ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model.

Angiogenesis inhibitors have been used to treat some cancers, but the therapeutic potential of these agents for gastric cancer has remained unclear. To investigate their therapeutic potential, we examined the effect of ZD6474, an agent that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2; KDR) tyrosine kinase and epidermal growth factor receptor (EGFR) tyrosine kinase, in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line, 58As1. ZD6474 (100 mg/kg/day, p.o., 2 weeks) significantly inhibited tumor growth (p < 0.05 vs. control) and reduced tumor dissemination into the peritoneal cavity (p < 0.05 vs. control). In addition, to identify putative tumor biomarkers that would reflect the effects of ZD6474 treatment in clinical settings, we examined the gene expression profiles of implanted gastric tumors treated with ZD6474 in vivo. Twenty-eight candidate genes were identified, including IGFBP-3, ADM, ANGPTL4, PLOD2, DSIPI, NDRG1, ENO2, HIG2 and BNIP3L, which are known to be hypoxia-inducible genes. These genes and gene products may be useful biomarkers for monitoring the effects of ZD6474 treatment. ZD6474 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line, 44As3. In conclusion, our results suggest that ZD6474 may have clinical activity against gastric cancer, particularly undifferentiated gastric cancer with peritoneal dissemination. We also identified putative biomarkers for monitoring the pharmacodynamic effects of ZD6474 by gene expression profiling.