Significance of circulating endothelial progenitor cells in metronomic chemotherapy against colorectal cancer

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Aim of the study is to clarify the antitumor efficacy of metronomic chemotherapy using irinotecan (CPT-11) combined with or without bevacizumab against colon cancer, and the significance of circulating endothelial cell (CEC) and endothelial progenitor cell (CEP) as a surrogate marker for the metronomic chemotherapy. KM12SM cells were implanted into the subcutis of nude mouse. After confirming that the implanted tumor had grown 5 mm in size, the Group A received intraperitoneal injection of 40 mg/kg CPT-11 every two weeks for 4 weeks [conventional maximum tolerated dose (MTD)], the Group B received 10 mg/kg twice per week (metronomic), the Group C received 10 mg/kgtwice per week combining with 5 mg/kg bevacizumab twice per week (metronomic+antiangiogenic), and the Control Group received 0.2 ml of PBS every week. Serial changes of CEC and CEP in peripheral blood and microvessel density (MVD) in tumor tissues was evaluated. The results show that the antitumor activity in the Group B and in the Group C was significantly higher than that in the Group A. A significant inhibition in CEP on day 15 in the metronomic therapy Group B and Group C was found compared with that in the Control Group. Whereas there was no significant difference in CEC and CEP between each group on days 4 and 8, there was difference in pattern of changes between CEP and CEC in the metronomic groups. The CEP was consistently inhibited until day 15, while the CEC tended to increase at day 4 and then decrease at day 15. The MVD on day 15 in the metronomic groups was significantly lower than that in the Group A. In conclusion, metronomic chemotherapy of CPT-11 with or without bevacizumab for colon cancer was more effective than the MTD therapy via antiangiogenic effects. Sequential measurement of CEP may be a predictive factor for the efficacy and a decisive factor for optimal dose of metoronomic therapy in colon cancer.