Korean J Urol.  2004 Mar;45(3):255-262.

Anti-angiogenic Effect of Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(ZD1839) against Murine Renal Cell Carcinoma Orthotopic Model

• Oh HY
• Kwon SM
• Kim SI
• Hong SJ

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 (1x10(4)cells/10microliter) 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 4.68microM and 5.43microM, 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.

Keyword

Renal cell carcinoma; Pathologic neovascularization; ZD1839, Genistein

MeSH Terms

Angiogenesis Inhibitors
Animals
Carcinoma, Renal Cell*
Epidermal Growth Factor*
Gelatin Sponge, Absorbable
Genistein
Inhibitory Concentration 50
Kidney
Mice
Microvessels
Neovascularization, Pathologic
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor*
Sepharose
Tumor Burden
Vascular Endothelial Growth Factor A
von Willebrand Factor
Angiogenesis Inhibitors
Epidermal Growth Factor
Genistein
Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Sepharose
Vascular Endothelial Growth Factor A
von Willebrand Factor