Synergistic interaction between gefitinib (Iressa, ZD1839) and paclitaxel against human gastric carcinoma cells.

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.

• Authors: Jong-Kook Park, Sang-Hak Lee, Jin-Hyoung Kang, Kazuto Nishio, Nagahiro Saijo, Hyo-Jeong Kuh
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 15 Issue 8 Pg. 809-18 (Sep 2004) ISSN: 0959-4973 [Print] England
• PMID: 15494644 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Formazans
• MLH1 protein, human
• Neoplasm Proteins
• Nuclear Proteins
• Organoplatinum Compounds
• Quinazolines
• Tetrazolium Salts
• Oxaliplatin
• MTT formazan
• ErbB Receptors
• MutL Protein Homolog 1
• Paclitaxel
• Gefitinib
• Fluorouracil

Topics

• Adaptor Proteins, Signal Transducing
• Base Pair Mismatch (genetics)
• Carrier Proteins
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA Repair (genetics)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor (methods)
• Drug Synergism
• Drug Therapy, Combination
• ErbB Receptors (drug effects, genetics)
• Fluorouracil (pharmacology)
• Formazans
• G1 Phase (drug effects)
• G2 Phase (drug effects)
• Gefitinib
• Gene Expression (drug effects, genetics)
• Humans
• Inhibitory Concentration 50
• Models, Biological
• MutL Protein Homolog 1
• Neoplasm Proteins (drug effects, genetics)
• Nuclear Proteins
• Organoplatinum Compounds (pharmacology)
• Oxaliplatin
• Paclitaxel (pharmacology)
• Quinazolines (pharmacology)
• Stomach Neoplasms (pathology)
• Tetrazolium Salts