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1.
Invest New Drugs ; 31(3): 599-604, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22623066

RESUMO

BACKGROUND: A phase I study was performed to evaluate dose-limiting toxicity and the recommended dose for the oral fluoropyrimidine S-1 administered concurrently with thoracic radiotherapy (TRT) in elderly (≥ 70 years of age) patients with locally advanced non-small cell lung cancer. METHODS: S-1 was administered on days 1 to 14 and 22 to 35 at oral doses of 65 or 80 mg m(-2) day(-1). TRT was administered in 2-Gy fractions five times weekly for a total dose of 60 Gy. Twelve previously untreated patients were treated with S-1 at 65 (n=6) or 80 (n=6) mg m(-2) day(-1). RESULTS: All patients completed the planned 60 Gy of TRT. Dose-limiting toxicity included pneumonitis (n=2), infection (n=1), and stomatitis (n=1), each of grade 3, but each event was reversible. The recommended dose for S-1 was determined to be 80 mg m(-2) day(-1). No patient experienced toxicity of grade 4. The dose intensity of S-1 was well maintained and the combination of S-1 plus TRT was well tolerated overall. The overall response rate was 83.3 %, with a median survival time of 34.0 months. CONCLUSIONS: Administration of S-1 at 80 mg m(-2) day(-1) on days 1 to 14 and 22 to 35 can be safely combined with concurrent TRT in elderly patients with locally advanced non-small cell lung cancer.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Ácido Oxônico/administração & dosagem , Tegafur/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Ácido Oxônico/efeitos adversos , Tegafur/efeitos adversos
2.
Cancer Discov ; 2(10): 922-33, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22956644

RESUMO

EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptor ErbB-2/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Afatinib , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cetuximab , Classe I de Fosfatidilinositol 3-Quinases , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Mutação , Fosfatidilinositol 3-Quinases/genética , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Interferência de RNA , RNA Interferente Pequeno , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética
3.
Clin Cancer Res ; 18(22): 6219-26, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-22843788

RESUMO

PURPOSE: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. EXPERIMENTAL DESIGN: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. RESULTS: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. CONCLUSIONS: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Fusão Oncogênica/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Crizotinibe , Humanos , Concentração Inibidora 50 , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Células Tumorais Cultivadas/efeitos dos fármacos
4.
J Thorac Oncol ; 7(5): 913-8, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22722791

RESUMO

INTRODUCTION: The presence of the transforming fusion gene echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC) is a predictive marker for the efficacy of anaplastic lymphoma kinase inhibitors. However, the currently available assays for the detection of the different variants of EML4-ALK have limitations. METHODS: We developed an assay system for the detection of EML4-ALK variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, or 7 transcripts in total RNA obtained from formalin-fixed, paraffin-embedded (FFPE) specimens of NSCLC tissue. The assay is based on region-specific polymerase chain reaction amplification of EML4-ALK complementary DNA followed by specific single-base primer extension and analysis of the extension products by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The assay was validated by fluorescence in situ hybridization and the results confirmed by subcloning and sequencing of polymerase chain reaction products. RESULTS: Evaluation of the analytic sensitivity of the assay with serial dilutions of plasmids containing EML4-ALK complementary DNA sequences revealed it to be capable of the reliable detection of one copy of each plasmid per reaction. The assay also detected EML4-ALK variants 1 or 3 in three FFPE samples of surgically resected NSCLC shown to be positive for anaplastic lymphoma kinase rearrangement by fluorescence in situ hybridization. Furthermore, the assay identified variant 1 of EML4-ALK in 3 of 20 FFPE biopsy samples from patients with advanced NSCLC. All positive samples were confirmed by subcloning and sequencing. CONCLUSIONS: Our novel assay is highly sensitive and effective for the detection of EML4-ALK in FFPE specimens.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Rearranjo Gênico , Variação Genética/genética , Neoplasias Pulmonares/diagnóstico , Proteínas de Fusão Oncogênica/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Viabilidade , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Inclusão em Parafina , Prognóstico , Células Tumorais Cultivadas
5.
J Thorac Oncol ; 6(10): 1624-31, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21716144

RESUMO

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. METHODS: The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. RESULTS: Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. CONCLUSIONS: Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Amplificação de Genes , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Crizotinibe , Inativação Gênica , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , RNA Interferente Pequeno/genética , Survivina
6.
Clin Cancer Res ; 17(8): 2140-8, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21415216

RESUMO

PURPOSE: EML4-ALK (echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer. The purpose of the present study was to characterize the mechanism of malignant transformation by EML4-ALK. EXPERIMENTAL DESIGN: We established NIH 3T3 cells that stably express variant 1 or 3 of EML4-ALK and examined the signaling molecules that function downstream of EML4-ALK. RESULTS: Forced expression of EML4-ALK induced marked activation of extracellular signal-regulated kinase (ERK) and STAT3, but not that of AKT. Inhibition of ERK or STAT3 signaling resulted in substantial attenuation of the proliferation of cells expressing either variant of EML4-ALK, suggesting that these signaling pathways function downstream of EML4-ALK in lung cancer cells. The specific ALK inhibitor TAE684 induced apoptosis that was accompanied both by upregulation of BIM, a proapoptotic member of the Bcl-2 family, and by downregulation of survivin, a member of the inhibitor of apoptosis protein (IAP) family, in EML4-ALK-expressing NIH 3T3 cells as well as in H3122 human lung cancer cells harboring endogenous EML4-ALK. Depletion of BIM and overexpression of survivin each inhibited TAE684-induced apoptosis, suggesting that both upregulation of BIM and downregulation of survivin contribute to TAE684-induced apoptosis in EML4-ALK-positive lung cancer cells. Furthermore, BIM and survivin expression was found to be independently regulated by ERK and STAT3 signaling pathways, respectively. CONCLUSIONS: ALK inhibitor-induced apoptosis is mediated both by BIM upregulation resulting from inhibition of ERK signaling as well as by survivin downregulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas de Membrana/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição STAT3/metabolismo , Quinase do Linfoma Anaplásico , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica/genética , Feminino , Humanos , Immunoblotting , Proteínas Inibidoras de Apoptose/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/genética , Células NIH 3T3 , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Interferência de RNA , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Survivina , Transfecção
7.
Cancer Res ; 70(24): 10402-10, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21159653

RESUMO

The molecular mechanism by which epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non-small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation-positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation-positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI-induced apoptotic death in these cells.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Receptores ErbB/antagonistas & inibidores , Genes erbB-1 , Neoplasias Pulmonares/enzimologia , Proteínas Associadas aos Microtúbulos/biossíntese , Mutação , Quinazolinas/farmacologia , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe , Técnicas de Silenciamento de Genes , Humanos , Proteínas Inibidoras de Apoptose , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Proteína Oncogênica v-akt/antagonistas & inibidores , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Survivina
8.
Mol Cancer Ther ; 9(6): 1647-56, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20530710

RESUMO

Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação/genética , Quinazolinas/uso terapêutico , Timidilato Sintase/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Afatinib , Substituição de Aminoácidos/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Fator de Transcrição E2F1/metabolismo , Fluoruracila/farmacologia , Gefitinibe , Glutamatos/farmacologia , Guanina/análogos & derivados , Guanina/farmacologia , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Camundongos , Ácido Oxônico/farmacologia , Pemetrexede , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proto-Oncogene Mas , Quinazolinas/farmacologia , Tegafur/farmacologia
9.
Mol Cancer Ther ; 9(5): 1198-207, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20424000

RESUMO

Amplification of human epidermal growth factor receptor 2 (HER2) has been detected in 20% to 30% of gastric cancers and is associated with a poor outcome. Combination therapies with HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for gastric cancer with HER2 amplification. We have now investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the HER2-targeting agents lapatinib or trastuzumab in gastric cancer cells with or without HER2 amplification. We used 5-fluorouracil (5FU) instead of S-1 for in vitro experiments, given that tegafur, a component of S-1, is metabolized to 5FU in the liver. The combination of 5FU and HER2-targeting agents synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in gastric cancer cells with HER2 amplification, but not in those without it. Lapatinib or trastuzumab also induced downregulation of thymidylate synthase (TS) expression and activity only in cells with HER2 amplification. The combination of 5FU and TS depletion by RNA interference also exhibited an enhanced proapoptotic effect in cells with HER2 amplification. These observations thus suggest that lapatinib-induced or trastuzumab-induced downregulation of TS is responsible, at least in part, for the synergistic antitumor effect of combined treatment with 5FU and HER2-targeting agents. The antitumor effect of the combination of S-1 and HER2-targeting agents in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and HER2-targeting agents is a promising treatment option for gastric cancer with HER2 amplification.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Ácido Oxônico/administração & dosagem , Quinazolinas/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Tegafur/administração & dosagem , Animais , Anticorpos Monoclonais Humanizados , Carcinoma/genética , Carcinoma/patologia , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Fluoruracila/administração & dosagem , Amplificação de Genes , Humanos , Lapatinib , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Trastuzumab , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Mol Cancer Ther ; 9(5): 1188-97, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20406949

RESUMO

Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G(1) arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G(1) arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores de Fatores de Crescimento/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Proteína Tirosina Quinase CSK , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dasatinibe , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Indóis/farmacologia , Concentração Inibidora 50 , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptores de Fatores de Crescimento/antagonistas & inibidores , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Sulfonas/farmacologia , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Quinases da Família src
11.
Jpn J Clin Oncol ; 40(1): 54-9, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19837690

RESUMO

OBJECTIVE: The optimal management of elderly patients with limited-disease small cell lung cancer (LD-SCLC) has not been established. METHODS: The records of elderly (>or=70 years of age) patients with LD-SCLC who had been treated with etoposide and cisplatin chemotherapy with early concurrent twice-daily thoracic radiotherapy (TRT) were reviewed retrospectively. RESULTS: Of the 25 elderly patients with LD-SCLC identified, 12 (48%) individuals received etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT. The main toxicities of this treatment regimen were hematologic, with neutropenia of Grade 4 being observed in all patients and febrile neutropenia of Grade 3 in eight patients during the first cycle of chemoradiotherapy. The toxicity of TRT was acceptable, with all patients completing the planned radiotherapy within a median of 29 days (range, 19-33). No treatment-related deaths were observed. The median progression-free survival and overall survival times were 14.2 months (95% confidence interval, 4.3-18.2) and 24.1 months (95% confidence interval, 11.3-27.2), respectively. CONCLUSIONS: Etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT was highly myelotoxic in elderly patients with LD-SCLC, although no treatment-related deaths were observed in our cohort. Prospective studies are required to establish the optimal schedule and dose of chemotherapy and TRT in such patients.


Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Idoso , Antineoplásicos/uso terapêutico , Cisplatino/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/radioterapia , Masculino , Estadiamento de Neoplasias , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/radioterapia , Análise de Sobrevida
12.
Cancer Res ; 69(16): 6515-21, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19638574

RESUMO

Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non-small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G(1) arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G(1) arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G(1) arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G(1) arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant KRAS, respectively. The G(1) arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS.


Assuntos
Benzenossulfonatos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Genes ras , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Piridinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ciclina E/genética , Sistemas de Liberação de Medicamentos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes ras/fisiologia , Genótipo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/fisiologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Células Tumorais Cultivadas
13.
J Thorac Oncol ; 3(9): 1073-5, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18758316

RESUMO

Cancer chemotherapy is not well established for patients on hemodialysis (HD). A 77-year-old man on HD presented with small cell lung cancer. He was treated with the combination of carboplatin and etoposide while the pharmacokinetics of the drugs were monitored. The patient showed a response with manageable toxicity and remained progression free for at least 8 months. The area under the concentration-time curve for each antitumor agent in the patient was within the therapeutic range achieved in individuals with normal renal function. Carboplatin and etoposide chemotherapy combined with HD thus allowed the drugs to achieve an appropriate area under the concentration-time curve and sufficient efficacy in a small cell lung cancer patient with chronic renal failure.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Pulmonares/metabolismo , Diálise Renal , Carcinoma de Pequenas Células do Pulmão/metabolismo , Idoso , Área Sob a Curva , Carboplatina/administração & dosagem , Nefropatias Diabéticas/terapia , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Humanos , Falência Renal Crônica/terapia , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico
14.
J Thorac Oncol ; 3(2): 187-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18303442

RESUMO

Large cell neuroendocrine carcinoma (LCNEC) is a relatively new category of pulmonary neuroendocrine tumor. Although it was first detected in the lung, LCNEC has since been found in a variety of extrapulmonary sites. We now describe a patient who was diagnosed with LCNEC originating from the mediastinum, an extremely rare disorder. An increased serum concentration of alpha-fetoprotein (AFP) in the patient was reduced by chemotherapy in association with tumor shrinkage. Furthermore, the tumor was confirmed immunohistochemically to produce AFP. To our knowledge, this is the first report of a LCNEC that produces AFP.


Assuntos
Carcinoma Neuroendócrino/sangue , Neoplasias do Mediastino/sangue , alfa-Fetoproteínas/metabolismo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Neuroendócrino/patologia , Carcinoma Neuroendócrino/terapia , Humanos , Masculino , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/terapia , Terapia Neoadjuvante , Tomografia Computadorizada por Raios X
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