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1.
Br J Cancer ; 98(1): 71-6, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18059397

RESUMO

Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib+FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate=34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated 'in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/metabolismo , NF-kappa B/metabolismo , Adenocarcinoma/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/metabolismo , Receptores ErbB/genética , Feminino , Fluoruracila/administração & dosagem , Gefitinibe , Dosagem de Genes , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Compostos Organoplatínicos/administração & dosagem , Quinazolinas/administração & dosagem , Taxa de Sobrevida
2.
J Immunol ; 162(1): 503-9, 1999 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-9886426

RESUMO

CD14 is a major receptor for the bacterial endotoxin LPS. Since CD14 is specifically and highly expressed on the surface of monocytic cells, it has been used as a monocyte/macrophage differentiation marker. To identify elements that are critical for the direction of the tissue-specific expression of CD14, an 80-kb genomic DNA fragment containing the coding region of the CD14 gene, as well as a considerable amount of both upstream and downstream sequence, was used to generate transgenic mice. The analysis of mice from six different founder lines demonstrated that this genomic DNA fragment was sufficient to direct human CD14 gene expression in a monocyte-specific manner among hematopoietic cells. Furthermore, the data lead us to a new finding that CD14 is highly expressed in the human liver, a primary organ involved in the acute phase response. These transgenic mice provide a useful model to analyze the biological function of human CD14.


Assuntos
Regulação da Expressão Gênica/imunologia , Receptores de Lipopolissacarídeos/biossíntese , Receptores de Lipopolissacarídeos/genética , Lipopolissacarídeos/metabolismo , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Animais , Clonagem Molecular , Éxons , Humanos , Íntrons , Receptores de Lipopolissacarídeos/química , Fígado/imunologia , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Receptores Imunológicos/química , Sequências Reguladoras de Ácido Nucleico/imunologia , Transgenes/imunologia
3.
Cell Immunol ; 143(2): 348-56, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1511481

RESUMO

Thymocyte death is a complex phenomenon under the control of different signals and stimuli. We evaluated the effect of elevated temperature (heat shock, HS) on mouse thymocyte apoptosis. Incubation of thymocytes at 43 degrees C for 20 min induced DNA fragmentation and cell death, but it was also able to decrease the apoptosis induced by dexamethasone (DEX), TPA or Ca2+ ionophore. The anti-apoptotic effect was correlated with induction of heat shock proteins (HSPs) and abolished by protein synthesis inhibition. On the other hand, HS-induced unlike DEX-induced apoptosis was not inhibited by protein synthesis and mRNA transcription inhibitors, the PKC inhibitors H-7 and staurosporine, or interleukin-4 (IL-4), but only by Zn2+. These results suggest that HS interferes in thymocyte death by either inducing or inhibiting thymocyte apoptosis and that the induction process mechanisms are different from those of GCH.


Assuntos
Morte Celular , Dexametasona/farmacologia , Temperatura Alta , Timo/citologia , Animais , Calcimicina/farmacologia , Dano ao DNA , Proteínas de Choque Térmico/biossíntese , Camundongos , Camundongos Endogâmicos C3H , Acetato de Tetradecanoilforbol/farmacologia
5.
Pharmacol Res ; 26 Suppl 2: 5-9, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1409324

RESUMO

Glucocorticoid hormones (GCH) and IL-2 induce apoptotic cell death by a PKC-dependent mechanism. IL-4 counteracts apoptosis by inhibiting PKC activity. GCH and IL-2 show antagonistic effects on apoptosis when administered together. These data indicate that PKC activation in response to different stimuli can both enhance or reduce thymocyte survival.


Assuntos
DNA/metabolismo , Glucocorticoides/farmacologia , Proteína Quinase C/metabolismo , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Dexametasona/farmacologia , Citometria de Fluxo , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C3H , Linfócitos T/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologia
6.
Int J Clin Lab Res ; 21(4): 300-3, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1591384

RESUMO

Glucocorticoid hormones, calcium ionophores and anti-CD3 monoclonal antibodies induce apoptosis in mouse thymocytes. This type of cell death, which is characterized by an extensive DNA fragmentation into oligonucleosomal subunits, occurs in the intrathymic process of negative selection, and is involved in the deletion of autoreactive T-cells during thymic maturation. A number of cytokines are able to modulate apoptosis, and interleukins, including interleukin-1, interleukin-2, and interleukin-4, play a crucial role in thymic maturation and T-cell development. We tested the effects of several cytokines on the glucocorticoid hormone-induced apoptosis of mouse thymocytes in vitro, and demonstrated that interleukin-1 alpha, interleukin-2, and interleukin-4 inhibit the apoptosis induced by dexamethasone, but that interleukin-3 and interleukin-6 exert no noteworthy effect. Dose-response experiments indicated that interleukin-4 is more potent than interleukin-1 alpha and interleukin-2 in inhibiting dexamethasone-induced apoptosis. Furthermore, interleukin-4 fully inhibited the DNA fragmentation induced by the protein kinase-C activator 12-O-tetradecanoylphorbol-13-acetate, but was ineffective against apoptosis induced by the calcium ionophore A23187. These results suggest that interleukins regulate the thymic selection process by acting as modulators of the negative selection process.


Assuntos
Dexametasona/farmacologia , Interleucinas/fisiologia , Linfócitos T/efeitos dos fármacos , Timo/citologia , Animais , Calcimicina/farmacologia , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Replicação do DNA , Interleucinas/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Linfócitos T/citologia , Acetato de Tetradecanoilforbol/farmacologia
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