Synergistic interaction between gefitinib (Iressa, ZD1839) and paclitaxel against human gastric carcinoma cells.
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.
Park
Jong-Kook
JK
Research Institute of New Drug Development, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, South Korea.
Lee
Sang-Hak
SH
Kang
Jin-Hyoung
JH
Nishio
Kazuto
K
Saijo
Nagahiro
N
Kuh
Hyo-Jeong
HJ
D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D005562:Formazans; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D000077156:Gefitinib; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000473:pathology*; D013778:Tetrazolium Salts
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005562:Formazans; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D011799:Quinazolines; D013778:Tetrazolium Salts; D000077150:Oxaliplatin; C079782:MTT formazan; D066246:ErbB Receptors; D000070957:MutL Protein Homolog 1; D017239:Paclitaxel; D000077156:Gefitinib; D005472:Fluorouracil