생쥐 신세포암 세포주 동소 이식 마우스 모델에서 선택적 표피 성장 인자 수용체 Tyrosine Kinase Inhibitor (ZD1839)의 항혈관신생 효과

Abstract

PURPOSE: ZD1839(IressaTM) is a selective epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) known to block the cell signaling pathway. However, the effect of ZD1839 in relation to renal cell carcinoma, which is highly angiogenic, has not been reported. Using an orthotopic model of murine renal cell carcinoma(Renca), we evaluated the inhibitory effect of ZD1839 on tumor growth and angiogenesis. MATERIALS AND METHODS: Renca cells (1x104cells/10mul) were first adsorbed in Gelfoam and were implanted into the balb/cj mouse kidney followed by obturation with the agarose bar. Then, tumor formation was assessed every week for 4 weeks. IC50 was obtained for ZD1839 and genistein in vitro. 7 days after the implantation, the mice were divided into three groups, and normal saline, ZD1839(40mg/kg/day), and genistein (80mg/ kg/day) were subcutaneously injected for 14 days. 21 days after the implantation, the mice were sacrificed, and tumor volume measurement and analysis of microvessel density(MVD) were performed using the factor VIII-related antigen and vascular endothelial growth factor(VEGF). RESULTS: Renca tumors, which formed in the renal parenchyme and had a circular shape, reached the peak growth velocity between 14 and 21 days. MVD was the highest at 14 days of implantation. IC50 for ZD1839 and genistein were 4.68mug and 5.43mug, respectively. Tumor growth after the treatment with ZD1839 and genstein was inhibited by 86%(p<0.01) and 49%(p<0.05), respectively, compared to the control. MVD of ZD1839 and genistein-treated groups were 50%(p<0.01) and 29%(p<0.05) lower, respectively, and VEGF levels were 24%(p<0.05) and 27%(p<0.05) lower, respectively, compared to the control. CONCLUSIONS: This orthotopic implantation method of the Renca cell is an effective model for demonstrating the effect of an angiogenesis inhibitor. Our results suggest that the anti-angiogenesis effect of ZD1839 in the Renca orthotopic implantation model partially contributes to the tumor growth inhibition, and that ZD1839 may be more effective than genistein in the tumor growth regulation through the inhibition of angiogenesis.