Preclinical activity of gefitinib in non-keratinizing nasopharyngeal carcinoma cell lines and biomarkers of response
| Autor: | Brigette B Y, Ma, Vivian W Y, Lui, Fan Fong, Poon, S C Cesar, Wong, Ka Fai, To, Elaine, Wong, Honglin, Chen, Kwok Wai, Lo, Qian, Tao, Anthony T C, Chan, Margaret Heung Ling, Ng, Suk Hang, Cheng |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
DNA Mutational Analysis
Nasopharyngeal neoplasm Antineoplastic Agents Apoptosis Biology medicine.disease_cause Biomarkers Pharmacological Proto-Oncogene Proteins p21(ras) Gefitinib Cell Line Tumor Proto-Oncogene Proteins otorhinolaryngologic diseases medicine Humans Neoplasm Invasiveness Pharmacology (medical) EGFR Gene Amplification Epidermal growth factor receptor skin and connective tissue diseases Head and neck cancer neoplasms Cell Proliferation Pharmacology Preclinical Studies Cell growth Cell Cycle Nasopharyngeal Neoplasms Cell cycle medicine.disease respiratory tract diseases ErbB Receptors Gene Expression Regulation Neoplastic stomatognathic diseases Oncology Nasopharyngeal carcinoma Drug Resistance Neoplasm Quinazolines ras Proteins Cancer research biology.protein KRAS Drug Screening Assays Antitumor medicine.drug |
| Zdroj: | Investigational New Drugs |
| Popis: | This study evaluated the preclinical activity and molecular predictors of response to gefitinib (Iressa®, Astra Zeneca Inc, UK) in nasopharyngeal carcinoma (NPC). The activity of gefitinib was evaluated in four human NPC cell lines-HK1, HONE-1, CNE2, C666-1. A representative gefitinib-sensitive (HK1, IC50 = 250 nM) and gefitinib-resistant cell line (HONE-1, IC 50 > 15 μM) were selected and compared for expression of epidermal growth factor receptor (EGFR) and related ligands, and activation of downstream proteins. Gefitinib induced G1 cycle arrest, apoptosis and inhibited cell invasion more significantly in HK1 than HONE-1 cells. HK1 expressed higher levels of p-EGFR, lower p-AKT and phospho-signal transducer and activator of transcription 3 (p-STAT3) than other cell lines. EGFR gene was found to be amplified in HK1. Gefitinib at IC50 concentrations significantly suppressed EGF-induced activation of p-EGFR, phospho-mitogen-activated protein kinase (p-MAPK) and p-STAT3, but p-AKT showed persistent activation in HK1 and HONE-1 cells. There was no difference in EGFR-ligand expression between the 4 NPC cell lines. In NPC samples derived from non-responders to gefitinib, 50% and 60% showed cytoplasmic and nuclear pi-EGFR expression, respectively, and 33% showed p-AKT expression. EGFR or KRAS mutations were not detected. This study suggests that most NPC cell lines are intrinsically resistant to gefitinib (except HK1 cells), and further studies are needed to confirm whether EGFR gene amplification and persistent AKT activation may influence response to gefitinib in NPC. © 2009 Springer Science+Business Media, LLC. published_or_final_version Springer Open Choice, 01 Dec 2010 |
| Databáze: | OpenAIRE |
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