Antitumor effect on human gastric cancer and induction of apoptosis by vascular endothelial growth factor neutralizing antibody.

Induction of apoptosis by antiangiogenic therapy has been suggested as a new anticancer strategy. To clarify the mechanism of the antitumor effect achieved by inhibition of vascular endothelial growth factor (VEGF), which is a major mediator of angiogenesis, we used an orthotopic transplantation model of human gastric carcinoma line (MT2) treated with a monoclonal VEGF neutralizing antibody (VEGF Ab). We histologically examined the microvessel density (MVD) and the apoptotic index (AI) in this model. Transplanted tumor growth was significantly inhibited by the VEGF Ab (P = 0.03), and there was a significant decrease in the number of mice with liver metastasis (P = 0.004). The MVD detected by immunohistochemical staining with ER-MP12 antibody was 33.6 +/- 8.0 in the control group and 21.1 +/- 5.4 in the treated group, and the difference was significant (P < 0.0001). The AI values of the control and treated groups were 4.73 +/- 1.11 and 7.26 +/- 1.62, respectively, and this difference is also significant (P < 0.0001). However, the expression of VEGF mRNA in transplanted tumors did not show a significant difference between the control and treated groups. These results suggest that the antitumor effect of the VEGF Ab on human gastric carcinoma is exerted by inducing mild hypoxia followed by apoptosis, which does not influence VEGF mRNA expression in the carcinoma.