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1.
J Cancer Res Clin Oncol ; 149(8): 4623-4628, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36171456

RESUMO

PURPOSE: Neoadjuvant therapy followed by surgical resection is one of the preferred treatment option for locally advanced non-small cell lung cancer (NSCLC). For patients with mesenchymal-epithelial transition (MET) factor exon 14 skipping (METex14) mutations, the use of MET-tyrosine kinase inhibitors (TKIs) showed high efficiency and reduced toxicity compared with first-line standard chemotherapy. However, it is unknown whether preoperative induction targeted therapy of MET-TKIs is feasible and safe. METHODS: Here, we reported 3 cases of locally advanced unresectable NSCLC with METex14 mutations receiving induction therapy of MET-TKI savolitinib as first-line therapy or second-line therapy when they experienced disease progression after preoperative chemotherapy. RESULTS: All these 3 patients achieved significant tumor size shrinkage and their unresectable tumors became resectable after the treatment of savolitinib. No serious adverse events were observed during the treatment. They recovered well postoperatively, and no significant events were identified. CONCLUSIONS: Preoperative induction treatment with MET-TKI savolitinib showed its safety and effectiveness and may be an alternative option for neoadjuvant therapy for NSCLC patients with METex14 mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Estudos de Viabilidade , Quimioterapia de Indução , Proteínas Proto-Oncogênicas c-met/genética , Mutação , Éxons , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia
2.
BMJ Open ; 12(8): e056043, 2022 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-36038163

RESUMO

INTRODUCTION: Lung cancer was the most common malignancy and the leading cause of cancer-related death in China or worldwide, and surgery is still the preferred treatment for early-stage non-small cell lung cancer (NSCLC). The pattern of lymph node metastasis was found potentially lobe specific, and thus, lobe-specific lymph node dissection (L-SLND) was proposed to be an alternative to systematic lymph node dissection (SLND) for the treatment of early-stage NSCLC. METHODS AND ANALYSIS: The LobE-Specific lymph node diSsectiON trial is a single-institutional, randomised, double-blind and parallel controlled trial to investigate the feasibility of L-SLND in clinically diagnosed stage IA1-2 NSCLC with ground-glass opacity components (≥50%). The intraoperative frozen section examination of surgical tissues confirms the histological type of NSCLC. We hypothesise that L-SLND (experimental group) is not inferior to SLND (control group) and intend to include 672 participants for the experimental group and 672 participants for the control group with a follow-up duration of 60 months. The primary outcomes are 5-year disease-free survival and 5-year overall survival. The secondary outcomes are metastatic lymph node ratio, postoperative complication incidence and mortality, duration of operation, duration of anaesthesia (min), the volume of bleeding (mL) and drainage volume. The intention-to-treat analysis would be performed in the trial. ETHICS AND DISSEMINATION: This trial was approved by the ethics committee on biomedical research, West China Hospital of Sichuan University (2021-332). Informed consent would be obtained from all participants, and dissemination activities would include academic conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: This trial was registered in the Chinese Clinical Trial Registry, ChiCTR2100048415.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Intervalo Livre de Doença , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/patologia , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
ANZ J Surg ; 91(11): E696-E702, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34405519

RESUMO

BACKGROUND: Whether dissection of left lower paratracheal (4L) lymph node has any impact on survival of patients with left-sided non-small cell lung cancer (NSCLC) remains unclear. We conducted the first meta-analysis to compare the survival of patients treated with 4L lymph node dissection (LND) and those without for left-sided NSCLC. METHODS: We systematically searched relevant studies from PubMed, Embase, and Web of Science on February 6, 2020. Data for analysis included 5-year overall survival (OS) and disease-free survival (DFS) rates, OS, and DFS. We calculated risk ratio (RR) for pooling 5-year OS and DFS rates and extracted hazard ratio (HR) from multivariate analysis for pooling OS and DFS. RESULTS: We finally included three retrospective cohort studies with propensity score-matched analysis consisting of 2103 patients. Meta-analysis showed that patients treated with 4L LND yielded significantly higher 5-year OS (67.7% vs. 54.6%; fixed effects models: RR = 0.75; 95% confidence interval [CI] = [0.67, 0.84]; p < 0.001; I2  = 0%) and DFS (53.3% vs. 44.8%; fixed effects models: RR = 0.85; 95% CI = [0.76, 0.95]; p = 0.003; I2  = 41.7%) rates than patients without 4L LNDS. Moreover, dissection of 4L lymph node was significantly associated with better OS (fixed effects model: HR = 0.66; 95% CI = [0.57, 0.76]; p < 0.001; I2  = 45.7%) and DFS (fixed effects model: HR = 0.67; 95% CI = [0.52, 0.87]; p = 0.003; I2  = 0%). No significant heterogeneities were observed. CONCLUSIONS: Dissection of 4L lymph node could significantly improve both 5-year OS and DFS rates and 4L LND was a favorable prognostic factor for patients with left-sided NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Dissecação , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
4.
Nutrition ; 90: 111345, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34166897

RESUMO

OBJECTIVES: Sarcopenia is commonly encountered in patients with advanced cancer, but the role of sarcopenia in predicting prognosis in this group of patients receiving immune checkpoint inhibitors (ICIs) remains undetermined. The aim of this study was to performed the first meta-analysis focusing on the prognostic value of sarcopenia in patients with advanced cancer who were treated with ICIs comprehensively. METHODS: A systematic search for relevant studies in the Web of Science, PubMed, and Embase was conducted on August 19, 2020. Outcomes including response rate, 1-y progression-free survival (PFS) rate, 1-y overall survival (OS) rate, and hazard ratios (HRs) of PFS and OS were extracted. Meta-analysis was performed by using the STATA version 12 software package. RESULTS: Nine cohort studies consisting of 740 patients with advanced cancer receiving ICIs were finally included for analysis. Our meta-analysis found that patients with sarcopenia tended to have a lower response rate than those without the disease (30.5 versus 15.9%; P = 0.095). Furthermore, patients with sarcopenia yielded a significantly shorter 1-y PFS rate (32 versus 10.8%; risk ratio [RR], 1.31; P < 0.001) and 1-y OS rate (66 versus 43%; RR, 1.71; P < 0.001) than patients without sarcopenia. Moreover, sarcopenia was found to be an independent, unfavorable prognostic factor of PFS (HR, 1.79; P < 0.001) and OS (HR, 2.11; P < 0.001) in patients with advanced cancer receiving ICIs. Subgroup analysis further confirmed the unfavorable predictive value of sarcopenia in patients with advanced non-small cell lung cancer and those with melanoma receiving ICIs. CONCLUSIONS: Sarcopenia proved to be an independent, unfavorable prognostic factor in patients with advanced cancer receiving ICIs. Routine assessment of sarcopenia status and correction of sarcopenic status should be emphasized for patients treated with ICIs. Further research with sufficient adjustments for confounding factors are warranted to better elucidate the prognostic value of sarcopenia in these patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Sarcopenia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Prognóstico , Sarcopenia/diagnóstico , Sarcopenia/etiologia
5.
World J Surg ; 45(8): 2610-2618, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33899137

RESUMO

BACKGROUNDS: Whether sex has any impact on the risk of lymph node (LN) metastasis (LNM) in patients with early-stage non-small cell lung cancer (NSCLC) remains controversial. Therefore, we aimed to objectively compared the risk of LNM between female and male patients with early-stage NSCLC so as to figure out whether sex-different extent of surgery may be justified for treating these patients. METHODS: We retrospectively collected clinical data of patients undergoing lobectomy or segmentectomy with systematic hilar and mediastinal LN dissection for clinical stage IA peripheral NSCLC from June 2014 to April 2019. Both multivariate logistic regression analysis and propensity score-matched(PSM) analysis were applied to compare the risk of LNM between female and male patients. RESULTS: We finally included a total of 660 patients for analysis. In the analysis of unmatched cohorts, there was no significant different rate of LNM (12.4% Vs 13.9%, P=0.556), hilar/intrapulmonary LNM (8.4% Vs 10.7%, P=0.318) and mediastinal LNM(7.9% Vs 7.5%, P=0.851) between female and male patients. In the multivariate analysis, sex was not found to be an independent predictor of LN in these patients. Moreover, in the analysis of well-matched cohorts generated by PSM analysis, there was still no significant different rate of LNM (13.8% Vs 13.4%, P=0.892), hilar/intrapulmonary LNM (9.1% Vs 11.2%, P=0.442) and mediastinal LNM (9.1% Vs 6.5%, P=0.289) between female and male patients. CONCLUSIONS: Sex was not an independent predictor of LNM in early-stage NSCLC and there is no sufficient evidence justifying for sex-different extent of surgical resection for these patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos
6.
World J Surg ; 45(3): 897-906, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33230587

RESUMO

BACKGROUND: Whether video-assisted thoracoscopic surgery (VATS) sleeve lobectomy could be an alternative to traditional thoracotomy sleeve lobectomy in treating centrally located non-small cell lung cancer (NSCLC) remains unclear. Therefore, we conducted the first meta-analysis to compare the effects of VATS sleeve lobectomy with thoracotomy sleeve lobectomy. METHODS: We systematically searched relevant studies from Pubmed, Embase, and Web of Science on May 12, 2020. Data for analysis included short-term outcomes (blood loss, lymph node dissected, operation time, hospital stay, complications) and long-term outcomes (3-year overall survival (OS) and progression-free survival (PFS) rates). We calculated the weighted mean differences (WMDs) for continuous data and risk ratio (RR) for pooling categorical data. RESULTS: We finally included 5 retrospective cohort study consisting of 436 patients. VATS sleeve lobectomy yielded significantly less blood loss (WMD = -37.83; 95% confidence intervals (CIs) = [-58.56, -17.11]; P < 0.001) than thoracotomy sleeve lobectomy and comparable total number of dissected lymph node to thoracotomy sleeve lobectomy (WMD = - 0.07; 95%CI = [-1.14, 0.99]; P = 0.89). However, VATS sleeve lobectomy consumed significantly more operation time than thoracotomy sleeve lobectomy (WMD = 49.00; 95%CI = [14.67, 83.34]; P = 0.005). VATS sleeve lobectomy yielded significantly less postoperative hospital stay time than thoracotomy sleeve lobectomy (WMD = -1.68; 95%CI = [-2.98, -0.39]; P = 0.011) and comparable postoperative complication rate to thoracotomy sleeve lobectomy (RR = 0.84; 95%CI = [0.49, 1.44]; P = 0.52). Moreover, VATS sleeve lobectomy yielded comparable 3-year OS (RR = 1.08; 95%CI = [0.95, 1.22]; P = 0.23) and PFS (RR = 1.15; 95%CI = [0.96, 1.37]; P = 0.13) rates to thoracotomy sleeve lobectomy. No significant heterogeneities were observed. CONCLUSIONS: VATS sleeve lobectomy yielded less surgical trauma than thoracotomy sleeve lobectomy and improved postoperative recovery without compromising oncological prognosis. Even though VATS sleeve lobectomy may consume more operation time, it could be recommended as an alternative to thoracotomy sleeve lobectomy for treating centrally located NSCLC in carefully selected cases.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Humanos , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida , Toracotomia
7.
Sci Rep ; 10(1): 9587, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32533050

RESUMO

Whether age has any impact on the risk of lymph node (LN) metastasis in patients with early-stage non-small cell lung cancer (NSCLC) remains controversial. Therefore, we aimed to objectively compare the risk of LN metastasis between elderly and young patients so as to justify for age-different extent of surgical resection for treating these patients. We retrospectively collected clinical data of patients undergoing lobectomy or segmentectomy with systematic hilar and mediastinal LN dissection for clinical stage IA peripheral NSCLC from January 2015 to December 2018. Both multivariate logistic regression analysis and propensity score-matched (PSM) analysis were applied to compare the risk of LN metastasis between elderly (>65 years old) and young (≤65 years old) patients. We finally included a total of 590 patients for analysis (142 elderly patients and 448 young patients). In the analysis of unmatched cohorts, young patients tended to have higher rates of hilar/intrapulmonary LN (13.4% VS 9.2%) and mediastinal LN metastasis (10.5% VS 6.3%) than elderly patients. In the multivariate analysis, age was found to be an independent predictor of both hilar/intrapulmonary (Odds ratio(OR) = 2.065, 95%confidence interval(CI): 1.049-4.064, P = 0.036) and mediastinal (OR = 2.400, 95%CI: 1.083-5.316, P = 0.031) LN metastasis. Moreover, in the analysis of well-matched cohorts generated by PSM analysis, young patients had significantly higher rates of hilar/intrapulmonary (18.8% VS 9.4%, P = 0.039) and mediastinal LN metastasis (17.1% VS 6.0%, P = 0.008) than elderly patients. Therefore, age remains to be an independent predictor of LN metastasis in early-stage NSCLC and age-different extent of surgical resection may be justified for these patients.


Assuntos
Adenocarcinoma de Pulmão/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/secundário , Neoplasias Pulmonares/patologia , Pneumonectomia/métodos , Adenocarcinoma de Pulmão/cirurgia , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos
8.
Interact Cardiovasc Thorac Surg ; 30(4): 582-587, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31965162

RESUMO

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'In lung cancer patients with unexpected pleural metastasis detected during operation, is surgical resection of primary tumour superior to exploratory thoracotomy without resection in improving long-term survival?'. Altogether, 1443 papers were found using the reported search, of which 1 meta-analysis and 10 retrospective observational cohort studies represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. One meta-analysis and 9 cohort studies found that surgical resection of the primary tumour, on the discovery of pleural metastases, yielded a better overall survival than exploratory thoracotomy alone, while 1 cohort study showed no difference. Six studies found that main tumour resection was an independent favourable prognostic factor for overall survival in lung cancer patients with unexpected pleural metastasis detected during operation, while 3 cohort studies also showed improved progression-free survival over exploratory thoracotomy. Therefore, we conclude that surgical resection of the primary tumour is superior to exploratory thoracotomy in treating lung cancer patients with unexpected pleural metastasis detected during operation.


Assuntos
Neoplasias Pulmonares/cirurgia , Estadiamento de Neoplasias/métodos , Neoplasias Pleurais/cirurgia , Toracotomia/métodos , Idoso , Humanos , Período Intraoperatório , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Masculino , Metástase Neoplásica , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/secundário , Pneumonectomia , Estudos Retrospectivos , Resultado do Tratamento
9.
Ann Surg Oncol ; 27(2): 472-480, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31617120

RESUMO

OBJECTIVE: We investigated the possible lobe-specific lymph node (LN) metastasis pattern of early-stage peripheral non-small cell lung cancers (NSCLC) and define the extent of lobe-specific LN dissection for them. METHODS: We retrospectively collected clinical data of patients undergoing lobectomy or segmentectomy with systematic lymphadenectomy for clinical T1N0M0 peripheral NSCLC from January 2015 to December 2018. The LN metastasis pattern was analyzed by tumor lobe location. RESULTS: A total of 590 patients were included for analysis. The mean number of total dissected LNs was 12.3 ± 5.8 and 8.2 ± 4.1 for total dissected mediastinal LNs. The rate of mediastinal LN metastasis was 9.5%. For cases of upper lobe tumor and lower lobe tumor, 8.8% and 6.0% of them respectively metastasized to the upper LN zone (P = 0.274). However, upper lobe tumors hardly metastasized to the subcarinal (0.3%) and lower (0.3%) LN zones while for lower lobe tumors, the rate of LN metastasis was 10.2% and 5.4% respectively (both P < 0.001). However, all cases (100%) metastasizing from lower lobes to the upper LN zone had a tumor size of 2-3 cm, whereas cases with a tumor size ≤ 2 cm had no metastasis (0%). None of the tumors in the right middle lobe metastasized to the lower LN zone (0%). CONCLUSIONS: A lobe-specific LN metastasis pattern was observed in clinical stage IA peripheral NSCLC. For tumors in upper lobes (≤ 3 cm), there may be no need to dissect lower mediastinal LNs and for tumors in lower lobes (≤ 2 cm), dissecting upper mediastinal LNs may not be required.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/cirurgia , Linfonodos/cirurgia , Neoplasias do Mediastino/secundário , Pneumonectomia/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , China/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Pulmonares/patologia , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Masculino , Neoplasias do Mediastino/epidemiologia , Neoplasias do Mediastino/etiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos
10.
Ann Thorac Surg ; 109(4): 1079-1085, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31846634

RESUMO

BACKGROUND: We aimed to investigate the pattern of regional lymph node (LN) metastasis of early-stage non-small cell lung cancer (NSCLC) to provide novel rationale for surgical choice (lobectomy, segmentectomy, or wedge resection) for these patients. METHODS: We retrospectively collected clinical data of patients undergoing lobectomy with systematic mediastinal LN dissection or sampling for cT1N0M0 peripheral NSCLC from January 2015 to December 2018. The regional LN metastasis pattern was analyzed based on tumor size. RESULTS: We included a total of 354 patients for analysis. The rate of hilar or intrapulmonary LN metastasis was 13.6%. When stratified by tumor size, NSCLC less than or equal to 1 cm had no hilar or intrapulmonary LN metastasis (0%) while NSCLC greater than 2 cm but less than or equal to 3 cm had a significantly high rate of hilar or intrapulmonary LN metastasis (18.4%) and the rates of hilar, interlobar, and peripheral LN metastasis were also relatively high (5.4%, 5.4%, and 12.2%, respectively). NSCLC greater than 1.5 cm but less than or equal to 2 cm also had relatively high rates of hilar (6.5%) and peripheral (18.3%) LN metastasis, while NSCLC greater than 1 cm but less than or equal to 1.5 cm had significantly low rates of hilar or intrapulmonary (2.5%) and peripheral (2.5%) LN metastasis. Radiographic feature and histology were found to be independent predictors of regional LN metastasis. CONCLUSIONS: The pattern of regional LN metastasis in clinical stage IA peripheral NSCLC was significantly influenced by tumor size, which may provide evidence on surgical choice (lobectomy, segmentectomy, or wedge resection) for these early-stage NSCLC patients based on tumor size.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Pneumonectomia , Adulto , Idoso , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Seleção de Pacientes , Estudos Retrospectivos , Carga Tumoral
11.
J Thorac Dis ; 10(8): 4831-4837, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30233856

RESUMO

BACKGROUND: Locally advanced lung cancers involving both right upper lung lobe and superior vena cava (SVC) requiring both lung resection and SVC reconstruction are generally deemed unresectable. However, previous evidence has proved that such patients could benefit from surgery if radical resection is achieved. Generally, a hemi-clamshell approach is adopted to complete such resection. However, it has the limitation of insufficient exposure of posterior mediastinum. Therefore, we introduced a two-step surgical approach combining sternotomy and thoracotomy for such lung cancers. METHODS: A two-step surgical approach combining median sternotomy and subsequent posterolateral thoracotomy, via which radical lobectomy with systematic lymphadenectomy and SVC reconstruction could be successfully achieved, was described. RESULTS: We have performed such surgery via the two-step surgical approach combining median sternotomy and subsequent posterolateral thoracotomy in five patients from January 2017 to March 2018. All those patients achieved radical resection of the lung cancer with lobectomy and systematic lymphadenectomy and SVC reconstruction with artificial blood vessels, and had an uneventful postoperative recovery without any major complications. CONCLUSIONS: Our initial experience proved that this two-step surgical approach combining median sternotomy and subsequent posterolateral thoracotomy was safe and feasible for locally advanced lung cancers requiring both lung resection and SVC reconstruction.

12.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 39(5): 701-5, 2008 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-19024294

RESUMO

OBJECTIVE: To study the approach of targeting expression of suicide gene HSV-TK driven by human telomerase catalytic subunit (hTERT) promoter in lung cancer cells, and to investigate inhibitory effect of HSV-TK/GCV driven by hTERT promoter on proliferation of lung cancer cell line A549 in vitro and in vivo. METHODS: (1) Recombinant expression vectors of HSV-TK driven by hTERT promoter and SV40 promoter (pGL3-hTp-TK and pGL3-SV40-TK) were transfected into telomerase-positive human lung adenocarcinoma cell A549 and telomerase-negative human embryonic lung fibroblast cell MRC-5. The mRNA expression of TK gene was detected with RT-PCR method; (2) With the treatment of GCV, the proliferation of above transfected cells was investigated by MTT assay; Influence of GCV on apoptosis and cell cycle of these cells was evaluated with flow cytometry; (3) After the subcutaneously transplantation of A549 cells into nude mice, intra-tumor injection of plasmid-liposome as well as intra-peritoneal injection of GCV were performed to stUdy anti-tumor effects of pGL3-hTp-TK/GCV and pGL3-SV40-TK/GCV in vivo. RESULTS: (1) Enzyme digestion and PCR suggested that recombinant plasmids of pGL3-hTp-TK and pGL3-SV40-TK were successfully constructed; TK mRNA expression was detected in both A549 and MRC-5 cells transfected with pGL3-SV40-TK, also in A549 transfected with pGL3-hTp-TK, but not in MRC-5 transfected with pGL3-hTp-TK; (2) GCV showed significant inhibition effect on proliferation of A549 and MRC-5 transfected with pGL3-SV40-TK in vitro, also on that of A549 transfected with pGL3-hTp-TK, but not of MRC-5 transfected with pGL3-hTp-TK; With the treatment of GCV, apoptosis index (AI) of A549 cells transfected with pGL3-SV40-TK and pGL3-hTp-TK (21.58% and 23.19% respectively) increased significantly, compared with that of A549 transfected with pGL3-hTp and blank control; GCV enhanced the effects on AI in MRC-5 transfected with pGL3-SV40-TK (9.35%), but not with pGL3-hTp-TK (0.88%); (3) Inhibition ratio of pGL3-SV40-TK/GCV and pGL3-hTp-TK/GCV to transplanted tumor of A549 in nude mice (46.7% and 40.5% respectively) were significantly higher than that of negative control groups (9.7%, 14.3%, 7.0% and 8.0% respectively). CONCLUSION: TK gene driven by hTERT promoter could express selectively in lung cancer cell. Lung cancer cell could be specifically inhibited by HSV-TK/GCV driven by hTERT promoter in vitro and in vivo.


Assuntos
Genes Transgênicos Suicidas/genética , Herpesvirus Humano 1/genética , Neoplasias Pulmonares/patologia , Telomerase/genética , Timidina Quinase/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Animais , Apoptose/genética , Sistemas de Liberação de Medicamentos , Ganciclovir/farmacologia , Terapia Genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas/genética , Células Tumorais Cultivadas
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 24(2): 148-52, 2007 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-17407070

RESUMO

OBJECTIVE: To study selective killing effect of herpes simplex virus-thymidine kinase/ganciclovir (Hsv-tk/GCV) driven by human telomerase catalytic subunit (hTERT) promoter on lung cancer cell line A549 in vitro. METHODS: (1) Expression plasmids of Hsv-tk gene driven by hTERT promoter and sv40 promoter respectively (pGL3-hTp-tk and pGL3-sv40-tk) were transfected into telomerase-positive human lung adenocarcinoma cell line A549 and telomerase-negative fetal lung fibroblast cell line MRC-5. Reverse transcription-PCR was performed to detect expression of tk gene in above transfected cell lines; (2) Inhibition effect on proliferation of above transfected cell lines treated with GCV was investigated with MTT method; (3) Influence of GCV on apoptosis and cell cycle of above transfected cell lines was investigated with flow cytometry. RESULTS: (1) tk mRNA expression was detected in both A549 and MRC-5 transfected with pGL3-sv40-tk, also in A549 transfected with pGL3-hTp-tk, but not in pGL3-hTp-tk transfected MRC-5; (2) GCV showed significant inhibition effects on proliferation of pGL3-sv40-tk transfected A549 and MRC-5 in vitro, also on that of pGL3-hTp-tk transfected A549, but not on that of pGL3-hTp-tk transfected MRC-5; (3) Treated with GCV, apoptosis index (AI) of pGL3-sv40-tk transfected A549 and MRC-5 as well as pGL3-hTp-tk transfected A549 (21.58%, 9.35% and 23.19% respectively) increased significantly, compared with A549, MRC-5 transfected with pGL3-hTp (0.78% and 0.55% respectively) and A549, MRC-5 without plasmid transfection as blank control (2.17% and 0.60% respectively); GCV had no influence on AI of pGL3-hTp-tk transfected MRC-5 (0.88%). CONCLUSION: tk gene driven by hTERT promoter could express selectively in lung cancer cell A549. Hsv-tk/GCV driven by hTERT promoter could selectively inhibit proliferation of lung cancer cell.


Assuntos
Ganciclovir/farmacologia , Regiões Promotoras Genéticas/genética , Telomerase/genética , Timidina Quinase/genética , Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Terapia Genética/métodos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Simplexvirus/enzimologia , Simplexvirus/genética , Transfecção , Proteínas Virais/genética
14.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 37(4): 497-501, 2006 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-16909587

RESUMO

OBJECTIVE: To clone sequence of hTERT promoter and study its transcriptional activity and its relationship with hTERT mRNA expression and telomerase activity in various kinds of human lung cancer cells and normal cells, and to investigate the targeting transcriptional activity of hTERT promoter in tumor cells. METHODS: About 1.1 kb promoter of the 5'flanking sequence of the hTERT was amplified from genomic DNA isolated from 293 cells by polymerase chain reaction (PCR). After being confirmed by DNA sequencing, the hTERT promoter was inserted into luciferase reporter vectors (pGL3-basic) to reconstruct a recombinant named pGL3-hTERTp. Then pGL3-hTERTp was transiently transfected into lung cancer cell A549, SPC-A-1, LTEPa-2, NCI-H446, YTMLC-9, GLC-82, 95D, A2, and normal cell of MRC-5. The transcriptional activities of hTERT promoter in various cells were determined by measuring the luciferase activities. hTERT mRNA expression and telomerase activity were determined by RT-PCR and TRAP ELISA. RESULTS: Eelectrophoresis demonstrated that the hTERT promoter amplified by PCR was about 1.1 kb long, and DNA sequencing showed a sequence the same as the hTERT promoter registered in GenBank being 1084 bp in length. The recombinant of plasmid pGL3-hTERTp was confirmed by double digestion and PCR methods with correct results. hTERT mRNA and telomerase activity were expressed in all of eight lung cancer cell lines at varied levels, but not expressed in normal cell. Transient transfection assay and Luciferase assay also revealed that hTERT promoter had different transcriptional activities in various lung cancer cells, but no transcriptional activity was shown in normal cells. CONCLUSION: 1084 bp hTERT promoter cloned has specific transcriptional activities in various telomerase-positive lung cancer cells, and it may act as control element in tumor-targeting gene therapy.


Assuntos
Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Telomerase/metabolismo , Sequência de Bases , Clonagem Molecular , Humanos , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Telomerase/biossíntese , Telomerase/genética , Transcrição Gênica , Ativação Transcricional
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