression-free survival) than non-responders (3-year PFS 84.81% vs 39.75%, p < 0.001). Low-risk groups defined by radiomics signature had significant better PFS than high-risk groups (3-year PFS 76.24% vs 48.04%, p < 0.05). CONCLUSIONS: Multiparametric MRI-based radiomics could be helpful for personalized risk stratification and treatment in NPC patients receiving IC. KEY POINTS: • MRI Radiomics can predict IC response and survival in non-endemic NPC. • Radiomics signature in combination with clinical data showed excellent predictive performance. • Radiomics signature could separate patients into two groups with different prognosis.


Assuntos
Quimioterapia de Indução/métodos , Imagem por Ressonância Magnética/métodos , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/mortalidade , Nomogramas , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Máquina de Vetores de Suporte , Análise de Sobrevida , Resultado do Tratamento
7.
J BUON ; 24(5): 2056-2061, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31786875

RESUMO

PURPOSE: Nasopharyngeal carcinoma is one of common and vicious cancers of head and neck. The main purpose of this study was to examine the anticancer effects of the naturally occurring compound Ginsenoside (Rg1) against paclitaxel-resistant human nasopharyngeal cancer cells along with evaluation of its effects on cell autophagy, apoptosis, ROS production, cell cycle progression and m-TOR/PI3K/AKT signalling pathway. METHODS: The viability of SUNE1 cancer cell line and NP460 normal cell line was checked by CCK8 counting assay. Apoptosis-related studies were examined by fluorescent microscopy using acridine orange (AO)/ethidium bromide (EB) staining as well as flow cytometry using annexin V assay. Further, transmission electron microscopy (TEM) was used to study autophagic effects induced by Ginsenoside (Rg1). Western blot assay was used to study the effects of Ginsenoside on apoptosis and on autophagy-related protein expressions including Bax, Bcl-2, LC3-ll. RESULTS: The results indicated that Ginsenoside (Rg1) reduces the viability of the nasopharyngeal carcinoma cells in a dose-dependent manner, showing IC50 of 15 µM in cancer cells and IC50 of 80 µM in normal cell lines. The AO/EB staining showed that Ginsenoside (Rg1) inhibits the viability of cancer cells via induction of apoptotic cell death which was correlated with increase in Bax and decrease in Bcl-2 levels. Electron microscopic analysis showed that Ginsenoside (Rg1) caused the development of autophagosomes in cancer cells. Similarly, Ginsenoside (Rg1) increased the expression of LC3-II protein, indicating autophagic cell death. Ginsenoside (Rg1) also induced dose-dependent S phase cell cycle arrest. Western blot analysis showed that Ginsenoside (Rg1) has the potential to block m-TOR/PI3K/AKT signalling pathway. CONCLUSIONS: In conclusion, the results of this study clearly indicate that Ginsenoside (Rg1) could be developed as a potent candidate drug against nasopharyngeal cancer provided further in vivo studies as well as toxicological studies are carried out.


Assuntos
Autofagia/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ginsenosídeos/farmacologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteína Oncogênica v-akt/genética , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Espécies Reativas de Oxigênio/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 1014-1019, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878998

RESUMO

Objective To explore the effect of miR-129-1-3p on cisplatin sensitivity of chemo-resistant epithelial nasopharyngeal carcinoma HNE19/CDDP cells and the related mechanism. Methods Human nasopharyngeal carcinoma HNE1 cells and cisplatin-resistant HNE19/CDDP cells were cultured. Cisplatin resistance index of cisplatin-resistant HNE1/CDDP cells was tested by MTT assay. The levels of miR-129-1-3p and WEE1 mRNA in HNE1 and HNE19/CDDP cells were measured by real-time quantitative PCR. miR-129-1-3p mimics and unrelated sequence control (miR-129-1-3p NC) were transfected into HNE1/CDDP cells using LipofectamineTM 2000. The drug sensitivity (IC50) of these cells to cisplatin was determined by MTT assay. The protein expression level of WEE1 was determined by Western blot analysis. The 3'-UTR of WEE1 was cloned into luciferase reporter vector and its luciferase activity was detected to verify whether miR-129-1-3p targets WEE1. Results Resistance index of HNE1/CDDP cells to cisplatin was 5.29. The expression level of miR-129-1-3p in the HNE1 cells was significantly higher than that in the HNE1/CDDP cells. The mRNA expression level of WEE1 in the HNE1 cells was lower than that in the HNE1/CDDP cells. The level of miR-129-1-3p was negatively correlated with the level of WEE1 mRNA (r=-0.9784). The IC50 of cisplatin was significantly reduced in the HNE1/CDDP cells after transfected with miR-129-1-3p mimics. The protein expression level of WEE1 in the cells transfected with miR-129-1-3p mimics significantly decreased as compared with the control group and blank group. The miR-129-1-3p regulated the 3'-UTR of WEE1 and reduced the expression activity of luciferase. Conclusion miR-129-1-3p could reverse cisplatin resistance of HNE1/CDDP nasopharyngeal carcinoma cells via inhibiting WEE1 expression.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico
9.
Medicine (Baltimore) ; 98(51): e18484, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31861031

RESUMO

Although induction chemotherapy (IC) combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy (CC) is the new standard treatment option in locoregionally advanced nasopharyngeal carcinoma (NPC), many patients fail to receive CC. The aim of this study was to investigate long-term survival outcomes and toxicities in these patients who are treated with IC before IMRT without CC.We retrospectively reviewed 332 untreated, newly diagnosed locoregionally advanced NPC patients who received IC before IMRT alone at our institution from May 2008 through April 2014. The IC was administered every 3 weeks for 1 to 4 cycles. Acute and late radiation-related toxicities were graded according to the acute and late radiation morbidity scoring criteria of the radiation therapy oncology group. The accumulated survival was calculated according to the Kaplan-Meier method. The log-rank test was used to compare the difference in survival.With a median follow-up duration of 65 months (range: 8-110 months), the 5-year estimated locoregional relapse-free survival, distant metastasis-free survival, progression-free survival (PFS), and overall survival rates were 93.4%, 91.7%, 85.8%, and 82.5%, respectively. Older age and advanced T stage were adverse prognostic factors for overall survival, and the absence of comorbidity was a favorable prognostic factor for PFS. However, acceptable acute complications were observed in these patients.IC combined with IMRT alone provides promising long-term survival outcomes with manageable toxicities. Therefore, the omission of CC from the standard treatment did not affect survival outcomes.


Assuntos
Quimioterapia de Indução , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Radioterapia de Intensidade Modulada , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China/epidemiologia , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/radioterapia , Estudos Retrospectivos , Falha de Tratamento , Adulto Jovem
10.
Drug Des Devel Ther ; 13: 3207-3216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31686783

RESUMO

Objective: We aimed to investigate the efficacy and safety of cetuximab (CTX) or nimotuzumab (NTZ) on the addition of palliative chemotherapy (PCT) in patients with de novo metastatic nasopharyngeal carcinoma (NPC). Materials and methods: From 2007 to 2016, 451 eligible patients with de novo metastatic NPC were enrolled in the study. With propensity score matching technique, we created a well-balanced cohort by matching patients who received CTX/NTZ plus PCT (62 patients) with those receiving PCT alone (248 patients) in a ratio of 1:4. The primary endpoint was overall survival (OS). All potential prognostic factors were involved in the multivariate analysis with the Cox regression hazards model. Kaplan-Meier curves were used to compare the survival status, and log-rank test to measure the significance. Results: The median follow-up time was 27.7 months (range, 1-126 months). No significant difference in survival was observed between the CTX/NTZ plus PCT group and PCT group. (3-year OS: 63.0% vs 58.1%; P=0.485). The administration of CTX/NTZ was not found to be an independent prognostic factor in multivariate analysis. With regard to toxicity, the development of a G3-4 skin reaction and mucositis was more common in patients receiving CTX plus PCT. Interaction effects analysis did not show any significant interaction effects on OS between the treatment regimen and prognostic factors (P>0.05). Conclusion: The efficacy of CTX/NTZ and PCT is comparable to single PCT treatment in terms of survival outcomes among de novo metastatic NPC patients. Moreover, the application of CTX exacerbated skin reactions and mucositis.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cetuximab/farmacologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Pontuação de Propensão , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab/administração & dosagem , Cetuximab/efeitos adversos , Estudos de Coortes , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/metabolismo , Estudos Retrospectivos , Análise de Sobrevida
11.
J Exp Clin Cancer Res ; 38(1): 468, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730000

RESUMO

BACKGROUND: The deubiquitinase USP7 has been identified as an oncogene with key roles in tumorigenesis and therapeutic resistance for a series of cancer types. Recently small molecular inhibitors have been developed to target USP7. However, the anticancer mechanism of USP7 inhibitors is still elusive. METHODS: Cell viability or clonogenicity was tested by violet crystal assay. Cell apoptosis or cell cycle was analyzed by flow cytometry, and chromosome misalignment was observed by a fluorescent microscopy. The protein interaction of PLK1 and USP7 was detected by tandem affinity purification and high throughput proteomics, and further confirmed by co-immunoprecipitation, GST pull-down and protein co-localization. The correlation between USP7 level of tumor tissues and taxane-resistance was evaluated. RESULTS: Pharmacological USP7 inhibition by P5091 retarded cell proliferation and induced cell apoptosis. Further studies showed that P5091 induced cell cycle arrest at G2/M phase, and particularly induced chromosome misalignment, indicating the key roles of USP7 in mitosis. USP7 protein was detected in the PLK1-interacted protein complex. USP7 interacts with PLK1 protein through its PBD domain by catalytic activity. USP7 as a deubiquitinase sustained PLK1 protein stability via the C223 site, and inversely, USP7 inhibition by P5091 promoted the protein degradation of PLK1 through the ubiquitination-proteasome pathway. By overexpressing PLK1, USP7 that had been depleted by RNAi ceased to induce chromosome misalignment in mitosis and again supported cell proliferation and cell survival. Both USP7 and PLK1 were overexpressed in taxane-resistant cancer cells, and negatively correlated with the MP scores in tumor tissues. Either USP7 or PLK1 knockdown by RNAi significantly sensitized taxane-resistant cells to taxane cell killing. CONCLUSION: This is the first report that PLK1 is a novel substrate of USP7 deubiquitinase, and that USP7 sustained the protein stability of PLK1. USP7 inhibition induces cell apoptosis and cell cycle G2/M arrest, and overcomes taxane resistance by inducing the protein degradation of PLK1, resulting in chromosome misalignment in mitosis.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Peptidase 7 Específica de Ubiquitina/genética , Peptidase 7 Específica de Ubiquitina/metabolismo , Apoptose/efeitos dos fármacos , Cromossomos , Cromossomos Humanos , Docetaxel/farmacologia , Resistencia a Medicamentos Antineoplásicos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HEK293 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Masculino , Mitose/fisiologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Proteases/farmacologia , Estabilidade Proteica , Transdução de Sinais , Tiofenos/farmacologia , Transfecção , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores
12.
Biomed Res Int ; 2019: 8592921, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687403

RESUMO

This investigation aims to study the effect of curcumin on the proliferation, cycle arrest, and apoptosis of Epstein-Barr virus- (EBV-) positive nasopharyngeal carcinoma (NPC) cells. EBV+ NPC cells were subjected to curcumin treatment. The cell viability was evaluated with the CCK-8. Cell cycle and apoptosis were analyzed by flow cytometry analysis. Expression (protein and mRNA) levels were detected with western blotting and quantitative real-time PCR, respectively. Curcumin efficiently reduced the viability of EBV+ NPC cells. Curcumin induced the cycle arrest of the HONE1 and HK1-EBV cells positive for EBV. Moreover, curcumin treatment promoted the NPC cell apoptosis, via the mitochondria- and death receptor-mediated pathways. Furthermore, curcumin decreased the expression of EBNA1 in the HONE1 and HK1-EBV cells and inhibited the transcriptional level of EBNA1 in the HeLa cells. Curcumin induced EBNA1 degradation via the proteasome-ubiquitin pathway. In addition, curcumin inhibited the proliferation of HONE1 and HK1-EBV cells positive for EBV, probably by decreasing the expression level of EBNA1. In both the HONE1 and HK1-EBV cells, curcumin inhibited the EBV latent and lytic replication. Curcumin could reduce the EBNA1 expression and exert antitumor effects against NPC in vitro.


Assuntos
Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/patogenicidade , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/virologia , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/virologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitina/metabolismo , Replicação Viral/efeitos dos fármacos
13.
BMC Cancer ; 19(1): 1122, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744469

RESUMO

BACKGROUND: To assess the efficacy of Nimotuzumab in combination with first-line chemoradiotherapy treatment in Chinese patients with primary III-IVb stage nasopharyngeal carcinoma. METHODS: Patients with primary locoregionally advanced nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin-based chemotherapy between January 2008 and December 2013 at a single institution were retrospectively reviewed. Group A received at least 6 doses of Nimotuzumab, while Group B did not receive Nimotuzumab. A propensity score matching method was used to match patients from each group in a 1:3 ratio. RESULTS: In total, 730 eligible patients were propensity matched, with 184 patients in Group A and 546 patients in Group B. Significant differences were not observed in the patient and tumor characteristics between Group A and Group B. At a median follow-up of 74.78 months (range 3.53-117.83 months), locoregional recurrence, distant failure and death were observed in 10.68, 11.10 and 16.03% of all patients, respectively. The estimated 5-year locoregional relapse-free survival, distant metastasis-free survival, progression-free survival and overall survival in the Group A versus Group B were 85.34% versus 89.79% (P = 0.156), 93.09% versus 85.61% (P = 0.012), 79.96% versus 77.99% (P = 0.117) and 88.91% versus 78.30% (P = 0.006), respectively. CONCLUSIONS: This nimotuzumab-containing regimen resulted in improved long-term survival of III-IVb stage NPC patients and warrants further prospective evaluation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/mortalidade , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/mortalidade , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
BMC Med ; 17(1): 190, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31640711

RESUMO

BACKGROUND: In locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone. METHODS: All patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts. RESULTS: Three imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25-0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (pinteraction <  0.001). This trend was also found in the validation cohort with high (n = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06-0.51, p <  0.001) and low ICTOS (n = 175, p = 0.31), with a significant treatment interaction (pinteraction = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors. CONCLUSION: An imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01245959 . Registered 23 November 2010.


Assuntos
Quimioterapia de Indução , Imagem por Ressonância Magnética/métodos , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Estudos de Coortes , Tomada de Decisões , Progressão da Doença , Feminino , Humanos , Quimioterapia de Indução/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto/estatística & dados numéricos , Carcinoma Nasofaríngeo/epidemiologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/epidemiologia , Neoplasias Nasofaríngeas/patologia , Valor Preditivo dos Testes , Prognóstico , Planejamento da Radioterapia Assistida por Computador/métodos , Planejamento da Radioterapia Assistida por Computador/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
15.
Radiat Oncol ; 14(1): 182, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640719

RESUMO

BACKGROUND: Patients with N3 stage nasopharyngeal carcinoma (NPC) are at high risk for treatment failure. This study aims to assess the efficacy of maintenance chemotherapy (MC) using S-1 (MC-S1), a novel oral fluoropyrimidine agent, following definitive chemoradiotherapy (CRT) using intensity-modulated radiotherapy (IMRT) in patients with N3 nasopharyngeal carcinoma (N3-NPC). METHODS: A retrospective review was conducted for all N3-NPC treated with CRT with MC (CRT-MC) or without MC (CRT-non-MC) during 2014-2016. Toxicities with MC were recorded. Overall survival (OS), locoregional failure-free survival (LFFS) and distant metastasis free survival (DMFS) were compared between CRT-MC vs. CRT-non-MC cohorts. RESULTS: A total of 130 N3 patients were identified, of whom 21 (16.2%) were treated with CRT-MC, and 109 (83.8%) with CRT-non-MC. Patient characteristics did not significantly differ between the CRT-MC and CRT-non-MC groups, with the exception of the number of cycles of neoadjuvant chemotherapy. Following IMRT 69 patients achieved a complete response (CR) (CRT-MC: 10; CRT-non-MC: 59), 61 had a partial response (PR) (11 vs. 50), and none maintained stable disease (SD) or developed progression of disease (PD). After a median follow-up of 41 months for surviving patients, a significant differences in OS (76.3% vs. 95.2%, p = 0.046) and DMFS (70.3% vs. 90.5%, p = 0.043) but not LFFS (84.9% vs. 100%, p = 0.091) at 3 years were observed between the CRT-non-MC and CRT-MC groups. Skin hyperpigmentation, leucopenia, fatigue, neutropenia, anorexia and nausea were the common but not severe (grade 1-2) toxicities of MC. CONCLUSIONS: Using MC-S1 in N3-NPC patients following IMRT achieved superior survival to the CRT-non-MC patients. The toxicities of MC-S1 were mild and tolerable. Further clinical trials are required to evaluate the efficacy of MC-S1 in N3-NPC patients.


Assuntos
Quimiorradioterapia/métodos , Quimioterapia de Manutenção/métodos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Adolescente , Adulto , Idoso , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia , Ácido Oxônico , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Tegafur , Adulto Jovem
16.
Medicine (Baltimore) ; 98(32): e16592, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393358

RESUMO

RATIONALE: Refractory nasopharyngeal carcinoma is challenging to treat and at present there is no standard treatment or any good choice. PATIENT CONCERNS: Although the three patients in our case reports had already underwent multiple treatments before, they still suffered from disease recurrence of nasopharyngeal carcinoma. DIAGNOSIS: They were diagnosed as refractory nasopharyngeal carcinoma. INTERVENTIONS: A continuous infusion of Endostar, an antiangiogenic agent, combined with chemotherapy and radiation therapy was given to treat the patients. OUTCOMES: Patients showed complete or partial response to the combined therapy as evidenced by regression of tumors and decrease in plasma Epstein-Barr virus (EBV) DNA load. LESSONS: Continuous infusions of Endostar in combination with chemotherapy and/or radiation therapy showed promising efficacy and safety. The combination therapy indicates a new approach to treat refractory nasopharyngeal carcinoma.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Endostatinas/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adulto , Quimiorradioterapia/métodos , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/terapia
18.
Phytomedicine ; 63: 153058, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31394414

RESUMO

BACKGROUND: Sulforaphane (SFN), a natural compound present in cruciferous vegetable, has been shown to possess anti-cancer activities. Cancer stem cell (CSC) in bulk tumor is generally considered as treatment resistant cell and involved in cancer recurrence. The effects of SFN on nasopharyngeal carcinoma (NPC) CSCs have not yet been explored. PURPOSE: The present study aims to examine the anti-tumor activities of SFN on NPC cells with CSC-like properties and the underlying mechanisms. METHODS: NPC cells growing in monolayer culture, CSCs-enriched NPC tumor spheres, and also the NPC nude mice xenograft were used to study the anti-tumor activities of SFN on NPC. The population of cells expressing CSC-associated markers was evaluated using flow cytometry and aldehyde dehydrogenase (ALDH) activity assay. The effect of DNA methyltransferase 1 (DNMT1) on the growth of NPC cells was analyzed by using small interfering RNA (siRNA)-mediated silencing method. RESULTS: SFN was found to inhibit the formation of CSC-enriched NPC tumor spheres and reduce the population of cells with CSC-associated properties (SRY (Sex determining Region Y)-box 2 (SOX2) and ALDH). In the functional study, SFN was found to restore the expression of Wnt inhibitory factor 1 (WIF1) and the effect was accompanied with the downregulation of DNMT1. The functional activities of WIF1 and DNMT1 were confirmed using exogenously added recombinant WIF1 and siRNA knockdown of DNMT1. Moreover, SFN was found to inhibit the in vivo growth of C666-1 cells and enhance the anti-tumor effects of cisplatin. CONCLUSION: Taken together, we demonstrated that SFN could suppress the growth of NPC cells via the DNMT1/WIF1 axis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos Fitogênicos/farmacologia , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Isotiocianatos/farmacologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Brassicaceae/química , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , DNA (Citosina-5-)-Metiltransferase 1/genética , Humanos , Isotiocianatos/administração & dosagem , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Adv Exp Med Biol ; 1155: 533-541, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468429

RESUMO

Taurine displays anti-tumor activity in some kinds of human cancers. However, the underlying mechanisms are poorly understood. Epstein-Barr virus-related nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer in Southeast Asia with the highest incidence in South China. We examined an apoptosis-inducing effect of taurine against NPC cells (HK1 and HK1-EBV) to clarify the mechanisms of anti-tumor effects of taurine by immunocytochemical methods. We observed that taurine induced cleavage of caspase-9/3 in a concentration-dependent manner, suggesting the involvement of mitochondrial apoptotic signals. Both PTEN and p53 activation were detected in a dose-dependent manner after taurine treatment in NPC cells. In conclusion, taurine may play an anti-tumor role by activating tumor suppressor PTEN and p53.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Taurina/farmacologia , Linhagem Celular Tumoral , China , Humanos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
20.
Artigo em Chinês | MEDLINE | ID: mdl-31315360

RESUMO

Objective: To understand the mechanism of chemotherapy resistance in nasopharyngeal carcinoma under hypoxic conditions through the perspective of protein SUMOylation modification. Methods: Cobalt chloride (CoCl(2)) was used to establish the hypoxic model of human nasopharyngeal carcinoma CNE1 cells. Then, the cell cycle was detected by flow cytometry, and the expression level of small ubiquitin-related modifier(SUMO) and cyclin-dependent kinase 6 (CDK6) proteins were detected by western blotting. MTT assay was used to determine the median lethal dose (IC(50)) of cancer cells against cisplatin, and enzyme-linked immunosorbent assay (ELISA) was used to determine lactate dehydrogenase (LDH) level. Results: The cell cycle of CNE1 induced by hypoxia was arrested in G0/G1 phase.The results of Western blot showed that the protein expression level of CDK6 in CNE1 cells was lower than that in the control group (0.83±0.25 vs. 0.43±0.21, t=14.67, P=0.003). The protein level of conjugated SUMO1 was significantly lower than that in the control group (2.69±0.48 vs. 1.38±0.31, t=17.22, P=0.001), while the level of free SUMO1 protein was significantly higher than that in the control group (2.01±0.43 vs. 2.60±0.59, t=15.45, P=0.002).The LC50 of CNE1 cells in the control group was significantly lower than that in the hypoxic group (29.44 µg/ml vs. 97.72 µg/ml, t=12.79, P=0.001). After CNE1 cells received 50 µg/ml cisplatin for 48 h, the LDH content in the supernatant of the control group was significantly higher than that in the hypoxic group ((541.49±64.59) ng/ml vs. (234.67±41.03) ng/ml, t=11.94, P=0.007)). The apoptosis rate of CNE1 cells in the control group was significantly higher than that in the hypoxic group ((76.64±5.37)% vs. (32.84±4.77) ng/ml, t=8.49, P=0.003)). Conclusion: Hypoxia can dissociate the covalent modification of CDK6 and SUMO1, inhibit cell cycle and increase the chemotherapy resistance of nasopharyngeal carcinoma.


Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Hipóxia/fisiopatologia , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Sumoilação/fisiologia , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Quinase 6 Dependente de Ciclina/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Carcinoma Nasofaríngeo/fisiopatologia , Neoplasias Nasofaríngeas/fisiopatologia , Proteína SUMO-1/metabolismo
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