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1.
Ann Palliat Med ; 9(5): 2943-2952, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32819122

RESUMO

BACKGROUND: SHP2, a widely expressed phosphatase, which has been linked to the initiation, progression and prognosis of various malignancies. We previously identified a new SHP2 anchorage protein Hook1 in the alveolar II epithelial cells, and it is suggested that Hook1 is a novel endogenous suppressor molecule of SHP2 phosphatase activity. Nevertheless, few studies have been mentioned the clinicopathological and prognostic relevance of SHP2 and Hook1 expression in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 61 patients with NSCLC receiving gemcitabine plus carboplatin chemotherapy were studied. Immunohistochemical staining was conducted to determine the protein expression of SHP2 and Hook1. The relationships between gene expression and clinical and pathological factors, as well as prognosis, were evaluated. RESULTS: A significant correlation was observed between the SHP2 and Hook1 expression, with a total expression rate of 71.4%. The positive expression of Hook1 in adenocarcinoma and in stage IIIb-IV was higher than that in patients with squamous (73.5% vs. 31.2%, P=0.013) and I-IIIa (75% vs. 48.8%, P=0.05), suggesting that Hook1 might act as an indicator of NSCLC status. However, no significant correlation was observed between Hook1 expression and survival time (P>0.05). In contrast, patients with negative SHP2 expression had a higher survival rate (median overall survival 68 vs. 24 months, P=0.003). Cox multivariate regression analysis showed that SHP2 was an independent indicator for overall survival (P=0.009). CONCLUSIONS: The present study suggested that NSCLC patients with negative SHP2 expression could benefit from gemcitabine plus carboplatin chemotherapy, and further study is needed to confirm the prognostic value of SHP2 and Hook1.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Anquirinas , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Desoxicitidina/análogos & derivados , Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Platina , Prognóstico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Tirosina , Gencitabina
2.
J Biol Chem ; 295(40): 13798-13811, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-32737199

RESUMO

Transforming growth factor ß (TGFß) signaling plays an important role in regulating tumor malignancy, including in non-small cell lung cancer (NSCLC). The major biological responses of TGFß signaling are determined by the effector proteins SMAD2 and SMAD3. However, the regulators of TGFß-SMAD signaling are not completely revealed yet. Here, we showed that the scaffolding protein PDLIM5 (PDZ and LIM domain protein 5, ENH) critically promotes TGFß signaling by maintaining SMAD3 stability in NSCLC. First, PDLIM5 was highly expressed in NSCLC compared with that in adjacent normal tissues, and high PDLIM5 expression was associated with poor outcome. Knockdown of PDLIM5 in NSCLC cells decreased migration and invasion in vitro and lung metastasis in vivo In addition, TGFß signaling and TGFß-induced epithelial-mesenchymal transition was repressed by PDLIM5 knockdown. Mechanistically, PDLIM5 knockdown resulted in a reduction of SMAD3 protein levels. Overexpression of SMAD3 reversed the TGFß-signaling-repressing and anti-migration effects induced by PDLIM5 knockdown. Notably, PDLIM5 interacted with SMAD3 but not SMAD2 and competitively suppressed the interaction between SMAD3 and its E3 ubiquitin ligase STUB1. Therefore, PDLIM5 protected SMAD3 from STUB1-mediated proteasome degradation. STUB1 knockdown restored SMAD3 protein levels, cell migration, and invasion in PDLIM5-knockdown cells. Collectively, our findings indicate that PDLIM5 is a novel regulator of basal SMAD3 stability, with implications for controlling TGFß signaling and NSCLC progression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Movimento Celular , Proteínas com Domínio LIM/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/metabolismo , Proteólise , Proteína Smad3/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Humanos , Proteínas com Domínio LIM/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Knockout , Camundongos Nus , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteína Smad3/genética , Ubiquitina-Proteína Ligases/genética
3.
Onco Targets Ther ; 12: 5897-5906, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413587

RESUMO

BACKGROUND: We previously reported that Hook1 inhibits the phosphatase activity of SHP2 in the regulation of the epithelial-mesenchymal transition (EMT) in lung cancer. In this study, we performed a comprehensive analysis of SHP2 and Hook1 expression and relationships with the prognosis of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 121 patients with NSCLC were included in this study. Expression of SHP2 and Hook1 was assessed by immunohistochemistry and Western blot analysis. The overall survival rate of NSCLC patients was analysed using Cox's ratio hazard multivariate analysis and the log-rank test. RESULTS: In tumour tissue specimens, positive expression rates of SHP2 proteins were 58.4% by immunohistochemical analysis. A significant correlation between expression of SHP2 and that of Hook1 was observed. Based on Western blot analysis, we found that Hook1 was downregulated and that SHP2 has a tendency to overexpress without statistical significance in NSCLC tissues compared with their levels in normal lung tissues. The median overall survival (OS) of NSCLC patients who presented low levels of SHP2 expression were better (40 vs 24 months, p=0.004) than those of patients who exhibited high levels of SHP2 expression. The results of multivariate analysis showed that the level of SHP2 expression was an independent prognostic factor for OS. CONCLUSION: SHP2 might play an important role in NSCLC and has the potential to serve as a clinical biomarker or NSCLC.

4.
Pak J Pharm Sci ; 30(3): 713-720, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28653914

RESUMO

Chemotherapy is considered a high-risk procedure where system failures are more likely to occur. Failure mode and effects analysis (FMEA) is a systematic, multidisciplinary team-based approach to error prevention. We described our experience of using FMEA as a prospective risk-management technique throughout the chemotherapy process. The occurrence, detectability and severity were assessed. Fifteen potential risk factors associated with 10 failure modes were identified. Improvement measures were proposed according to risk priority number. A computerized physician order entry (CPOE) and complete prescription audit system (CPAS) were introduced to reduce potential risks during chemotherapy. Introduction of this system was associated with a decrease from 2.60% to 0.60%. As a result, FMEA is a useful tool to evaluate potential risk in healthcare processes.


Assuntos
Antineoplásicos/uso terapêutico , Análise do Modo e do Efeito de Falhas na Assistência à Saúde , Erros de Medicação/prevenção & controle , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Humanos , Sistemas de Registro de Ordens Médicas , Gestão de Riscos
5.
Cancer Chemother Pharmacol ; 76(1): 163-70, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26003539

RESUMO

PURPOSE: To investigate the correlation between protein expression of breast cancer susceptibility gene 1 (BRCA1) and topoisomerase IIß-binding protein 1 (TopBP1) and clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. METHODS: Immunohistochemical staining was conducted to detect the protein expression of BRCA1 and TopBP1 in 101 cases of NSCLC and to correlate these with clinical features, disease progression, and patient survival. Chi-square test (χ (2)-test) was used to evaluate categorical variables. Spearman's rank order correlation was used to analyze continuous variables. Overall survival rate of NSCLC patients was analyzed by Kaplan-Meier survival curve and log-rank test. Relevant factors affecting the survival of patients with advanced NSCLC were analyzed by COX proportional hazards regression model. RESULTS: A total of 101 NSCLC patients were included in the present study. In tumor tissue specimens, positive expression rates of BRCA1 and TopBP1 proteins were 51.5 and 57.4 %, respectively. A significant correlation between the positive expression of BRCA1 and the positive expression of TopBP1 was observed (P < 0.001, r = 0.326). No significant correlation between BRCA1/TopBP1 and age, gender, smoking status, performance status score, pathohistological type, or clinical stage was detected (P > 0.05). During the follow-up period, 65 patients died, and 86 patients showed progression at the end of the study. The survival rate of patients with negative BRCA1 protein expression was higher than that in patients with positive BRCA1 protein expression [median overall survival (OS) 34 vs. 21 months, HR 1.913, 95 % CI 1.161-3.150, P = 0.011]. Similarly, the survival rate of patients with negative TopBP1 expression was higher than that in patients with positive TopBP1 (median OS 36 vs. 23 months, HR 1.931, 95 % CI 1.157-3.224, P = 0.012). No significant correlation between protein expression of BRCA1 or TopBP1 with NSCLC disease progression was observed (P > 0.05). CONCLUSIONS: The present study indicates NSCLC patients with negative BRCA1 and TopBP1 expression showed better prognosis than those with positive protein expression.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Transporte/biossíntese , Proteínas de Ligação a DNA/biossíntese , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/biossíntese , Biomarcadores Tumorais/biossíntese , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Gencitabina
6.
J Biol Chem ; 289(49): 34152-60, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25331952

RESUMO

The epithelial-mesenchymal transition (EMT) is an essential process for embryogenesis. It also plays a critical role in the initiation of tumor metastasis. Src homology 2 (SH2)-domain containing protein-tyrosine phosphatase-2 (SHP2) is a ubiquitously expressed protein-tyrosine phosphatase and is mutated in many tumors. However, its functional role in tumor metastasis remains largely unknown. We found that TGFß1-induced EMT in lung epithelial A549 cells was partially blocked when SHP2 was decreased by transfected siRNA. The constitutively active form (E76V) promoted EMT while the phosphatase-dead mutation (C459S) and the SHP2 inhibitor PHPS1 blocked EMT, which further demonstrated that the phosphatase activity of SHP2 was required for promoting TGFß1-induced EMT. Using the protein-tyrosine phosphatase domain of SHP2 as bait, we identified a novel SHP2-interacting protein Hook1. Hook1 was down-regulated during EMT in A549 cells. Overexpression of Hook1 inhibited EMT while knockdown of Hook1 promoted EMT. Moreover, both the protein-tyrosine phosphatase domain and N-terminal SH2 domain of SHP2 directly interacted with Hook1. Down-regulation of Hook1 increased SHP2 activity. These results suggested that Hook1 was an endogenous negative regulator of SHP2 phosphatase activity. Our data showed that the protein-tyrosine phosphatase SHP2 was involved in the process of EMT and Hook1 repressed EMT by regulating the activation of SHP2. SHP2-Hook1 complex may play important roles in tumor metastases by regulating EMT in cancer cells.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Proteínas Associadas aos Microtúbulos/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fator de Crescimento Transformador beta1/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células HEK293 , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
7.
J Zhejiang Univ Sci B ; 13(11): 875-83, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23125080

RESUMO

OBJECTIVE: XRCC1 polymorphism is a research hotpot in individual treatment for non-small cell lung cancer (NSCLC). To obtain the association between XRCC1 polymorphism and clinical outcome of platinum-based treatment for NSCLC, a meta-analysis was conducted. METHODS: Databases including PubMed, Embase, Cochrane, and Chinese National Knowledge Infrastructure (CNKI) were searched for publications that met the inclusion criteria. A fixed effect model was used to estimate pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) for the association between XRCC1 Arg399Gln and response or survival of platinum-based treatment for advanced NSCLC. A chi-squared-based Q-test was used to test the heterogeneity hypothesis. Egger's test was used to check publication bias. RESULTS: Seventeen published case-control studies that focus on the association between XRCC1 Arg399Gln and response or survival of platinum-based treatment for advanced NSCLC in 2256 subjects were included in this meta-analysis, of whom 522 were AA genotypes (23.2% frequency), 916 AG genotypes (40.6% frequency), and 818 GG genotypes (36.2% frequency). The overall response rate (ORR) was 45.2% (110/243) for AA genotype patients, 29.9% for AG genotype (73/244), and 30.7% for GG genotype (124/403). The heterogeneity test did not show any heterogeneity and the Egger's test did not reveal an obvious publication bias among the included studies. The meta-analysis indicated that AA genotype patients presented higher response rates toward platinum drug treatment compared with G model (GG+GA) patients (GG vs. AA model: OR=0.489, 95% CI 0.266-0.900, P=0.021; AG vs. AA model: OR=0.608, 95% CI 0.392-0.941, P=0.026; GA+AA vs. GG model: OR=1.259, 95% CI 0.931-1.701, P=0.135; GG+GA vs. AA model: OR=0.455, 95% CI 0.313-0.663, P=0.0001). However, no evidence validates XRCC1 associates with the survival following platinum drug therapy. CONCLUSIONS: Our meta-analysis suggested that XRCC1 Arg399Gln is related with the sensitivity of NSCLC patients to platinum-based treatment. AA genotype patients present more desirable curative effectiveness compared with other patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Platina/farmacologia , Compostos de Platina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Genótipo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
8.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 41(5): 540-6, 2012 09.
Artigo em Chinês | MEDLINE | ID: mdl-23086647

RESUMO

OBJECTIVE: To investigate the expression of RRM1 and ERCC1 genes in tumor tissues and peripheral blood lymphocytes of advanced non-small cell lung cancer (NSCLC). METHODS: Tissue and peripheral blood samples were collected from 49 advanced NSCLC patients treated with gemcitabine plus carboplatin. The expressions of RRM1 and ERCC1 mRNA in tumor tissue and peripheral lymphocytes were detected by real-time fluorescent quantitative PCR. The relationship of gene expression with clinical characteristics,chemotherapy response and prognosis was analyzed. RESULTS: The RRM1 expression in tumor tissues was positively correlated with that in peripheral blood lymphocytes,while no significant correlation was observed between ERCC1 expression in tumor tissues and that in peripheral blood (rs=0.332 and 0.258; P=0.020 and 0.073, respectively). The expression of RRM1 and ERCC1 in tumor tissues peripheral lymphocytes was synchronous (rs=0.634 and 0.351; P<0.001 and 0.013, respectively). There was no significant correlation of gene expression with gender, age, smoking status, performance status, clinical stages and histological types of patients (P>0.05). Significant difference was found in response rate to chemotherapy (P<0.05,P<0.01,P<0.05),median survival time (P<0.05,P<0.01,P<0.05) and 1-year survival rate (P<0.01,<0.05,P<0.05) between patients with low RRM1 and ERCC1 expression levels in tumor tissues or low RRM1 expression levels in peripheral blood and those with high RRM1 and ERCC1 expression levels. The patients with low ERCC1 expression levels in tumor tissues gained higher 2-year survival rate (P<0.05). There was no correlation of the expression of ERCC1 in peripheral blood with the response to chemotherapy and prognosis (P>0.05). CONCLUSION: The expression of RRMI and ERCC1 genes in tumor tissues and RRM1 in peripheral blood lymphocytes is closely correlated with the response to chemotherapy and prognosis of patients with advanced NSCLC treated with gemcitabine plus carboplatin.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Prognóstico , Ribonucleosídeo Difosfato Redutase
9.
J Zhejiang Univ Sci B ; 12(3): 174-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21370501

RESUMO

OBJECTIVE: To evaluate the predictive values of gene expressions of ribonucleotide reductase M1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) in peripheral blood from Chinese patients with non-small-cell lung cancer (NSCLC) treated with gemcitabine plus platinum. METHODS: Forty Chinese patients with advanced NSCLC were recruited and received gemcitabine 1 200 mg/m(2) on Days 1 and 8 plus carboplatin AUC 5 on Day 1. RRM1 and BRCA1 expression levels in peripheral blood were detected by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Kaplan-Meier survival curve and log-rank test were performed to evaluate the correlation between gene expression and overall survival for these subjects. RESULTS: No correlation was observed between gene expression of RRM1 and that of BRCA1 (P>0.05), but there was a strong correlation between the expression of RRM1 and the response to chemotherapy (P=0.003). Subjects with low RRM1 expression levels in peripheral blood had longer survival time than those with high RRM1 expression levels (16.95 vs. 12.76 months, log-rank 3.989, P=0.046). However, no significant association between BRCA1 expression levels and survival time was found (16.80 vs. 13.77 months, log-rank 0.830, P=0.362). CONCLUSIONS: Patients with low RRM1 expression levels in peripheral blood have a greater response to chemotherapy and longer survival time. Advanced NSCLC patients with low RRM1 expression levels may benefit from gemcitabine plus platinum therapy. RRM1 mRNA expression in peripheral blood could be used to predict the prognosis of NSCLC treated by gemcitabine and platinum.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Antineoplásicos/farmacologia , Proteína BRCA1/sangue , Proteína BRCA1/genética , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Feminino , Genes BRCA1 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Ribonucleosídeo Difosfato Redutase , Resultado do Tratamento , Gencitabina
10.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 39(6): 628-33, 2010 11.
Artigo em Chinês | MEDLINE | ID: mdl-21166058

RESUMO

OBJECTIVE: To develop a method for the detection of RRM1, ERCC1 and BRCA1 gene expression by SYBR real-time fluorescent quantitative PCR in non-small cell lung cancer tissues and peripheral blood. METHODS: The plasmid standard of RRM1, ERCC1, BRCA1 and ß-actin genes was constructed. SYBR real-time PCR was performed, and the standard curve was established. The expressions of RRM1, ERCC1 and BRCA1 mRNA in non-small cell lung cancer tissues and peripheral blood were detected. RESULT: The standard curve presented linearity. The liquate curves of standard gene were all single apex, indicating that a good specificity was obtained. CONCLUSION: The developed SYBR real-time fluorescent quantitative PCR has advantage of convenient operation, low cost, good specificity and high veracity.


Assuntos
Proteína BRCA1/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Neoplasias Pulmonares/metabolismo , Reação em Cadeia da Polimerase/métodos , Proteínas Supressoras de Tumor/genética , Actinas/genética , Proteína BRCA1/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Proteínas de Ligação a DNA/sangue , Endonucleases/sangue , Feminino , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , RNA Mensageiro/sangue , Ribonucleosídeo Difosfato Redutase , Proteínas Supressoras de Tumor/sangue
11.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 36(4): 391-5, 2007 07.
Artigo em Chinês | MEDLINE | ID: mdl-17717833

RESUMO

OBJECTIVE: To investigate the relationship between peak concentration (Cmax) of gemcitabine at fixed-dose-rate and its hematological toxicity profile in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Twenty-one patients received gemcitabine at a fixed dose rate (1200 mg/m2 over 120 min) with carboplatin. Plasma concentrations of gemcitabine were measured by ion-pair reversed-phase high-performance liquid chromatography. RESULTS: The mean value of Cmax in 21 eligible patients was(4.95+/-2.42) microg *ml(-1). The main hematological toxicity was grade III-IV thrombocytopenia and neutropenia. The mean percentages of reduction of WBC, NEC, PLTC and Hb of 21 patients were (38.3+/-38.1)%, (31.3+/-73.6)%, (31.8+/-53.5)% and (12.0+/-12.2)%, respectively. The C(max)of gemcitabine and the percentage of reduction in WBC showed a significant correlation (r2=0.4575, P<0.05). A significant correlation (r2=0.5671, P<0.05) was also observed between the percentage of reduction of PLTC and Cmaxof gemcitabine. CONCLUSION: The results of relationship between Cmax and toxicity profile suggest that gemcitabine administration should be individualized in order to decrease the occurrence of ADR.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Neutropenia/induzido quimicamente , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/efeitos adversos , Carboplatina/sangue , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Cromatografia Líquida de Alta Pressão , Desoxicitidina/efeitos adversos , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Trombocitopenia/induzido quimicamente , Gencitabina
12.
J Zhejiang Univ Sci B ; 8(5): 307-13, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17542057

RESUMO

OBJECTIVE: To conduct a randomized comparative trial of pharmacokinetics, efficacy and toxicity profile treatment with 1200 mg/m(2) gemcitabine using standard 30-min infusion or fixed dose rate (FDR) infusion [10 mg/(m(2) x min)] on days 1 and 8 plus carboplatin AUC (area under curve) 5 on day 1 in Chinese non-small-cell cancer patients. Twelve patients were enrolled in this study. METHODS: Plasma gemcitabine concentrations were measured by ion-pair reversed phase high performance liquid chromatography. Antitumoral activity and toxicity of gemcitabine was assessed according to World Health Organization criteria. RESULTS: The obtained mean parameters, such as T(1/2) (elimination half time), AUC, and CL (clearance), were consistent with those reported in literature. Qualified response rate in our study was 33.3% for standard arm and 50% for FDR arm. Additional 50% and 33.3% patients contracted stable disease (SD) in standard arm and FDR arm, respectively. The predominant toxicity was hematologic, and patients in the standard infusion arm experienced consistently more hematologic toxicity. CONCLUSION: Pharmacokinetic and clinical data in this trial support the continued evaluation of the FDR infusion strategy with gemcitabine.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Desoxicitidina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Povo Asiático , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Gencitabina
13.
Cancer Chemother Pharmacol ; 60(2): 211-8, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17124596

RESUMO

PURPOSE: To investigate the efficacy and relationship between plasma concentrations at the end of infusion (C(end of infusion)) and toxicity profile of fixed-dose-rate gemcitabine plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were given gemcitabine by 120 min infusion [at a fixed dose rate (FDR) of 10 mg/m(2)/min] on days 1 and 8 of a 21-day cycle, immediately followed by carboplatin AUC 5 by 4 h infusion on day 1. C (end of infusion) of gemcitabine was determined by ion-pair reversed-phase high-performance liquid chromatography (HPLC). RESULTS: By the close-out date, in our study population, the estimated median time to tumor progression (TTP) was 7 months (95% CI 4-10 months), median overall survival (OS) was 12 months (95% CI 11.2-12.8 months). The mean value of C (end of infusion) of 21 eligible patients was 16.48 +/- 8.07 micromol/l (range 27.43-2.87 micromol/l). The main hematological toxicities were transient grade 3-4 thrombocytopenia. The mean percentages of reduction of WBC, NEC, PLTC and Hb of 21 eligible patients were 38.3 +/- 38.1%, 31.3 +/- 73.6%, 31.8 +/- 53.5% and 12.0 +/- 12.2%, respectively. The analysis of the C(end of infusion) of gemcitabine and the percentage of reduction in WBC showed a significant correlation (r(2) = 0.4575; p < 0.05). A significant correlation (r(2) = 0.5671; p < 0.05) was also observed between the percentage of reduction of PLTC and C(end of infusion) of gemcitabine infusion. CONCLUSION: The clinical data in this trial supports the further evaluation the regimen in advanced NSCLC patients, due to its predictable kinetic behavior and less severe toxicity profile than expected.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Carboplatina/administração & dosagem , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Feminino , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Taxa de Sobrevida , Gencitabina
14.
J Zhejiang Univ Sci B ; 6(5): 446-50, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15822162

RESUMO

To determine the pharmacokinetics of gemcitabine (2',2'-difluorodeoxycytidine) in Chinese non-small-cell lung cancer (NSCLC) patients. Six study subjects were administered gemcitabine at a fixed dose rate of 10 mg/m(2) per min (1200 mg/m(2), two hours infusion), and carboplatin and plasma gemcitabine concentrations were measured by ion-pair reversed-phase high-performance liquid chromatography (HPLC). 3P97 Pharmaceutical Kinetics Software was used for the calculation of pharmacokinetic parameters. The obtained mean parameters, elimination half life (t(1/2)) (10.67+/-3.38 min), area under the curve (AUC) (7.55+/-1.53 (microg x h)/ml), and clearance (CL) (3940.05+/-672.08 ml/min), were consistent with those reported in literature. The hematologic toxicology result showed that the regimen was effective on and tolerated by the patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/sangue , Desoxicitidina/análogos & derivados , Adolescente , Adulto , Idoso , China , Desoxicitidina/administração & dosagem , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Gencitabina
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