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1.
Acta Pharmacol Sin ; 42(4): 641-647, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32737470

RESUMO

For follicular lymphoma (FL) with grade 1/2, the complete response (CR) rate of the first-line R-CHOP treatment was significantly low. In this study, we assessed the rationality of the administration of rituximab for FL patients with grade 1/2 based on concentration-response relationship analyses. Thus, we conducted a prospective pharmacokinetic (PK) study in 68 FL patients with grades 1-3 treated with R-CHOP at 21-day intervals. Plasma rituximab concentrations were quantified using ELISA and the population PK modeling was established with Phoenix® NLMETM. The first cycle trough concentration (C1-trough) of rituximab was a significant independent risk factor for achieving CR in matched-pair logistic regression analysis, rather than the concentrations in later cycles; the recommendatory minimum optimal C1-trough was 13.60 µg/mL. Patients with grade 1/2 had significantly lower C1-trough compared with grade 3 (12.21 µg/mL vs. 23.45 µg/mL, P < 0.001), only 30% patients with grade 1/2 could reach 13.60 µg/mL, compared with 91.67% in patients with grade 3, which was in accord with its unsatisfactory CR rates (43.33% vs. 76.32%). The stage indicating the tumor burden (the target) was a crucial influence factor for C1-trough, accounting for 40.70% of its variability, 70% patients with grade 1/2 were stage IV in this study, since the systemic therapy only started at the disseminated disease stage. The initial dose of 1800 mg was recommended by Monte Carlo simulation for patients with grade 1/2. In summary, low C1-trough accounted for low-grade FL's unsatisfactory CR rate, designing the first dosage of rituximab should be a very important component of individualized therapy for FL.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Antineoplásicos/farmacocinética , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Prednisona/uso terapêutico , Estudos Prospectivos , Rituximab/farmacocinética , Vincristina/uso terapêutico , Adulto Jovem
2.
J Med Internet Res ; 23(1): e24619, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33395398

RESUMO

BACKGROUND: The COVID-19 outbreak has increased challenges associated with health management, especially cancer management. In an effort to provide continuous pharmaceutical care to cancer patients, Sun Yat-sen University Cancer Center (SYSUCC) implemented a remote pharmacy service platform based on its already existing web-based hospital app known as Cloud SYSUCC. OBJECTIVE: The aim of this study was to investigate the characteristics, acceptance, and initial impact of the Cloud SYSUCC app during a COVID-19 outbreak in a tertiary cancer hospital in China. METHODS: The total number of online prescriptions and detailed information on the service were obtained during the first 6 months after the remote service platform was successfully set up. The patients' gender, age, residence, primary diagnosis, drug classification, weekly number of prescriptions, and prescribed drugs were analyzed. In addition, a follow-up telephonic survey was conducted to evaluate patients' satisfaction in using the remote prescription service. RESULTS: A total of 1718 prescriptions, including 2022 drugs for 1212 patients, were delivered to 24 provinces and municipalities directly under the Central Government of China between February 12, 2020, and August 11, 2020. The majority of patients were female (841/1212, 69.39%), and 90.18% (1093/1212) of them were aged 31-70 years old. The top 3 primary diagnoses for which remote medical prescriptions were made included breast cancer (599/1212, 49.42%), liver cancer (249/1212, 20.54%), and thyroid cancer (125/1212, 10.31%). Of the 1718 prescriptions delivered, 1435 (83.5%) were sent to Guangdong Province and 283 (16.5%) were sent to other provinces in China. Of the 2022 drugs delivered, 1012 (50.05%) were hormonal drugs. The general trend in the use of the remote prescription service declined since the 10th week. A follow-up telephonic survey found that 88% (88/100) of the patients were very satisfied, and 12% (12/100) of the patients were somewhat satisfied with the remote pharmacy service platform. CONCLUSIONS: The remote pharmacy platform Cloud SYSUCC is efficient and convenient for providing continuous pharmaceutical care to patients with cancer during the COVID-19 crisis. The widespread use of this platform can help to reduce person-to-person transmission as well as infection risk for these patients. Further efforts are needed to improve the quality and acceptance of the Cloud SYSUCC platform, as well as to regulate and standardize the management of this novel service.


Assuntos
COVID-19/epidemiologia , Neoplasias/tratamento farmacológico , Satisfação do Paciente , Serviço de Farmácia Hospitalar/estatística & dados numéricos , SARS-CoV-2 , Telemedicina/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Pandemias , Inquéritos e Questionários , Centros de Atenção Terciária , Adulto Jovem
3.
Acta Pharmacol Sin ; 37(9): 1251-8, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27498776

RESUMO

AIM: Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients. METHODS: A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d). RESULTS: Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62- and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C0D7/D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers. CONCLUSION: The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients.


Assuntos
Citocromo P-450 CYP3A/genética , Diploide , Imunossupressores/sangue , Transplante de Rim , Polimorfismo de Nucleotídeo Único , Tacrolimo/sangue , Adolescente , Adulto , Idoso , China , Estudos de Coortes , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Testes Farmacogenômicos , Análise de Regressão , Tacrolimo/administração & dosagem , Tacrolimo/uso terapêutico , Adulto Jovem
4.
Yao Xue Xue Bao ; 51(8): 1240-4, 2016 08.
Artigo em Zh | MEDLINE | ID: mdl-29897725

RESUMO

The study aims to investigate the associations of SLCO1B1 polymorphisms with tacrolimus concentrations in Chinese renal transplant recipients. Blood samples and clinical data were collected from 89 renal transplant recipients with tacrolimus treatment. CYP3A5*3 genotypes were detected by PCR-RFLP method and SLCO1B1(rs2306283, rs4149032) genotypes were detected by Agena Bioscience Mass ARRAY® system. Trough concentrations of tacrolimus on day 7 after renal transplantation were collected from clinical data. Correlations between genetic polymorphisms and tacrolimus concentrations were analyzed by SPSS. In CYP3A5 nonexpressers, the dose-adjusted concentration of tacrolimus in SLCO1B1 rs2306283 CC carriers was considerably higher than that in CT and TT carriers. The results illustrated that SLCO1B1 rs2306283 polymorphisms were associated with tacrolimus concentrations, and genotyping for this SNP may be useful for individualized medicine of tacrolimus.


Assuntos
Imunossupressores/sangue , Transplante de Rim , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Tacrolimo/sangue , Adulto , Povo Asiático/genética , China , Citocromo P-450 CYP3A/genética , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Imunossupressores/farmacocinética , Rim , Masculino , Polimorfismo de Nucleotídeo Único , Tacrolimo/farmacocinética
5.
Yao Xue Xue Bao ; 49(4): 530-4, 2014 Apr.
Artigo em Zh | MEDLINE | ID: mdl-24974473

RESUMO

To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.


Assuntos
Anticonvulsivantes , Carbamazepina , Epilepsia/sangue , Ácido Valproico , Adolescente , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Carbamazepina/sangue , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Interações Medicamentosas , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Ácidos Graxos Monoinsaturados/sangue , Feminino , Humanos , Masculino , Ácido Valproico/sangue , Ácido Valproico/farmacocinética , Ácido Valproico/uso terapêutico , Adulto Jovem
6.
Virol J ; 10: 314, 2013 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-24161012

RESUMO

BACKGROUND: Epstein-Barr virus (EBV) is an etiological cause of many human lymphocytic and epithelial malignancies. EBV expresses different genes that are associated with three latency types. To date, as many as 44 EBV-encoded miRNA species have been found, but their comprehensive profiles in the three types of latent infection that are associated with various types of tumors are not well documented. METHODS: In the present study, we utilized poly (A)-tailed quantitative real-time RT-PCR in combination with microarray analysis to measure the relative abundances of viral miRNA species in a subset of representative lymphoid and epithelial tumor cells with various EBV latency types. RESULTS: Our findings showed that the miR-BHRF1 and miR-BART families were expressed differentially in a tissue- and latency type-dependent manner. Specifically, in nasopharyngeal carcinoma (NPC) tissues and the EBV-positive cell line C666-1, the miR-BART family accounted for more than 10% of all detected miRNAs, suggesting that these miRNAs have important roles in maintaining latent EBV infections and in driving NPC tumorigenesis. In addition, EBV miRNA-based clustering analysis clearly distinguished between the three distinct EBV latency types, and our results suggested that a switch from type I to type III latency might occur in the Daudi BL cell line. CONCLUSIONS: Our data provide a comprehensive profiling of the EBV miRNA transcriptome that is associated with specific tumor cells in the three types of latent EBV infection states. EBV miRNA species represent a cluster of non-encoding latency biomarkers that are differentially expressed in tumor cells and may help to distinguish between the different latency types.


Assuntos
Perfilação da Expressão Gênica , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/fisiologia , MicroRNAs/genética , RNA Viral/genética , Latência Viral , Biópsia , Células Cultivadas , Humanos , Leucemia Linfoide/virologia , MicroRNAs/biossíntese , Análise em Microsséries , Neoplasias Epiteliais e Glandulares/virologia , RNA Viral/biossíntese , Reação em Cadeia da Polimerase em Tempo Real
7.
Zhong Yao Cai ; 35(2): 254-9, 2012 Feb.
Artigo em Zh | MEDLINE | ID: mdl-22822673

RESUMO

OBJECTIVE: To study the influences of Shengbanfang on CYP3A1 activities of SD rat and provide suggestions for drug combinations. METHODS: 25 male SD rats were devided into 5 groups randomly,and treated with saline( NS, ig, 10 mg/(kg/d) ,qd,14 d), dexamethasone (DEX, ig, 100 mg/(kg x d), qd, 3 d), high dose of Shengbanfang (HD, ig, 8.645 g/kg, bid, 14 d), middle dose of Shengbanfang (MD, ig, 4.322 g/kg, bid, 14 d) and low dose of Shengbanfang (LD, ig, 2.161 g/kg, bid, 14 d), respectively. The HPLC method was established and validated to determine the productive velocity of 6beta-hydroxytestosterone and measure the activity of CYP3Al. RESULTS: Under the optimized incubation conditions, the productive rates of 6beta-hydroxytestosterone of HD, MD, LD, NS and DEX, groups were (55.82 +/- 5.97), (65.10 +/- 6.83), (60.89 +/- 6.53), (62.17 +/- 6.55), (126.73 +/- 15.40) micromol/(L x mg pro x min). There were significant differences between Shengbanfang groups compared with dexamethasone group, but there was no significant difference between Shengbanfang groups and the control group (NS). CONCLUSION: Shengbanfang has no induce effect on the enzymic activity of CYP3Al in SD rats.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Dexametasona/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Microssomos Hepáticos/enzimologia , Testosterona/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Ativação Enzimática/efeitos dos fármacos , Hidroxitestosteronas/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Plantas Medicinais/química , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico
8.
Zhong Yao Cai ; 34(10): 1648-51, 2011 Oct.
Artigo em Zh | MEDLINE | ID: mdl-22372157

RESUMO

OBJECTIVE: To predict the potential molecular target proteins of Yinchenhao decocation by computer systems biology approaches. METHODS: For text mining, TCMGeneDIT was used to retrieve association information regarding genes or proteins, Artemisiae scopariae of 17 main compounds absorbed into blood after oral administration of Yinchenhao decoction, target identificetion and analysis was conducted to determine the target proteins of those compounds using PharmMapper sever. The proteins which had direct interaction with predictive target proteins were selected by screening BIND, BioGRID, DIP, HPRD, IntAct, MINT database. RESULTS: Four and eight proteins were found to respectively associate with Artemisiae scopariae herba and Rhei radix et rhizome. Six components including rhein, emodin, 6, 7-dimethoxy coumarin not only directly interacted with target proteins which were proved by experiments, but also interacted with other related proteins. Eight components such as isofradin-3-O-glycoside could only play assistant roles by interacting with related proteins. CONCLUSION: The result provides useful information for further research. It is expected it would be helpful for understanding the molecular mechanism of Yinchenhao decoction. Taken together, the protocol developed in the study may lead to a deeper understanding of a system as a whole in the mechanism of Chinses formula.


Assuntos
Desenho de Fármacos , Medicamentos de Ervas Chinesas/química , Medicina Tradicional Chinesa , Plantas Medicinais/química , Proteínas/metabolismo , Biologia de Sistemas , Coleta de Dados/métodos , Bases de Dados de Proteínas , Combinação de Medicamentos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Proteínas/química
9.
CNS Neurosci Ther ; 25(5): 612-620, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30676695

RESUMO

AIMS: It is well established that exposure of common anesthetic isoflurane in early life can induce neuronal apoptosis and long-lasting cognitive deficit, but the underlying mechanisms were not well understood. The cell cycle protein Cyclin B1 plays an important role in the survival of postmitotic neurons. In the present study, we investigated whether cyclin B1-mediated cell cycle activation pathway is a contributing factor in developmental isoflurane neurotoxicity. METHODS: Postnatal day 7 mice were exposed to 1.2% isoflurane for 6 hours. CR8 (a selective inhibitor of cyclin-dependent kinases) was applied before isoflurane treatment. Brain samples were collected 6 hours after discontinuation of isoflurane, for determination of neurodegenerative biomarkers and cell cycle biomarkers. RESULTS: We found that isoflurane exposure leads to upregulated expression of cell cycle-related biomarkers Cyclin B1, Phospho-CDK1(Thr-161), Phospho-n-myc and downregulated Phospho-CDK1 (Tyr-15). In addition, isoflurane induced increase in Bcl-xL phosphorylation, cytochrome c release, and caspase-3 activation that resulted in neuronal cell death. Systemic administration of CR8 attenuated isoflurane-induced cell cycle activation and neurodegeneration. CONCLUSION: These findings suggest the role of cell cycle activation to be a pathophysiological mechanism for isoflurane-induced apoptotic cell death and that treatment with cell cycle inhibitors may provide a possible therapeutic target for prevention of developmental anesthetic neurotoxicity.


Assuntos
Anestésicos Inalatórios/toxicidade , Encéfalo/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Isoflurano/toxicidade , Fármacos Neuroprotetores/farmacologia , Purinas/farmacologia , Piridinas/farmacologia , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Caspase 3/metabolismo , Ciclo Celular/fisiologia , Ciclina B1/metabolismo , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia
10.
Zhongguo Gu Shang ; 28(2): 101-5, 2015 Feb.
Artigo em Zh | MEDLINE | ID: mdl-25924488

RESUMO

OBJECTIVE: To research the application and clinical effect of titanium elastic nails (TEN) for the treatment of closed clavicular fracture in elder children. METHODS: From October 2010 to December 2012,16 elderly children with clavicular fracture of elder children were treated with internal fixation, including 9 boys and 7 girls with an average age of 14.2 yeats old ranging from 9 to 17 years. The mean time between injury and surgery was 2 to 6 days. Thirteen patients had a transverse fractures; 3 patients had a oblique fractures, excluding the long-oblique patients. Neer function score after 3 months follow-up and the shoulder activity degree after 3 weeks followed were compared respectively between the injured side and healthy side. Fracture reduction and healing were followed up by X-rays to analyze internal fixation with TEN technique. RESULTS: All patients were healed well after surgery. There were 2 cases with soft tissue irritation. No cases of infection, TEN broken, delayed healing or skin bursting were observed. All patients were followed up for 3 to 10 months,with an average of 7.2 months. There were no significant differences (t=2.12, P>0.05) between the healthy side (98.75±2.70) and injured side(96.69±6.22)of Neer score at 3 months during followed up. The shoulder activity at 3 weeks during followed up was different between both sides (P<0.05). The intramedullary nail was removed after X-rays at 12-18 weeks during followed up showed good bone healing,and the shoulder function was recovered well. CONCLUSION: Internal fixation with TEN for the treatment of clavicular fracture has advantages of a limited invasion, beauty, safety and reliability. This technique provides an ideal fixation option for the treatment of clavicular fracture in elder children.


Assuntos
Pinos Ortopédicos , Clavícula/lesões , Fixação Interna de Fraturas/métodos , Fraturas Ósseas/cirurgia , Adolescente , Criança , Clavícula/cirurgia , Elasticidade , Feminino , Humanos , Masculino , Titânio
11.
World J Gastroenterol ; 20(1): 183-92, 2014 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-24415871

RESUMO

AIM: To examine the status and clinical significance of anaplastic lymphoma kinase (ALK) gene alterations in hepatocellular carcinoma (HCC) patients. METHODS: A total of 213 cases of HCC were examined by fluorescent in situ hybridization using dual color break-apart ALK probes for the detection of chromosomal translocation and gene copy number gain. HCC tissue microarrays were constructed, and the correlation between the ALK status and clinicopathological variables was assessed by χ(2) test or Fisher's exact test. Survival analysis was estimated using the Kaplan-Meier approach with a Log-rank test. Univariate and multivariate analyses of clinical variables were performed using the Cox proportional hazards regression model. RESULTS: ALK gene translocation was not observed in any of the HCC cases included in the present study. ALK gene copy number gain (ALK/CNG) (≥ 4 copies/cell) was detected in 28 (13.15%) of the 213 HCC patients. The 3-year progression-free-survival (PFS) rate for ALK/CNG-positive HCC patients was significantly poorer than ALK/CNG-negative patients (27.3% vs 42.5%, P = 0.048), especially for patients with advanced stage III/IV (0% vs 33.5%, P = 0.007), and patients with grade III disease (24.8% vs 49.9%, P = 0.023). ALK/CNG-positive HCC patients had a significantly poorer prognosis than ALK/CNG-negative patients in the subgroup that was negative for serum hepatitis B virus DNA, with significantly different 3-year overall survival rates (18.2% vs 63.6%, P = 0.021) and PFS rates (18.2% vs 46.9%, P = 0.019). Multivariate Cox proportional hazards regression analysis suggested that ALK/CNG prevalence can predict death in HCC (HR = 1.596; 95%CI: 1.008-2.526, P = 0.046). CONCLUSION: ALK/CNG, but not translocation of ALK, is present in HCC and may be an unfavorable prognostic predictor.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Variações do Número de Cópias de DNA , Dosagem de Genes , Neoplasias Hepáticas/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Idoso , Quinase do Linfoma Anaplásico , Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , Fenótipo , Modelos de Riscos Proporcionais , Receptores Proteína Tirosina Quinases/análise , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Análise Serial de Tecidos
12.
Cancer Lett ; 344(2): 260-71, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24262659

RESUMO

Emerging evidence confirms that cancer stem cells (CSCs) are responsible for the chemoradioresistance of malignancies. EBV-encoded latent membrane protein 1 (LMP1) is associated with tumor relapse and poor prognosis of nasopharyngeal carcinoma (NPC). However, whether LMP1 induces the development of CSCs and the mechanism by which this rare cell subpopulation leads to radioresistance in NPC remain unclear. In the present study, LMP1-transformed NPC cells showed significant radioresistance compared to the empty vector control. We found that LMP1 up-regulated the expression of several stemness-related genes, increased the cell number of side population (SP) by flow cytometry analysis, enhanced the self-renewal properties of the cells in a spherical culture and enhanced the in vivo tumor initiation ability. We also found that LMP1 positively regulated the expression of the CSC marker CD44. The CD44(+/High) subpopulation of the LMP1-transformed NPC cells displayed more significant CSC characteristics than the CD44(-/Low) subpopulation of the LMP1-transformed NPC cells; these characteristics included the upregulation of stemness-related genes, in vitro self-renewal and in vivo tumor initiation ability. Importantly, the CD44(+/High) subpopulation displayed more radioresistance than the CD44(-/Low) subpopulation. Our results also demonstrated that phosphorylation of the DNA damage response (DDR) proteins, ATM, Chk1, Chk2 and p53, was inactivated in the LMP1-induced CD44(+/High) cells in response to DNA damage, and this was accompanied by a downregulation of the p53-targeted proapoptotic genes, which suggested that the inactivation of the p53-mediated apoptosis pathway was responsible for the radioresistance in the CD44(+/High) cells. Taken together, we found that LMP1 induced an increase in CSC-like CD44(+/High) cells, and we determined the molecular mechanism underlying the radioresistance of the LMP1-activated CSCs, highlighting the need of CSC-targeted radiotherapy in EBV-positive NPC.


Assuntos
Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/virologia , Células-Tronco Neoplásicas/efeitos da radiação , Células-Tronco Neoplásicas/virologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteínas da Matriz Viral/biossíntese , Animais , Apoptose/fisiologia , Apoptose/efeitos da radiação , Carcinoma , Herpesvirus Humano 4/metabolismo , Humanos , Raios Infravermelhos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/radioterapia , Células-Tronco Neoplásicas/metabolismo , Tolerância a Radiação , Transdução de Sinais/efeitos da radiação , Proteína Supressora de Tumor p53/metabolismo
13.
PLoS One ; 8(10): e78355, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24194922

RESUMO

Approximately 30% of patients with Epstein-Barr virus (EBV)-positive advanced nasopharyngeal carcinoma (NPC) display chemoresistance to cisplatin-based regimens, but the underlying mechanisms are unclear. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), a functional homologue of the tumor necrosis factor receptor family, contributes substantially to the oncogenic potential of EBV through the activation of multiple signaling pathways, and it is closely associated with a poorer prognosis for NPC. Recent studies show that EBV infection can induce the expression of many cellular miRNAs, including microRNA-21, a biomarker for chemoresistance. However, neither a link between LMP1 expression and miR-21 upregulation nor their cross talk in affecting chemoresistance to cisplatin have been reported. Here, we observed that stable LMP1-transformed NPC cells were less sensitive to cisplatin treatment based on their proliferation, colony formation, the IC50 value of cisplatin and the apoptosis index. Higher levels of miR-21 were found in EBV-carrying and LMP1-positive cell lines, suggesting that LMP1 may be linked to miR-21 upregulation. These data were confirmed by our results that exogenous LMP1 increased miR-21 in both transiently and stably LMP1-transfected cells, and the knock down of miR-21 substantially reversed the resistance of the NPC cells to cisplatin treatment. Moreover, the proapoptotic factors programmed cell death 4 (PDCD4) and Fas ligand (Fas-L), which were negatively regulated by miR-21, were found to play an important role in the program of LMP1-dependent cisplatin resistance. Finally, we demonstrated that LMP1 induced miR-21 expression primarily by modulating the PI3K/AKT/FOXO3a signaling pathway. Taken together, we revealed for the first time that viral LMP1 triggers the PI3K/Akt/FOXO3a pathway to induce human miR-21 expression, which subsequently decreases the expression of PDCD4 and Fas-L, and results in chemoresistance in NPC cells.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/metabolismo , Neoplasias Nasofaríngeas/tratamento farmacológico , Proteínas da Matriz Viral/metabolismo , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/genética , Western Blotting , Carcinoma , Linhagem Celular , Cisplatino/farmacologia , Ensaio de Unidades Formadoras de Colônias , Proteína Ligante Fas/antagonistas & inibidores , Proteína Ligante Fas/genética , Imunofluorescência , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Concentração Inibidora 50 , Luciferases , MicroRNAs/genética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/virologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Sais de Tetrazólio , Tiazóis , Proteínas da Matriz Viral/farmacologia
14.
Br J Pharmacol ; 166(5): 1669-83, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22233293

RESUMO

BACKGROUND AND PURPOSE: Besides targeting the well-known oncogenic c-Met, crizotinib is the first oral tyrosine kinase inhibitor inhibiting anaplastic lymphoma kinase (ALK) in clinical trials for the treatment of non-small cell lung cancer. Here, we assessed the possible reversal of multidrug resistance (MDR) by crizotinib in vitro and in vivo. EXPERIMENTAL APPROACH: 1-(4,5-Dimethylthiazol-2-yl)-3,5- diphenylformazan was used in vitro and xenografts in nude mice were used in vivo to investigate reversal of MDR by crizotinib. To understand the mechanisms for MDR reversal, the alterations of intracellular doxorubicin or rhodamine 123 accumulation, doxorubicin efflux, ABCB1 expression level, ATPase activity of ABCB1 and crizotinib-induced c-Met, Akt and ERK1/2 phosphorylation were examined. KEY RESULTS: Crizotinib significantly enhanced the cytotoxicity of chemotherapeutic agents which are also ABCB1 substrates, in MDR cells with no effect found on sensitive cells in vitro and in vivo. Additionally, crizotinib significantly increased intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in ABCB1-overexpressing MDR cells. Further studies showed that crizotinib enhanced the ATPase activity of ABCB1 in a concentration-dependent manner. However, expression of ABCB1 was not affected, and reversal of MDR by crizotinib was not related to the phosphorylation of c-Met, Akt or ERK1/2. Importantly, crizotinib significantly enhanced the effect of paclitaxel against KBv200 cell xenografts in nude mice. CONCLUSIONS AND IMPLICATIONS: Crizotinib reversed ABCB1-mediated MDR by inhibiting ABCB1 transport function without affecting ABCB1 expression or blocking the Akt or ERK1/2 pathways. These findings are useful for planning combination chemotherapy of crizotinib with conventional chemotherapeutic drugs.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Crizotinibe , Doxorrubicina/farmacocinética , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Rodamina 123/farmacocinética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Res ; 70(20): 7981-91, 2010 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-20876799

RESUMO

Apatinib, a small-molecule multitargeted tyrosine kinase inhibitor, is in phase III clinical trial for the treatment of patients with non-small-cell lung cancer and gastric cancer in China. In this study, we determined the effect of apatinib on the interaction of specific antineoplastic compounds with P-glycoprotein (ABCB1), multidrug resistance protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2). Our results showed that apatinib significantly enhanced the cytotoxicity of ABCB1 or ABCG2 substrate drugs in KBv200, MCF-7/adr, and HEK293/ABCB1 cells overexpressing ABCB1 and in S1-M1-80, MCF-7/FLV1000, and HEK293/ABCG2-R2 cells overexpressing ABCG2 (wild-type). In contrast, apatinib did not alter the cytotoxicity of specific substrates in the parental cells and cells overexpressing ABCC1. Apatinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin in the multidrug resistance (MDR) cells. Furthermore, apatinib significantly inhibited the photoaffinity labeling of both ABCB1 and ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. The ATPase activity of both ABCB1 and ABCG2 was significantly increased by apatinib. However, apatinib, at a concentration that produced a reversal of MDR, did not significantly alter the ABCB1 or ABCG2 protein or mRNA expression levels or the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2). Importantly, apatinib significantly enhanced the effect of paclitaxel against the ABCB1-resistant KBv200 cancer cell xenografts in nude mice. In conclusion, apatinib reverses ABCB1- and ABCG2-mediated MDR by inhibiting their transport function, but not by blocking the AKT or ERK1/2 pathway or downregulating ABCB1 or ABCG2 expression. Apatinib may be useful in circumventing MDR to other conventional antineoplastic drugs.


Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridinas/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Adenosina Trifosfatases/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Animais , Neoplasias da Mama , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo
17.
Ai Zheng ; 26(12): 1287-91, 2007 Dec.
Artigo em Zh | MEDLINE | ID: mdl-18076788

RESUMO

BACKGROUND & OBJECTIVE: Docetaxel is used to treat non-small cell lung cancer, breast cancer and ovarian cancer. It is indissolvable and the solvent containing polysorbate-80 and 13% solution of ethanol is used for injections. Its clinical application is limited because of frequent severe hypersensitive responses. This study was to prepare docetaxel (DOC) liposomes and investigate their pharmacokinetics in rabbits after intravenous administration. METHODS: DOC liposomes, with or without modification of polyethylene glycol (PEG), were prepared by thin-film ultrasonic dispersion method. The entrapment efficiency and mean diameter of the liposomes were measured. After intravenous administration in rabbits, plasma DOC concentration was detected by solid phase extraction high-performance liquid chromatography (SPE-HPLC). The pharmacokinetic parameters were calculated and analyzed by 3p87 pharmacokinetic program. RESULTS: The entrapment efficiency of DOC liposomes was above 75%. The mean diameter was about 150 nm. The half-life of distribution (T(1/2alpha)) were (0.17+/-0.04) h for market docetaxel injection (M-DOC), (0.31+/-0.11) h for common DOC liposome (L-DOC), and (0.32+/-0.06) h for PEG-2000-modified DOC long circulating liposome (PEG-DOC-LCL); the half-life of clearance (T(1/2beta)) were (8.54+/-1.05), (11.18+/-1.33), and (10.51+/-1.13) h, respectively; the apparent volume of distribution (V(d)) were (13.66+/-3.62), (8.65+/-1.11), and (6.31+/-0.55) L, respectively; the area under the concentration-time curve from 0 to 24 h (AUC(0-->24)) were (13.45+/-2.44), (22.83+/-3.57), and (29.31+/-5.96) mg x (h x L)(-1), respectively; the area under the concentration-time curve from 0 to infinity h (AUC(0-->infinity)) were (15.07+/-2.76), (28.70+/-4.95), and (36.95+/-9.13) mg x (h x L)(-1), respectively; the clearance (CL) were (1.10+/-0.18), (0.54+/-0.08), and (0.42+/-0.07) L/h, respectively. CONCLUSION: The thin-film prepared DOC liposomes have high entrapment efficiency and small particle size. Both liposomes, especially PEG-DOC-LCL, can raise AUC and prolong the resident time of drugs in the blood circulating system.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Lipossomos , Taxoides/administração & dosagem , Taxoides/farmacocinética , Animais , Área Sob a Curva , Docetaxel , Portadores de Fármacos , Composição de Medicamentos , Estabilidade de Medicamentos , Feminino , Injeções Intravenosas , Masculino , Tamanho da Partícula , Polietilenoglicóis , Coelhos
18.
Ai Zheng ; 25(8): 1052-8, 2006 Aug.
Artigo em Zh | MEDLINE | ID: mdl-16965693

RESUMO

BACKGROUND & OBJECTIVE: Lately, the prevention, treatment and research of cancer have developed rapidly. Antineoplastic drugs have become one of the major measures for cancer therapy. Many new antineoplastic drugs have been discovered and prepared, and used to treat tumors. Cancer Center of Sun Yat-sen University is one of the biggest cancer hospitals in South China. The use of antineoplastic drugs of this center can reflect changes in this area. This study was to analyze and evaluate the situation and trend of antineoplastic drugs used in Cancer Center, Sun Yat-sen University from 1996 and 2005, in order to provide references for the rational use of drugs in clinical application. METHODS: Consumption of antineoplastic drugs was analyzed by sum and defined daily dose (DDDs) ranking. RESULTS: The costs of antineoplastic drugs occupied 31.0%-48.8% of all drugs from 1996 to 2005; and the average increasing ratio is 21.5%. The cost rate of anti-cancer vegetable drugs and other genus increased the quickest, while the total costs of alkylate increased the slowest during the ten years. Some new monoantibodies and gene drugs were continuously applied in clinical use. CONCLUSION: The direction of the research and development of antineoplastic drugs is towards high efficiency, low toxicity and individualized use.


Assuntos
Anticorpos Monoclonais/economia , Antimetabólitos Antineoplásicos/economia , Antineoplásicos Fitogênicos/economia , Antineoplásicos/economia , Cisplatino/economia , Revisão de Uso de Medicamentos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Carboplatina/economia , Carboplatina/uso terapêutico , China , Cisplatino/uso terapêutico , Análise Custo-Benefício , Desoxicitidina/análogos & derivados , Desoxicitidina/economia , Desoxicitidina/uso terapêutico , Custos de Medicamentos/tendências , Humanos , Neoplasias/tratamento farmacológico , Paclitaxel/economia , Paclitaxel/uso terapêutico , Rituximab , Vimblastina/análogos & derivados , Vimblastina/economia , Vimblastina/uso terapêutico , Vinorelbina , Gencitabina
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