Cancer Res Treat.  2002 Oct;34(5):372-381.

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

• Jang JH
• Lee SH
• Kang JH
• Sun HS
• Nishio K
• Saijo N
• Kuh HJ

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.

Keyword

Oxaliplatin; 5-FU; Paclitaxel; ZD1839; Combination; Human gastric carcinoma

MeSH Terms

Cell Count
Cell Cycle
Cell Cycle Checkpoints
Cytotoxins
DNA Mismatch Repair
Flow Cytometry
Fluorouracil*
Humans*
Inhibitory Concentration 50
Paclitaxel*
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Robenidine
S Phase
Stomach Neoplasms
Cytotoxins
Fluorouracil
Paclitaxel
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Robenidine