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The aim of the present study was 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 (CECs) and endothelial progenitor cells (CEPs) as a surrogate marker for metronomic chemotherapy. KM12SM cells were implanted into the subcutis of nude mouse. After confirming that the implanted tumors had grown 5 mm in size, group A received an intraperitoneal injection of 40 mg/kg CPT-11 every two weeks for 4 weeks [conventional maximum-tolerated dose (MTD)], group B received 10 mg/kg twice weekly (metronomic), group C received 10 mg/kg twice weekly combined with 5 mg/kg bevacizumab twice weekly (metronomic + anti-angiogenic), and the control group received 0.2 ml of PBS every week. Serial changes of CECs and CEPs in peripheral blood and microvessel density (MVD) in the tumor tissues were evaluated. The results showed that the antitumor activity in group B and in group C was significantly higher than that in group A. A significant inhibition in CEPs on day 15 in the metronomic therapy groups B and C was noted when compared to that in the control group, while there was no significant difference in CECs and CEPs between the groups on days 4 and 8. The MVD on day 15 in metronomic groups was significantly lower than that in group A. In conclusion, metronomic chemotherapy of CPT-11 with or without bevacizumab for colon cancer was more effective than the MTD therapy via anti-angiogenic effects. Sequential measurement of CEPs may be a predictive factor for the efficacy and a decisive factor for the optimal dose of metronomic therapy in colon cancer.

experimental and therapeutic medicine

Circulating endothelial progenitor cells in metronomic chemotherapy using irinotecan and/or bevacizumab for colon carcinoma: Study of their clinical significance