Abstract
We have evaluated the antitumor effects of gefitinib (Iressa, ZD1839) in SNU-1 human gastric cancer cells (hMLH1-deficient and epidermal growth factor receptor-overexpressed) when given alone or as a doublet with oxaliplatin (LOHP), 5-fluorouracil (5-FU) or paclitaxel (PTX). The four drugs showed IC50s ranging from 1.81 nM to 13.2 microM. LOHP and PTX induced G2/M arrest, 5-FU increased S phase, and gefitinib increased G1 in a concentration-dependent manner. The analysis using the previously developed cytostatic TPi model showed that 64 and 80% of the overall growth inhibition was attributed to cell cycle arrest in cells exposed to 7.55 microM of LOHP or 10 nM of PTX for 72 h, respectively. PTX + gefitinib showed greatest synergism as determined by combination index analysis and apoptosis induced by PTX was potentiated by the co-administration of gefitinib. LOHP + gefitinib showed a similar, although to a lesser degree, synergistic effect. This study demonstrates the antitumor activity and the significant cell cycle arrest induced by gefitinib in SNU-1 human gastric carcinoma cells, and its synergistic interaction with LOHP and PTX.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Base Pair Mismatch / genetics
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Carrier Proteins
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Cell Division / drug effects
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Cell Line, Tumor*
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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DNA Repair / genetics
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor / methods
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Drug Synergism*
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Drug Therapy, Combination
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ErbB Receptors / drug effects
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ErbB Receptors / genetics
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Fluorouracil / pharmacology
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Formazans
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G1 Phase / drug effects
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G2 Phase / drug effects
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Gefitinib
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Gene Expression / drug effects
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Gene Expression / genetics
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Humans
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Inhibitory Concentration 50
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Models, Biological
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MutL Protein Homolog 1
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Neoplasm Proteins / drug effects
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Neoplasm Proteins / genetics
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Nuclear Proteins
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Organoplatinum Compounds / pharmacology
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Oxaliplatin
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Paclitaxel / pharmacology*
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Quinazolines / pharmacology*
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Stomach Neoplasms / pathology*
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Tetrazolium Salts
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Formazans
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MLH1 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Organoplatinum Compounds
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Quinazolines
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Tetrazolium Salts
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Oxaliplatin
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MTT formazan
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ErbB Receptors
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MutL Protein Homolog 1
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Paclitaxel
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Gefitinib
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Fluorouracil