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1.
Oncotarget ; 8(32): 53405-53418, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28881820

RESUMO

Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated-EGFRs was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type EGFR (WT-EGFR). Moreover, the time-to-event analysis model considering death as a competing risk revealed that, irrespective of survival, mutated-EGFRs predicted subsequent BM (SBM) in stage IIIB-IV patients (37.1% vs. 10.6%, HR=2.98, P=0.002) after adjusting for age (HR=2.00, P=0.012), gender, histological subtype, and smoking history. Notably, the younger mutated-EGFR subgroup was at a higher risk for SBM compared to the older WT-EGFR one (58.1% vs.10.9%, HR=6.57, P<0.001). Additionally, EGFR exon 19 deletion, despite having a slightly longer overall survival (20.6 vs. 14.2 months, P=0.368), was comparable to L858R mutation in predicting SBM (39.5% vs. 34.5%, HR=0.91, P=0.770). In vitro, the overexpression of mutated-EGFRs induced morphological changes towards a mesenchymal-like phenotype and promoted mobility in lung cancer cells. Clinically, mutated-EGFR NSCLC displayed a higher proportion of vimentin-positive expression (75.3% vs. 51.2%; P=0.007) and a shorter median time to SBM (23.5 months vs. not reached, P=0.017) than WT-EGFR NSCLC. These results suggest that NSCLC patients carrying mutated-EGFRs may require a higher frequency of brain imaging assessments than those with WT-EGFR to facilitate earlier SBM detection during follow-up.

2.
Eur J Med Chem ; 100: 151-61, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26081023

RESUMO

Numerous FLT3 inhibitors have been explored as a viable therapy for the treatment of acute myeloid leukemia (AML). However, clinical data have been underwhelming due to incomplete inhibition of FLT3 or the emergence of resistant mutations treated with these older agents. We previously developed a series of 3-phenyl-1H-5-pyrazolylamine derivatives as highly potent and selective FLT3 inhibitors with good in vivo efficacy using an intravenous (IV) route. However, the poor bioavailability of these pyrazole compounds limits the development of these promising antileukemic compounds for clinical use. Herein, we describe a novel class of 5-phenyl-thiazol-2-ylamine compounds that are multi-targeted FLT3 inhibitors. From this class of compounds, compound 7h was very potent against AML cell lines and exhibited excellent oral efficacy in AML xenograft models. In addition, further studies demonstrated that compound 7h exhibited potent in vitro and in vivo activities against clinically relevant AC220 (3)-resistant kinase domain mutants of FLT3-ITD.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Experimentais/tratamento farmacológico , Mutação Puntual/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
3.
Biomed Res Int ; 2014: 937429, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25250341

RESUMO

BACKGROUND: Cisplatin and carboplatin cause nephrotoxicity by forming platinum-DNA adducts and lead to cell death. METHODS: One-hundred and sixteen Taiwanese lung cancer patients who received cisplatin or carboplatin more than twice were recruited, and their genotypes were determined. The risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease (RIFLE) criteria were used to evaluate the occurrence of nephrotoxicity. A logistic regression, multiple regression with a classification and regression tree (CART), and the Framingham study risk score were used to analyze interactions between genetic and nongenetic factors in producing platinum-induced nephrotoxicity. RESULTS: ERCC1 118C and TP53 72Arg polymorphisms were associated with increased risks of platinum-induced nephrotoxicity. Other risk factors found included the platinum type, baseline serum creatinine (Scr), coadministration of vinorelbine, and the number of chemotherapy cycles. The overall prediction rate of the CART was 82.7%, with a sensitivity of 0.630 and specificity of 0.896. The Framingham study risk prediction model contained 7 factors. Its prediction rate was 84.5%, with a sensitivity of 0.643 and specificity of 0.909. CONCLUSIONS: Genetic polymorphisms of ERCC1 and TP53 are risk factors for nephrotoxicity. The CART analysis may provide a clinically applicable model to predict the risk of cisplatin- and carboplatin-induced nephrotoxicity.


Assuntos
Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Nefropatias/epidemiologia , Nefropatias/genética , Pneumopatias/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Criança , Comorbidade , Creatinina/sangue , Interpretação Estatística de Dados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Incidência , Nefropatias/sangue , Pneumopatias/sangue , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco/métodos , Distribuição por Sexo , Taiwan/epidemiologia , Adulto Jovem
4.
Mol Clin Oncol ; 2(2): 252-258, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24649342

RESUMO

Mutations in epidermal growth factor receptor (EGFR) commonly occur in non-small-cell lung cancer (NSCLC) patients characterized by female gender, never-smoker status and adenocarcinoma histology. The aim of this study was to determine whether gender is a confounding factor for EGFR mutations in NSCLC. To elucidate the confounding effect, Pearson's χ2 test and logistic regression models were used to correlate these characteristics with EGFR mutations in 426 NSCLC patients treated at our institutes. Of those 426 NSCLC patients, 47% were females, 57% were non-smokers and 84% had adenocarcinomas. The multivariate logistic regression analysis demonstrated that never-smoker status [odds ratio (OR)=3.49, 95% confidence interval (CI): 1.99-6.13; P<0.001)] and adenocarcinoma (OR=9.43, 95% CI 3.62-24.56; P<0.001) were associated with EGFR mutations; however, gender was not (OR=1.25, 95% CI: 0.73-2.15; P=0.416). Furthermore, gender was not associated with EGFR mutation subtypes (OR=1.19, 95% CI: 0.56-2.50; P=0.650). The frequency of EGFR mutations among females and males was not different in non-smokers (64.8 vs. 55.8%, P=0.204) or ever-smokers (27.8 vs. 24.2%, P=0.775). Therefore, if the assessment for EGFR mutation status was limited to non-smoking females with adenocarcinoma, up to 40% of the patients harboring EGFR mutations would be precluded from the benefit of EGFR inhibitor therapy. Our results indicated that gender is a confounding factor for EGFR mutations in NSCLC and suggested that gender may not be associated with tumorigenesis in NSCLC-harboring EGFR mutations.

5.
Int J Cancer ; 134(1): 65-71, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23797776

RESUMO

Human papillomavirus (HPV) has been implicated in multiple cancers, but its significance in lung cancer has remained controversial. As the prevalence of HPV 16/18 infection was higher in lung adenocarcinoma among Taiwanese females, the aim of our study was to evaluate the clinical impact of HPV infections in lung adenocarcinoma. Two hundred and ten patients were enrolled to investigate the associations of HPV status in tumors with clinical characteristics as well as its impact on overall survival. The methods to assess HPV status were by immunohistochemistry for HPV L1 capsid protein and E6 protein and by nested polymerase chain reaction for HPV 16 and HPV 18. HPV infections were identified in 35.2% of patients, and associated with localized and smaller sized tumors (p = 0.022 and p = 0.002, respectively). Patients with HPV infections had a significantly better survival (p = 0.023, by log-rank test) and a significantly reduced mortality risk after adjustments of age, tumor extent, epidermal growth factor receptor (EGFR) mutations status and treatments [adjusted hazard ratio = 0.68, 95% confidence interval (CI) = 0.49-0.96, p = 0.026, by multivariate Cox proportional hazards models]. Specifically, patients with both HPV infections and EGFR mutations had the best survival outcome [1-year survival rate, 68.5% (95% CI = 52.2-4.8%)]. Our findings indicate that HPV infections represent an independent prognostic factor for overall survival in patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/virologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/mortalidade , Adenocarcinoma de Pulmão , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Reação em Cadeia da Polimerase , Prognóstico , Modelos de Riscos Proporcionais
6.
PLoS One ; 8(12): e83266, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24376677

RESUMO

INTRODUCTION: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been associated with favorable progression free survival (PFS) in patients with non-small cell lung cancers (NSCLC) harboring EGFR mutations. However, a subset of this population doesn't respond to EGFR-TKI treatment. Therefore, the present study aimed to elucidate survival outcome in NSCLC EGFR-mutant patients who were treated with EGFR TKIs. METHODS: Among the 580 consecutive NSCLC patients who were treated at our facility between 2008 and 2012, a total of 124 treatment-naïve, advanced NSCLC, EGFR-mutant patients treated with EGFR TKIs were identified and grouped into non-responders and responders for analyses. RESULTS: Of 124 patients, 104 (84%) responded to treatment, and 20 (16%) did not; and the overall median PFS was 9.0 months. Notably, the PFS, overall survival (OS) and survival rates were significantly unfavorable in non-responders (1.8 vs. 10.3 months, hazard ratio (HR) = 29.2, 95% confidence interval (CI), 13.48-63.26, P<0.0001; 9.4 vs. 17.3 months, HR = 2.74, 95% CI, 1.52-4.94, P = 0.0008; and 58% vs. 82% in 6, 37% vs. 60% in 12, and 19 vs. 40% at 24 months, respectively). In multivariate analysis, treatment efficacy strongly affected PFS and OS, independent of covariates (HR = 47.22, 95% CI, 17.88-124.73, P<0.001 and HR = 2.74, 95% CI, 1.43-5.24, P = 0.002, respectively). However, none of the covariates except of the presence of EGFR exon 19 deletion in the tumors was significantly associated with better treatment efficacy. CONCLUSIONS: A subset of NSCLC EGFR-mutant patients displayed unfavorable survival despite EGFR TKI administration. This observation reinforces the urgent need for biomarkers effectively predicting the non-responders and for drug development overcoming primary resistance to EGFR TKIs. In addition, optimal therapeutic strategies to prolong the survival of non-responders need to be investigated.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Neoplasias Pulmonares/mortalidade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Éxons , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
7.
Lung Cancer ; 82(2): 319-23, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24018025

RESUMO

PURPOSE: Brain metastases (BM), a common occurrence in non-small cell lung cancer (NSCLC), usually lead to a poor prognosis. Recently, the selection of treatment modalities for BM has modestly improved patient survival and quality of life. Treatment choice is largely based on the number of BM, the presence of BM-related symptoms, and performance status. Therefore, early BM detection is crucial. In this study, we aimed to elucidate the factors associated with BM and identify subgroups of patients at higher risk for BM. METHODS AND PATIENTS: The medical records of 596 consecutive patients with stage I-IV NSCLC were reviewed between January 2006 and November 2011. A multivariate logistic regression (MLR) model was used to identify factors associated with BM. RESULTS: Among 482 eligible stage IIIB/IV NSCLC patients, 173 (36%) experienced BM during their disease course. On MLR analysis, female gender, age < 60 years and adenocarcinoma were associated with BM (OR = 1.71, 95% CI = 1.06-2.75, P = 0.028; OR = 2.11, 95% CI = 1.38-3.22, P = 0.001; and OR = 2.39, 95% CI = 1.16-4.92, P = 0.018, respectively). The actuarial incidence of BM varied widely from 14% to 59% in different subgroups; younger patients with adenocarcinoma tended to experience BM more than older patients with squamous cell carcinoma (OR = 6.88, 95% CI = 2.97-15.94, P < 0.001). Furthermore, the incidence of BM correlated closely with survival after NSCLC diagnosis, and it was 42%, 54% and 64% in patients who survived more than 3, 12 and 24 months, respectively. Notably, the number of BM, the size of the largest BM and the proportion of multiple BM, defined as more than 4 metastatic tumors in brain, were significantly different in NSCLC patients with and without BM-related symptoms or signs (4.0 ± 2.1 vs 2.7 ± 1.9, P < 0.001; 2.6 ± 1.5 vs 1.3 ± 1.0 CM, P < 0.001, and 50% vs 21%, P < 0.001, respectively). CONCLUSION: We found that subgroups of NSCLC patients characterized by younger age, female gender and adenocarcinoma are at higher risks for BM. These findings might be helpful to detect BM earlier and facilitate the design of clinical trials aiming at their prevention.


Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Adulto , Fatores Etários , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Risco
8.
Radiat Oncol ; 7: 181, 2012 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-23110940

RESUMO

BACKGROUND: The presence of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) is associated with increased radiosensitivity in vitro. However, the results from clinical studies regarding the radiosensitivity in NSCLC with mutant EGFR are inconclusive. We retrospectively analyzed our NSCLC patients who had been regularly followed up by imaging studies after irradiation for brain metastases, and investigated the impact of EGFR mutations on radiotherapy (RT). METHODS: Forty-three patients with brain metastases treated with RT, together with EGFR mutation status, demographics, smoking history, performance status, recursive partitioning analysis (RPA) class, tumor characteristics, and treatment modalities, were included. Radiological images were taken at 1 to 3 months after RT, and 3 to 6 months thereafter. Radiographic response was evaluated by RECIST criteria version 1.1 according to the intracranial images before and after RT. Log-rank test and Cox regression model were used to correlate EGFR mutation status and other clinical features with intracranial radiological progression-free survival (RPFS) and overall survival (OS). RESULTS: The median follow-up duration was 15 months. Patients with mutant EGFR had higher response rates to brain RT than those with wild-type EGFR (80% vs. 46%; p = 0.037). Logistic regression analysis showed that EGFR mutation status is the only predictor for treatment response (p = 0.032). The median intracranial RPFS was 18 months (95% CI = 8.33-27.68 months). In Cox regression analysis, mutant EGFR (p = 0.025) and lower RPA class (p = 0.026) were associated with longer intracranial RPFS. EGFR mutation status (p = 0.061) and performance status (p = 0.076) had a trend to predict OS. CONCLUSIONS: Mutant EGFR in NSCLC patients is an independent prognostic factor for better treatment response and longer intracranial RPFS following RT for brain metastases.


Assuntos
Neoplasias Encefálicas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Irradiação Craniana , Receptores ErbB/genética , Neoplasias Pulmonares/radioterapia , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
10.
World J Hepatol ; 2(1): 16-20, 2010 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21160952

RESUMO

Hepatocelluar carcinoma (HCC) is the most lethal cancer in the world. Most HCC over-express c-Myc, which plays a critical role in regulating cellular growth, differentiation and apoptosis in both normal and neoplastic cells. c-Myc is among the most frequently overexpressed genes in human cancers. Overexpression of c-Myc in hepatic cells leads to development of hepatocellular carcinoma. Here, we review the current progress in understanding physiologic function and regulation of c-Myc as well as its role in hepatic carcinogenesis and discuss the association of c-Myc activation in chronic hepatitis B infection and the upregulation of HIF-1/VEGF. We also explore the possibility of treating HCC by inhibiting c-Myc and examine the pros and cons of such an approach. Although this strategy is currently not available in clinics, with recent advances in better drug design, pharmacokinetics and pharmacogenetics, inhibition of c-Myc might become a novel therapy for HCC in the future.

11.
Leuk Lymphoma ; 51(5): 897-905, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20233051

RESUMO

Meisoindigo, a derivative of Indigo naturalis, has been used in China for chronic myeloid leukemia. In vitro cell line studies have shown that this agent might induce apoptosis and myeloid differentiation of acute myeloid leukemia (AML). In this study, we explored its mechanisms and potential in AML. NB4, HL-60, and U937 cells and primary AML cells were used to examine its effects and the NOD/SCID animal model was used to evaluate its in vivo activity. Meisoindigo inhibited the growth of leukemic cells by inducing marked apoptosis and moderate cell-cycle arrest at the G(0)/G(1) phase. It down-regulated anti-apoptotic Bcl-2, and up-regulated pro-apoptotic Bak and Bax and cell-cycle related proteins, p21and p27. Furthermore, it induced myeloid differentiation, as demonstrated by morphologic changes, up-regulation of CD11b, and increased nitroblue tetrazolium reduction activity in all cell lines tested. In addition, meisoindigo down-regulated the expression of human telomerase reverse transcriptase and enhanced the cytotoxicity of conventional chemotherapeutic agents, cytarabine and idarubicin. As with the results from cell lines, meisoindigo also induced apoptosis, up-regulated p21 and p27, and down-regulated Bcl-2 in primary AML cells. The in vivo anti-leukemic activity of meisoindigo was also demonstrated by decreased spleen size in a dose-dependent manner. Taking these results together, meisoindigo is a potential agent for AML.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Western Blotting , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Humanos , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Telomerase/metabolismo , Células Tumorais Cultivadas , Regulação para Cima , Proteína X Associada a bcl-2/metabolismo
12.
J Gene Med ; 12(1): 11-21, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19866481

RESUMO

BACKGROUND: Asthma is a chronic disease characterized by airway inflammation caused by the dysregulated production of cytokines secreted by allergen-specific type 2 T helper (Th2) cells. Although the Th1-promoting cytokine, interleukin (IL)-12, is capable of inhibiting Th2-driven allergen-induced airway changes in mice, IL-12 also aggravates the Th1-driven inflammatory pulmonary pathology. Further, IL-10 was found to exert both anti-inflammatory and immunoregulatory activities. To avoid the side-effects of IL-12, we hypothesized that the low-dose expression of IL-10 with concomitant IL-12 administration in the airway may represent a more effective therapy for allergic airway diseases. Thus, the present study explored the immunomodulatory and therapeutic effects of IL-10 combined with IL-12 in airway inflammation in allergic asthma. METHODS: Adenovirus-expressing murine IL-10 (Ad-IL-10) and IL-12 (Ad-IL-12) were co-administrated in an established murine model of ovalbumin (OVA)-induced asthma. RESULTS: We found that a single combined treatment of low doses of Ad-IL-10 and Ad-IL-12 efficiently inhibited the development of airway hyper-responsiveness compared to Ad-IL-10 or Ad-IL-12 treatment alone. Moreover, both Ad-IL-10 and Ad-IL-12 treatment reduced pulmonary infiltration of eosinophils and neutrophils. In addition, histological studies showed that combined treatment was able to reduce tumor necrosis factor-alpha-mediated airway inflammation induced by IL-12 treatment. Suppression of IL-4, IL-5, Keratinocyte-derived chemokine (KC) and eotaxin in bronchoalveolar lavage fluid was also noted in OVA-immunized mice with combined Ad-IL-10 and Ad-IL-12 treatment. CONCLUSIONS: Taken together, the results obtained in the present study indicate that co-administration of IL-12 and IL-10 may have therapeutic potential for the immunomodulatory treatment of allergic asthma.


Assuntos
Adenoviridae/genética , Asma/terapia , Terapia Genética/métodos , Inflamação/terapia , Interleucina-10/uso terapêutico , Interleucina-12/uso terapêutico , Animais , Asma/complicações , Asma/genética , Asma/fisiopatologia , Hiper-Reatividade Brônquica/complicações , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/terapia , Líquido da Lavagem Broncoalveolar/citologia , Movimento Celular , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Eosinófilos/patologia , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Interleucina-10/administração & dosagem , Interleucina-12/administração & dosagem , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Infiltração de Neutrófilos , Células Th2/imunologia
14.
Lung Cancer ; 64(1): 9-12, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18706736

RESUMO

Identifying the risk factors responsible for lung cancer especially for nonsmokers is critical for both its prevention and treatment. Studies have linked the polymorphisms in N-acetyltransferases (NAT2), a key enzyme for metabolism of hydrocarbons, with lung cancer in Asian female nonsmokers. Since a high percentage of lung adenocarcinoma in Asian female nonsmokers contains activating hotspot mutations in epidermal growth factor receptors (EGFR), we hypothesized that NAT2 polymorphisms might represent a risk factor in lung cancer with EGFR mutations. We studied NAT polymorphisms in 117 nonsmall cell lung cancer (NSCLC) patients and in 119 healthy controls and EGFR hotspot mutations in exons 18-21 in 100 of the 117 patients using polymerase chain reactions. NAT2 fast acetylator genotypes were significantly associated with patients with lung cancer (P = 0.04, odds ratio (OR): 1.90, 95% confidence interval (CI): 1.02-3.57). Further analyses revealed that NAT2 fast acetylator genotypes were significantly associated with NSCLC with wildtype EGFR (P = 0.008, OR: 3.16, 95% CI: 1.31-7.63), but not with those with EGFR mutations (P = 0.40). Therefore, NAT2 fast acetylator genotypes are a potential risk factor especially for lung cancer with wildtype EGFR.


Assuntos
Arilamina N-Acetiltransferase/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético/genética , Acetilação , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Arilamina N-Acetiltransferase/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Estudos de Casos e Controles , Receptores ErbB/metabolismo , Feminino , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Prognóstico , Medição de Risco , Fatores de Risco
16.
J Dermatol Sci ; 51(2): 121-30, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18440785

RESUMO

BACKGROUND: Patients with chronic ordinary urticaria (CU) are divided into two groups: 30-50% have chronic autoimmune urticaria, and the remainder have chronic idiopathic urticaria. CD4(+)CD25(+) regulatory T (Treg) cells play critical roles in maintaining peripheral tolerance and preventing autoimmunity, but the characteristics of Treg cells have not yet been defined in CU. OBJECTIVE: To identify whether CD4(+) T cells play an important immunoregulatory role in the etiology of CU, we determined the frequencies and functions of circulating CD4(+)CD25(+) and CD4(+)CD25(-) T cells in CU patients and healthy control subjects, with special focus on the characteristics of CD4(+)CD25(+) T cells. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from CU and healthy controls in this study. The frequency of CD4(+)CD25(+) T cells in PBMCs was detected by flow cytometry. The expression levels of forkhead box P3 (FOXP3) and transforming growth factor-beta (TGF-beta) in CD4(+)CD25(+) T cells were detected by real-time PCR. Furthermore, the suppressive function of CD4(+)CD25(+) T cells was analyzed. Additionally, the Th1/Th2 cytokine secretory profile in mitogen-stimulated CD4(+)CD25(-) T cells was measured by ELISA. RESULTS: An increased frequency of CD4(+)CD25(+) T cells was observed in CU patients (n=19) compared to control subjects (n=7). No significant difference was detected in the expression levels of FOXP3 or TGF-beta between CU patients (n=14) and control subjects (n=7). Strikingly, the suppressive capacity of CD4(+)CD25(+) Treg cells from 2 of 5 CU patients was partially defective. We also found that cytokine production from CD4(+)CD25(-) T cells was significantly reduced in CU patients (n=9) compared to healthy donors (n=11). CONCLUSIONS: Our data demonstrate that CD4(+)CD25(+) and CD4(+)CD25(-) T cells in PBMCs exhibit defective functions in CU patients.


Assuntos
Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos T Reguladores/fisiologia , Urticária/sangue , Urticária/fisiopatologia , Adolescente , Adulto , Autoimunidade/imunologia , Autoimunidade/fisiologia , Complexo CD3/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Criança , Pré-Escolar , Doença Crônica , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/fisiologia , Masculino , RNA Mensageiro/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Fator de Crescimento Transformador beta/metabolismo , Urticária/metabolismo
17.
Cancer Epidemiol Biomarkers Prev ; 17(3): 661-5, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18349284

RESUMO

Arylamine N-acetyltransferase-2 (NAT2) displays extensive genetic polymorphisms that affect the rates of acetylation of drugs and toxic compounds such as amine carcinogens. The association of NAT2 polymorphisms with adult brain tumors has been unclear. To investigate whether the NAT2 genotype is a risk factor of brain tumors, we determined the frequencies of three common polymorphisms in the NAT2 gene, NAT2*5 (T341C), NAT2*6 (G590A), and NAT2*7(G857A), in brain tumor patients and in age- and gender-matched control subjects (n = 27 in each group). Genotyping was carried out using PCR-RFLP and subjects were phenotyped as a fast or slow acetylator based on the genotypes. The odds ratio of NAT2*7 allele frequency was significantly higher in patients with brain tumor than in controls (odds ratio, 6.786; 95% confidence interval, 2.06-22.37; P = 0.003); in the mean time, NAT2*4/*7 genotype was significantly more common in the patient group than in controls (odds ratio, 6.19; 95% confidence interval, 1.68-22.79; P = 0.0039). The tumors in the patients with NAT2*7 allele tended to be high-grade astrocytoma or glioblastoma multiforme (P = 0.016). In conclusion, these data suggest that the presence of NAT2*7 allele might be a potential risk factor for the development of brain tumors in Taiwan.


Assuntos
Arilamina N-Acetiltransferase/genética , Neoplasias Encefálicas/genética , Alelos , Neoplasias Encefálicas/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Taiwan/epidemiologia
18.
Exp Hematol ; 36(2): 140-8, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18206725

RESUMO

OBJECTIVE: 2-Methoxyestradiol (2ME2) has been shown to induce apoptosis in leukemic cells, but its exact mechanism remains unclear. Because c-Myc plays a critical role in leukemogenesis, we evaluated whether 2ME2 acts on acute myeloid leukemia (AML) through modulation of c-Myc activity. MATERIALS AND METHODS: AML cell lines and primary AML leukemia were treated with 2ME2 and the relationship between 2ME2-induced apoptosis and changes in c-Myc activity was examined. RESULTS: 2ME2 induced mitochondrial apoptosis of human AML cells through increased reactive oxygen species. Further investigation showed that 2ME2 downregulated c-Myc expression in a time-dependent manner. Increased oxidative stress led to downregulation of c-Myc mRNA and protein, but did not affect the stability of c-Myc protein. To demonstrate the role of c-Myc in 2ME2-induced apoptosis, we ectopically expressed wild-type c-Myc in AML cells and found that ectopic expression of c-Myc abrogated the 2ME2-induced apoptosis. In addition, we showed that 2ME2 treatment inhibited phosphorylation of Akt and binding of nuclear factor-kappaB p65/p50 heterodimers to its DNA targets. As with results from cell lines studied, 2ME2 also induced cytotoxicity to primary AML cells and downregulated their c-Myc expression and induced apoptosis. CONCLUSION: Downregulation of c-Myc is critical for 2ME2-induced oxidative stress and apoptosis in AML cells. Our results might be extended to other types of cancers overexpressing c-Myc.


Assuntos
Apoptose/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Estradiol/análogos & derivados , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Moduladores de Tubulina/farmacologia , 2-Metoxiestradiol , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Estradiol/farmacologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Células U937
19.
Leuk Res ; 31(10): 1403-11, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17445886

RESUMO

Valproic acid (VPA), an agent used for neurological disorders, has been shown to be a novel class of histone deacetylase inhibitor (HDACI), able to induce apoptosis and myeloid differentiation of acute myeloid leukemia (AML). In this study, we examined the underlying mechanisms in VPA-mediated activities in AML cells. VPA not only inhibited the growth of HL-60, U937 and NB4 cells by causing cell-cycle arrest at G(0)/G(1) phase and apoptosis, but also induced morphologic and phenotypic changes. VPA markedly increased p21WAF1, and downregulated c-Myc expression at transcriptional levels. Ectopic expression of wildtype c-Myc and T58A mutant significantly inhibited VPA-mediated growth inhibition. As with results from cell line studies, VPA also downregulated c-Myc levels, and induced apoptosis and myeloid differentiation of primary AML cells, leading to decreased colony-forming ability. Given the role of c-Myc in leukemogenesis, our study suggests that VPA might be a potential therapeutic agent for AML.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Genes myc/efeitos dos fármacos , Leucemia Mieloide/metabolismo , Ácido Valproico/farmacologia , Doença Aguda , Apoptose/efeitos dos fármacos , Western Blotting , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mieloide/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Exp Hematol ; 34(11): 1480-9, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17046567

RESUMO

OBJECTIVE: The protooncogene c-Myc plays an important role in the control of cell proliferation, apoptosis, and differentiation, and its aberrant expression is frequently seen in multiple human cancers, including acute myeloid leukemia (AML). As c-Myc heterodimerizes with Max to transactivate downstream target genes in leukemogenesis. Inhibition of the c-Myc/Max heterodimerization by the recently identified small-molecule compound, 10058-F4, might be a novel antileukemic strategy. MATERIALS AND METHODS: HL-60, U937, and NB4 cells and primary AML cells were used to examine the effects of 10058-F4 on apoptosis and myeloid differentiation. RESULTS: We showed that 10058-F4 arrested AML cells at G0/G1 phase, downregulated c-Myc expression and upregulated CDK inhibitors, p21 and p27. Meanwhile, 10058-F4 induced apoptosis through activation of mitochondrial pathway shown by downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, 10058-F4 also induced myeloid differentiation, possibly through activation of multiple transcription factors. Similarly, 10058-F4-induced apoptosis and differentiation could also be observed in primary AML cells. CONCLUSION: Our study has shown that inhibition of c-Myc/Max dimerization with small-molecule inhibitors affects multiple cellular activities in AML cells and represents a potential antileukemic approach.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Leucemia Mieloide/metabolismo , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Tiazóis/farmacologia , Doença Aguda , Fatores de Transcrição de Zíper de Leucina Básica/antagonistas & inibidores , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Dimerização , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fase G1/efeitos dos fármacos , Células HL-60 , Humanos , Leucemia Mieloide/tratamento farmacológico , Células Mieloides/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Células U937 , Regulação para Cima/efeitos dos fármacos
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