Antitumor Activity of Oxaliplatin, 5-FU and Paclitaxel Given Alone or in Combination with ZD1839 in Human Gastric Carcinoma Cells in vitro

Abstract

Purpose: Oxaliplatin (LOHP), 5-FU, and paclitaxel (PTX) are considered highly active against advanced gastric carcinom as, 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 com bination 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 com bination). Materials and Methods: W e selected SNU-1 cells that showed DNA mism atch repair (MMR) deficiency and EGFR overexpression. Growth inhibition was m easured by MTT and by direct cell counting and cell cycle distribution by flow cytom etry. The com bination index (CI) was used to describe synergistic interaction. Results: The four drugs showed IC50s ranging from 1.81 nM to 13.2M. 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 increased in G1 in a concentration dependent manner. PTX +ZD1839 showed the greatest synergism and LOHP+ ZD1839 showed a sim ilar result. The cell cycle effect of PTX was potentiated by the coadm inistration 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 7.55M and 10 nM for 72 hr, respectively. Conclusion: This study dem onstrates the antitum or 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 com bination with LOHP or PTX against human gastric cancers that express EGFR. (Cancer Research and Treatm ent 2002;34:372-381) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key W ords: Oxaliplatin, 5-FU, Paclitaxel, ZD1839, Combination , Hum an gastric carcinom a