1Catholic Research Institutes of Medical Science, CatholicUniversity of Korea, Seoul, Korea. hkuh@catholic.ac.kr 2Division of Medical Oncology, Catholic University of Korea,Seoul, Korea. 3Division of Gastroenterology, Catholic University of Korea,Seoul, Korea. 4Pharmacology Division, National Cancer Center ResearchInstitute, Tokyo, Japan.
Published online: October 31, 2002.
ABSTRACT
PURPOSE: Oxaliplatin (LOHP), 5-FU, and paclitaxel (PTX) are considered highly active against advanced gastric carcinomas, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, ZD1839 is considered as a good candidate for the treatment of gastric cancers when given alone or in combination with cytotoxic agents. The present study evaluated the antitumor effects of these agents in SNU-1 human gastric cancer cells either alone or when given as a doublet (i.e., as a cytotoxic-cytostatic combination).
MATERIALS AND METHODS: We selected SNU-1 cells that showed DNA mismatch repair (MMR) deficiency and EGFR overexpression. Growth inhibition was measured by MTT and by direct cell counting and cell cycle distribution by flow cytometry. The combination index (CI) was used to describe synergistic interaction.
RESULTS: The four drugs showed IC50s ranging from 1.81 nM to 13.2microM. MTT assay appeared to underestimate the cytotoxicity of PTX, which was attributed to a significant resistant fraction (32%). LOHP and PTX induced G2/M arrest, 5-FU increased in S phase, and ZD1839 in-creased in G1 in a concentration dependent manner. PTX ZD1839 showed the greatest synergism and LOHP ZD1839 showed a similar result.
The cell cycle effect of PTX was potentiated by the coadministration of ZD1839. A previously developed cytostatic TPi model was used to assess the contribution of cell cycle arrest to overall growth inhibition, and 64% and 80% of the overall growth inhibition was attributed to cell cycle arrest for LOHP and PTX, when exposed to 7.55microM and 10 nM for 72 hr, respectively.
CONCLUSION: This study demonstrates the antitumor activity and significant cell cycle arrest effect of ZD1839 against human gastric carcinoma cells and its synergistic interaction with LOHP and PTX. These results provide a preclinical rationale for the clinical development of ZD1839 and its use in combination with LOHP or PTX against human gastric cancers that express EGFR.
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