Antiangiogenic Effect of ZD1839 against Murine Renal Cell Carcinoma (RENCA) in an Orthotopic Mouse Model

Abstract

Introduction: ZD1839 (IressaTM) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We evaluated the antitumor and antiangiogenesis activities of ZD1839 in a murine renal cell carcinoma (RENCA) model. Materials and Methods: The effect of ZD1839 on the cellular proliferation of RENCA cells in vitro was measured by colorimetric assay. For the in vivo studies, RENCA cells were adsorbed in Gelfoam and implanted into BALB/cJ mouse parenchyma with an agarose bar. Mice were treated with ZD1839 (40 mg/kg/day s.c.), genistein or saline for 14 days. Western blot analysis was performed to observe EGFR expression in RENCA cells and tumor tissues. Microvessel density (MVD) was quantified by immunostaining for factor VIII-related antigens and VEGF level was assayed by ELISA. Results: ZD1839 showed a dose-dependent inhibition of RENCA cellular proliferation. ZD1839 treatment resulted in a marked decrease in tumor growth compared with saline treatment. The MVD and VEGF in the RENCA tumors were decreased significantly by ZD1839 (p < 0.01 and p >0.05, respectively). Genistein also suppressed tumor growth and decreased MVD and VEGF level, but the efficacies were less than with ZD1839. Conclusion: The suppressive activity of ZD1839 on RENCA tumor growth was accompanied by decreases in the MVD and VEGF production. These results suggest that the antitumor effect of ZD1839 in a RENCA model is mediated partially by the inhibition of tumor angiogenesis.