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1.
JAMA ; 331(3): 201-211, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38227033

RESUMO

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.


Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos de Platina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Resposta Patológica Completa , Antineoplásicos/uso terapêutico , Terapia Combinada , Compostos de Platina/administração & dosagem , Compostos de Platina/uso terapêutico , Idoso
2.
BMC Med ; 21(1): 72, 2023 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-36829154

RESUMO

BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adolescente , Adulto , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/uso terapêutico , Quinase do Linfoma Anaplásico/uso terapêutico , Proteínas Proto-Oncogênicas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico
3.
Adv Ther ; 41(11): 4032-4048, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39230871

RESUMO

INTRODUCTION: SCT510 is a biosimilar to bevacizumab (Avastin) reference product (RP) that is approved for various metastatic cancers. In this study, we aimed to demonstrate the equivalence of SCT510 and bevacizumab in terms of efficacy, safety, immunogenicity and pharmacokinetics (PK) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Patients with non-squamous NSCLC were randomized equally to the SCT510 group (comprising SCT510, paclitaxel, and carboplatin) and the bevacizumab group (comprising bevacizumab, paclitaxel, and carboplatin) for 4-6 cycles, followed by maintenance monotherapy with SCT510. The primary endpoint was the objective response rate (ORR) at week 12. Secondary endpoints included 18-week ORR, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and 1-year survival rate, as well as assessments of safety, immunogenicity, and multi-dose PK analysis. RESULTS: Between March 29, 2019, and April 27, 2021, 989 patients were screened and 567 eligible patients were randomly assigned to the SCT510 group (285 patients) and the bevacizumab group (282 patients). The ORR at week 12 was 52.6% [95% confidence interval (CI) 46.66-58.55%] in the SCT510 group and 52.5% (95% CI 46.47-58.47%) in the bevacizumab group. The ORR at week 18 was 55.4% (95% CI 49.46-61.30%) for SCT510 and 55.7% (95% CI 49.68-61.62%) for bevacizumab. The ORR risk ratio (RR) at weeks 12 and 18 was 0.99 (90% CI 0.873-1.133) and 0.99 (90% CI 0.872-1.114), respectively, both within the pre-specified equivalence margin of 0.75-1.33. There were no differences between the two groups in relation to other secondary endpoints, specifically DCR, DOR, PFS, OS, and 1-year survival rate. The overall safety findings were similar between the two treatment groups, and both SCT510 and bevacizumab RP exhibited low immunogenicity. CONCLUSIONS: SCT510 is similar to bevacizumab in clinical efficacy, safety, immunogenicity, and PK in patients with advanced non-squamous NSCLC. The totality of the evidence supports the clinical equivalence of SCT510 and bevacizumab. TRIAL REGISTRATION: NCT03792074.


Assuntos
Bevacizumab , Medicamentos Biossimilares , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Bevacizumab/uso terapêutico , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Pessoa de Meia-Idade , Idoso , Método Duplo-Cego , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/uso terapêutico , Paclitaxel/administração & dosagem , Carboplatina/uso terapêutico , Carboplatina/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico
4.
Cancer Invest ; 31(4): 279-85, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23627410

RESUMO

Serum C-reactive protein (CRP), a sensitive marker of systemic inflammation, has been reported to be associated with the risk of a number of cancers including breast cancer. However, the results are inconsistent. To investigate the association between serum CRP levels and early breast cancer, we conducted a hospital-based case-control study among 506 newly diagnosed breast cancer patients and 506 controls with benign breast diseases matched by age and menopausal status. Odds ratios (ORs) were computed with unconditional logistic regression models, adjusted for major confounding factors. Relative to women with the lowest quartile of CRP level, women with the highest quartile had 1.65-fold increased breast cancer risk (OR: 1.65, 95% CI: 1.12-2.42) in a significant dose-response manner (p(trend) = .011). Stratification analysis revealed a positive association only for overweight postmenopausal women (highest CRP quartile versus lowest CRP quartile: OR: 2.78, 95% CI: 1.18-6.6). Multinominal logistic regression analysis showed that only hormonal receptor (HR) positive and human epidemiological receptor 2 (HER2) negative breast cancers had elevated serum CRP levels. We observed that elevated serum CRP levels are positively associated with early breast cancer, predominantly among overweight and postmenopausal women. This study provided epidemiological evidence that chronic inflammation might mediate the association between obesity and postmenopausal breast cancer. Although a positive association between serum CRP and HR positive/HER2 negative breast cancer is intriguing, further epidemiological studies are needed to confirm such findings.


Assuntos
Biomarcadores/sangue , Neoplasias da Mama/sangue , Proteína C-Reativa/metabolismo , Menopausa/sangue , Biomarcadores/metabolismo , Índice de Massa Corporal , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/sangue , Inflamação/genética , Inflamação/metabolismo , Modelos Logísticos , Menopausa/genética , Menopausa/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Pós-Menopausa/sangue , Pós-Menopausa/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Risco , Fatores de Risco
5.
Mol Cell Biochem ; 367(1-2): 195-203, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22581441

RESUMO

This study aimed to investigate the expression of Twist in gastric cancer tissues and its correlation between Twist and the epithelial-mesenchymal transition (EMT). By means of RT-PCR and Western blot, the mRNA and protein expressions of Twist, E-cadherin, and Vimentin in 61 gastric cancer tissues and adjacent normal tissues were detected. The positive rates of Twist, E-cadherin, and Vimentin mRNA expression in gastric cancer tissues were 73.9. 40.6, and 60.9 %, respectively; compared to the expression of these genes in adjacent normal tissues (2.9, 75.4, and 27.5 %), the differences were significant (p < 0.05). The E-cadherin protein expression level in gastric cancer tissues was significantly lower than that in the adjacent normal tissues (p < 0.05). After the transfection of Twist siRNA into the MKN45 cells, the protein expression of Twist was significantly reduced (p < 0.05), the protein expression of E-cadherin was significantly increased, and the number of cells that passed through the Transwell chamber was significantly lower than that in the non-transfected control group as well as the transfected control group (p < 0.05). Twist may be associated with the epithelial-mesenchymal transition in gastric cancer and the tumorigenesis, invasion, and metastasis of gastric cancer.


Assuntos
Transição Epitelial-Mesenquimal , Expressão Gênica , Proteínas Nucleares/metabolismo , Neoplasias Gástricas/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Adulto , Idoso , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Transformação Celular Neoplásica , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Neoplasias Gástricas/patologia , Proteína 1 Relacionada a Twist/genética , Vimentina/metabolismo
6.
Mol Biol Rep ; 39(3): 2821-9, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21674184

RESUMO

The association between single-nucleotide polymorphisms (SNPs) of the CYP1B1 gene and lung cancer risk is still ambiguous. In this meta analysis, we assessed 10 case-control studies included 7,067 cases and 9,374 controls of the association between CYP1B1 SNPs of Leu432Val (rs1056836, 432C>G), Asn453Ser (rs1800440, 453A>G), Ala119Ser (rs1056827, 119G>T), Arg48Gly (rs10012, 48C>G) and the risk of lung cancer. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of association between the polymorphism and lung cancer risk under codominant model, dominant model and additive model respectively. Although there were limitations, this meta analysis indicated that individuals with 432GG genotype had a 39.7% higher risk of having lung cancer than those with the 432CC genotype, and individuals with the 432G allele had a 26.3% increased risk as well. An increased risk of lung cancer of 2.13 fold was observed in individuals with 119TT genotype. For Arg48Gly, individuals with 48GG genotype had a significantly increased risk of lung cancer compared with individuals with 48CC (OR 3.859; 95% CI 2.536-5.87). Elevated risk of lung cancer were observed in dominant model (OR 2.115; 95% CI 1.653-2.705) as well. The risk of lung cancer was elevated as the frequency of G allele increased in additive model (P = 0.000). For individuals with the polymorphism at codon 453, no evidence of such association was observed. Furthermore, a possible association between the CYP1B1 polymorphism at codon 432 and the lung cancer could be detected in individuals of Caucasian origin, while a negative association was suggested in Asians and African-Americans. An increased lung cancer risk was also found in women with polymorphism at codon 453. These results are supportive for the hypothesis that the CYP1B1 432GG, 119TT and 48GG genotypes are low-penetrance risk factors for developing lung cancer, and further studies are needed to validate these associations.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Citocromo P-450 CYP1B1 , Feminino , Estudos de Associação Genética , Humanos , Padrões de Herança/genética , Masculino , Razão de Chances , Fatores de Risco
7.
Signal Transduct Target Ther ; 7(1): 25, 2022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35087031

RESUMO

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK-rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1-rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.


Assuntos
Quinase do Linfoma Anaplásico/genética , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas , Rearranjo Gênico , Neoplasias Pulmonares , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos
8.
Jpn J Clin Oncol ; 39(12): 791-6, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19797415

RESUMO

OBJECTIVE: This Phase II study was conducted to evaluate the effects of irinotecan plus capecitabine in patients with advanced gastric cancer (AGC) who had received a first-line therapy of 5-fluorouracil/platinum regimen. METHODS: Patients received capecitabine 1000 mg/m(2) b.i.d. on days 1-14 followed by a 7-day rest period, and irinotecan 100 mg/m(2) was administered through a 90 min intravenous infusion on days 1 and 8, based on a 3-week cycle. RESULTS: Forty-six (95.8%) of the 48 patients were assessable for response. Thirteen cases of partial response were confirmed, response rate of 27.1% (95% CI, 14.5-39.7%). The median follow-up period was 25.2 months. The median time to progression and overall survival for all patients were 4.1 months (95% CI, 3.4-4.8 months) and 7.6 months (95% CI, 5.1-10.1 months). Grade 3 diarrhea and hand-foot syndrome occurred in eight (17.4%) and two (4.3%) patients, respectively. The most common Grade 3/4 hematological adverse event was neutropenia in four (8.7%) patients. There were no treatment-related deaths during this study. CONCLUSION: Irinotecan plus capecitabine was a relatively active and tolerable regimen as a second-line chemotherapy for AGC. Further investigation of this regimen is warranted, including the addition of new biological agents such as bevacizumab or cetuximab to improve the salvage regimen.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Capecitabina , Cetuximab , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Estadiamento de Neoplasias
9.
Int J Mol Med ; 42(1): 149-160, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29717769

RESUMO

The aim of the present study was to reveal the potential molecular mechanisms of microsatellite instability (MSI) on the prognosis of gastric cancer (GC). The investigation was performed based on an RNAseq expression profiling dataset downloaded from The Cancer Genome Atlas, including 64 high­level MSI (MSI­H) GC samples, 44 low­level MSI (MSI­L) GC samples and 187 stable microsatellite (MSI­S) GC samples. Differentially expressed genes (DEGs) were identified between the MSI­H, MSI­L and MSI­S samples. Pathway enrichment analysis was performed for the identified DEGs and the pathway deviation scores of the significant enrichment pathways were calculated. A Multi­Layer Perceptron (MLP) classifier, based on the different pathways associated with the MSI statuses was constructed for predicting the outcome of patients with GC, which was validated in another independent dataset. A total of 190 DEGs were selected between the MSI­H, MSI­L and MSI­S samples. The MLP classifier was established based on the deviation scores of 10 significant pathways, among which antigen processing and presentation, and inflammatory bowel disease pathways were significantly enriched with HLA­DRB5, HLA­DMA, HLA­DQA1 and HLA­DRA; the measles, toxoplasmosis and herpes simplex infection pathways were significantly enriched with Janus kinase 2 (JAK2), caspase­8 (CASP8) and Fas. The classifier performed well on an independent validation set with 100 GC samples. Taken together, the results indicated that MSI status may affect GC prognosis, partly through the antigen processing and presentation, inflammatory bowel disease, measles, toxoplasmosis and herpes simplex infection pathways. HLA­DRB5, HLA­DMA, HLA­DQA1, HLA­DRA, JAK2, CASP8 and Fas may be predictive factors for prognosis in GC.


Assuntos
Instabilidade de Microssatélites , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Idoso , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Leishmaniose/genética , Masculino , Sarampo/genética , Anotação de Sequência Molecular , Redes Neurais de Computação , Prognóstico , Curva ROC , Reprodutibilidade dos Testes , Análise de Sobrevida , Resultado do Tratamento
10.
Cancer Lett ; 423: 86-94, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29548818

RESUMO

Metastatic invasion is the primary cause of treatment failure for GBM. EMT is one of the most important events in the invasion of GBM; therefore, understanding the molecular mechanisms of EMT is crucial for the treatment of GBM. In this study, high expression of DRR1 was identified to correlate with a shorter median overall and relapse-free survival. Loss-of-function assays using shDRR1 weakened the invasive potential of the GBM cell lines through regulation of EMT-markers. The expressions of p-AKT were significantly decreased after DRR-depletion in SHG44 and U373 cells. Moreover, the invasion was inhibited by the AKT inhibitor, MK-2206. The expression of Vimentin, N-cadherin, MMP-7, snail and slug was significantly inhibited by MK-2206, while the expression of E-cadherin was upregulated. Our results provide the first evidence that DRR1 is involved in GBM invasion and progression possibly through the induction of EMT activation by phosphorylation of AKT.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Glioblastoma/genética , Humanos , Masculino , Invasividade Neoplásica , Fosforilação , Prognóstico , Análise de Sobrevida , Regulação para Cima
11.
Zhongguo Fei Ai Za Zhi ; 8(5): 451-3, 2005 Oct 20.
Artigo em Zh | MEDLINE | ID: mdl-21205532

RESUMO

BACKGROUND: In most instances, advanced non-small cell lung cancer (NSCLC) is treated with primary chemotherapy. Many chemotherapy regimens can palliate cancer-related symptoms. Quality of life and modestly improved survival are very important especially for elderly patients. This clinical trial is to compare the efficacy and toxicity of gemcitabine and oxaliplatin (GO) versus gemcitabine and cisplatin (GP) in treatment of advanced NSCLC in elderly patients. METHODS: A total of 42 patients with advanced NSCLC diagnosed pathologically were randomly divided into GO group (gemcitabine 1000mg/m² on days 1, 8; oxaliplatin 65mg/m² on days 1, 8) and GP group (gemcitabine 1000mg/m² on days 1, 8; cisplatin 30mg/m² on days 1-3), 28 days as a cycle. All patients received two cycles of chemotherapy at least. RESULTS: In GO group, the response rate was 55.0%. Whereas in GP group, the response rate was 40.9%. The difference in response rate was not statistically significant between the two groups (P > 0.05). The median survival duration was 11.2 months in GO group and 11.8 months in GP group. The 1-year survival rate was 45% in GO group and 50% in GP group (P > 0.05). The main toxicities were well tolerated. Leukopenia and nausea/vomiting at grade III+IV, and alopecia and impaired renal function at grade I+II occurred more frequently in GP group than those in GO group (P < 0.05). CONCLUSIONS: Both of the two regimens are feasible, well-tolerated and effective in treatment of advanced NSCLC in elderly patients. GO regimen may be safer than GP regimen.

12.
Anticancer Drugs ; 19(8): 825-31, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18690095

RESUMO

The efficacy of chemotherapy for advanced gastric cancer with palliative intent compared with supportive care alone is now widely accepted. However, the survival advantage is small, and no internationally accepted standard regimen has emerged. This study is performed to evaluate the response rate, time to progression, and safety of the combination of capecitabine (1000 mg/m twice daily, days 1-14) plus oxaliplatin (130 mg/m as a 2-h intravenous infusion on day 1) every 3 weeks, in previously untreated Chinese patients with advanced gastric cancer. Sixty-five (95.6%) of the 68 patients were assessable for response. Three cases of complete response and 34 cases of partial response were confirmed, giving an overall response rate of 54.4% [95% confidence interval (CI), 42.6-66.2%]. The median time to progression and overall survival for all patients were 5.7 months (95% CI, 2.0-8.8 months) and 10.5 months (95% CI, 5.0-15.1 months). The most severe hematologic adverse event was neutropenia, which occurred with grade 3 intensity in three (4.6%) patients and grade 4 in one (1.5%) patient. Thrombocytopenia and leukopenia occurred with grade 3 intensity in five (7.7%) and three (4.6%) patients, respectively. However, no grade 4 thrombocytopenia and leukopenia were observed. Grade 1/2 nausea/vomiting and diarrhea were observed in 33 (50.8%), 17 (26.2%), 26 (40%), 44 (67.7%), and 13 (20%) patients, respectively, and grade 3 nausea/vomiting and diarrhea were observed in one (1.5%) and four (6.2%) patients. Yet, no grade 4 nonhematologic toxicity was observed. Capecitabine/oxaliplatin combination chemotherapy is active in Chinese patients with previously untreated advanced gastric cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , China , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do Tratamento
13.
Anticancer Drugs ; 19(10): 1013-8, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18827567

RESUMO

The fluoropyrimidine and platinum-based combination chemotherapy is now widely used as first-line therapy for advanced gastric cancer (AGC). Unfortunately, about half of all patients do not respond to the current first-line chemotherapy and furthermore, most patients who achieve response to first-line chemotherapy eventually experience disease progression. Although there is a need for effective salvage treatment after the failure of first-line chemotherapy, data on the safety and efficacy of second-line treatment in AGC is limited. The current study evaluated an experimental combination regimen of docetaxel (60 mg/m) as an intravenous infusion of less than 1 h, followed by oxaliplatin (130 mg/m) intravenously for less than 2 h. Both drugs were administered on day 1 of a 21-day cycle, in pretreated Chinese patients with AGC. The trial enrolled 48 patients of whom 46 (95.8%) were assessable for response. The median time to progression was 4.4 months (95% confidence interval (CI): 3.4-5.4 months) and the median overall survival was 7.2 months (95% CI: 6.6-12.1 months). Partial response was confirmed in 11 of 48 cases (22.9%; 95% CI: 10.9-34.9%) and no complete responses were seen. Significant hematologic toxicity was noted with grade 3 and grade 4 neutropenia occurring in 21.7 and 4.3% of patients, respectively, as well as grade 3 thrombocytopenia occurring in 4.3% of patients. Grade 3 febrile neutropenia occurred in 6.5% of the patients. There were no treatment-related deaths during on the study. In summary, docetaxel and oxaliplatin have modest activity with predictable hematologic toxicity when given as salvage therapy for Chinese patients treated earlier for AGC. Given the short duration of response more focus should be given to newer biologic agents and triplet regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Capecitabina , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Neoplasias Gástricas/mortalidade , Taxoides/administração & dosagem
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