Abstract
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Background:Although new drugs for colon cancer have been developed and survival is improving, the results are not sufficient. Novel treatment approaches and new drugs are necessary. Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. Tumor growth and metastasis, including colorectal cancer, are strongly dependent upon VEGF for angiogenesis. Ki23057 is a new small-synthetic tyrosine kinase inhibitor that blocks autophosphorylation of the VEGF receptor2 (VEGFR2). To determine the effect of Ki23057 as an anti-angiogenic agent, we studied the effect of Ki23057 for colon cancer and vascular endothelial cells in vitro and in vivo.
Materials and Methods: The effect of Ki23057 on the proliferation of three colon cancer cell lines (LM-H3, LoVo and LS174T) and human umbilical vein endothelial cells (HUVECs) was examined by means of the MTT assay. Capillary tube formation of endothelial cells was measured by coculture with normal human fibroblasts using an Angiogenesis kit (Kurabo, Osaka Japan). Ki23057 was added at a concentration of 0, 30 or 300 nM, followed by VEGF (10 ng/mL). The cells were cocultured for 11 days and stained with anti-CD31 antibody. The effect of Ki23057 on tyrosine phosphorylation of VEGFR2 in HUVECs was examined with immunoprecipitation. The effect of Ki23057 on the growth of LM-H3 xenografts and liver metastasis was examined in nude mice. Microvessels in the xenografted LM-H3 tumors were stained immunohistochemically using CD31 antibody.
Results: The proliferation of HUVECs was significantly inhibited by Ki23057 (≥10 nM). On the other hand, Ki23057 (1-102 nM) did not inhibit the proliferation of three colon cancer cell lines. Tube formation was inhibited in HUVECs treated with Ki23057 compared with controls. The average numbers of vessels were 4.50±0.71/HPF (without addition of VEGF and Ki23057), 7.94±1.33 /HPF (VEGF 10 ng/mL, without Ki23057), 1.47±0.37/HPF (with 10 ng/mL VEGF and 30 nM Ki23057) and 0.19±0.16/HPF (10 ng/mL VEGF and 300 nM Ki23057). Immunoprecipitation demonstrated that Ki23057 inhibited tyrosine phosphorylation of VEGFR2 in HUVECs. Ki23057 exhibited a significant inhibitory effect on the growth of the xenografted LM-H3 tumors. After day 3, tumor growth was more strongly inhibited in the treatment group compared with controls. Microvessel density in xenografted tumors treated with Ki23057 was less than that in controls. Compared with the control group, the treatment group exhibited significant inhibition of liver metastasis. The weight of the liver was 3.73±1.00 g in the control group and 2.43±0.52 g in the treatment group. The liver weights in the control group were significantly greater than in the treatment group (p<0.05).
Conclusions:Ki23057 may be a promising new antiangiogenic agent for colon cancer.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
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