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1.
Int J Oncol ; 40(6): 1805-12, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22344385

RESUMO

The epidermal growth factor receptor (EGFR) and related family member, HER-2, are often overexpressed simultaneously in patients with a variety of malignant tumors, and the combination may cooperatively promote cancer cell growth and survival. The purpose of this study was to examine antitumor effects of the combination treatment of cetuximab and trastuzumab on head and neck squamous cell carcinoma (HNSCC) using 16 HNSCC cell lines in terms of antiproliferative effect and antibody-dependent cell-mediated-cytotoxicity (ADCC). Previously we have reported the expression levels of EGFR mRNA on 16 HNSCC cell lines. All cell lines expressed mRNA for EGFR, HER-2 and HER-3; 12 cell lines expressed mRNA for HER-4; and 4 cell lines did not express mRNA for HER-4. In in vitro proliferation assay, the combination treatment of cetuximab and trastuzumab significantly lowered cell viability compared to either drug alone. The mRNA expression levels of EGFR and HER-2 were not correlated with the efficacy of the combination treatment of cetuximab and trastuzumab and the expression levels of HER-3 and HER-4 also showed no correlation with the efficacy of the combination treatment. We evaluated the gene status of HER-2 exons 23 and 24 in 16 HNSCC cell lines, but there was no mutation of HER-2 in any of the cell lines. Either drug showed ADCC in the 3 cell lines using peripheral blood mononuclear cells (PBMCs), however, a significant combination effect was not observed. Combined molecular targeted antibody drug therapy for EGFR and HER-2 may be useful in the treatment of HNSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cetuximab , Análise Mutacional de DNA , Sinergismo Farmacológico , Receptores ErbB/genética , Expressão Gênica , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Terapia de Alvo Molecular , Receptor ErbB-2/genética , Trastuzumab
2.
Cancer Sci ; 102(9): 1717-23, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21631644

RESUMO

Cetuximab is a chimeric IgG1 monoclonal antibody that targets epidermal growth factor receptor (EGFR). Cetuximab binds to EGFR and prevents phosphorylation of EGFR. Moreover, preclinical results have shown the ability of cetuximab to induce either complement-mediated tumor cell killing (CDC) or antibody-dependent cell-mediated-cytotoxicity (ADCC). We previously reported mutation in EGFR regarding head and neck squamous cell carcinoma (HNSCC) cell lines. In the present study, we analyzed the same 16 HNSCC cell lines for mutations in KRAS, PIK3CA, BRAF and PTEN. Furthermore, we evaluated cetuximab-mediated biological activities (antiproliferative effect by the MTT assay and ADCC) regarding these cell lines. Mutations in PIK3CA and PTEN were observed in two cell lines (2/16, 12.5%), but no mutation was observed in KRAS and BRAF. The antiproliferative effect of cetuximab by the MTT assay was not strong, and no correlation was observed between the antiproliferative effect of cetuximab and mutations in EGFR, KRAS, PIK3CA, BRAF and PTEN in these cell lines. Therefore, the mutation status of EGFR and downstream molecules were not useful for predicting the antitumor effects of cetuximab on HNSCC. Cetuximab-mediated ADCC was observed in these cell lines and might have been influenced by the expression of EGFR. Therefore, cetuximab-mediated ADCC seems to be an important part of the antitumor mechanisms of cetuximab and the expression levels of EGFR might influence the antitumor activity of cetuximab. Therefore, besides the antiproliferative effect of cetuximab by the MTT assay, it appeared important to evaluate cetuximab-mediated ADCC as well as EGFR expression in HNSCC cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Carcinoma/genética , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Células Escamosas/genética , Anticorpos Monoclonais Humanizados , Carcinoma/tratamento farmacológico , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Proliferação de Células , Cetuximab , Classe I de Fosfatidilinositol 3-Quinases , Genes ras , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Mutação , Neoplasias de Células Escamosas/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
3.
Oncol Lett ; 1(6): 1017-1020, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22870104

RESUMO

Gefitinib (ZD1839, Iressa(®)) is an orally active agent that inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR). Gefitinib has shown a high efficacy in patients with non-small cell lung carcinoma and specific mutations in the ATP-binding pocket of EGFR. These mutations, however, are extremely rare in squamous cell carcinomas of the head and neck (SCCHN). We previously showed that SCCHN cell lines with a heterozygous mutation (G/G→G/A) at nucleotide 2607 of EGFR are more sensitive to gefitinib than wild-type cell lines (79.5% higher IC(50)). To determine the relationship between the G/G and G/A genotypes, we assessed the EGFR gene copy number and the EGFR mRNA half-life in 16 different SCCHN cell lines. Fluorescence in situ hybridization showed that the EGFR copy number was significantly higher in the nine 2607G/A cell lines than in the seven 2607G/G cell lines (3.59±2.14 vs. 1.58±0.32 copies, a 2.27-fold difference). Similarly, the half life of EGFR mRNA was 2.24-fold higher in cell lines with the 2607G/A genotype than in those with wild-type. By contrast, the EGFR protein levels were inversely correlated with mRNA abundance. These findings suggest that sensitivity to gefitinib of cells with the heterozygous mutation (2607G/G→G/A) was closely associated with gene amplification, the prolongation of mRNA half-life and a decrease in EGFR protein.

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