To understand the mechanisms of the effects of combination treatments, we established animal models showing antitumor activity of bevacizumab as a monotherapy and in combination with capecitabine or capecitabine and oxaliplatin and measured thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF) levels. Tumor-inoculated nude mice were treated with bevacizumab, capecitabine, and oxaliplatin, alone or in combination, after tumor growth was confirmed and volume and microvessel density (MVD) in tumors were evaluated. Levels of TP and VEGF in the tumor were examined by ELISA. Bevacizumab showed significant antitumor activity as a monotherapy in three xenograft models (COL-16-JCK, COLO 205 and CXF280). The MVD in tumor tissues treated with bevacizumab was lower than that of the control. Antitumor activity of bevacizumab in combination with capecitabine was significantly higher than that of each agent alone (COL-16-JCK, COLO 205). Furthermore, the antitumor activity of bevacizumab in combination with capecitabine + oxaliplatin was significantly superior to that of capecitabine + oxaliplatin (COL-16-JCK). TP and VEGF levels were not increased by bevacizumab or capecitabine, respectively, suggesting there are other potentially efficacious mechanisms involved. In the present study we established human colorectal cancer xenograft models which reflect the efficacy of clinical combination therapies, capecitabine + bevacizumab and capecitabine + oxaliplatin + bevacizumab. We will further investigate the mechanisms of the combination therapies using these models.

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