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

本研究旨在探讨伊立替康(CPT-11)与贝伐单抗联合应用节律化疗对结肠癌的抗肿瘤作用，以及循环内皮细胞(CEC)和内皮祖细胞(CEP)作为节律化疗替代标志物的意义。将KM12SM细胞移植到裸鼠皮下。在确认肿瘤生长至5 mm后，A组给予CPT-11 40 mg/kg，每2周一次[常规最大耐受量]，连续4周，B组给予10 mg/kg，每周2次(节律)，C组给予10 mg/kg，每周2次，联合贝伐单抗5 mg/kg，每周2次(节律+抗血管生成)，对照组给予PBS 0.2ml/周。观察外周血CEC、CEP和肿瘤组织微血管密度(MVD)的动态变化。结果表明，B组和C组的抗肿瘤活性明显高于A组。节律疗法B组和C组第15天的CEP与对照组相比有明显的抑制作用。在第4天和第8天，各组之间的CEC和CEP无显著差异，但节拍组的CEP和CEC的变化规律有所不同。CPT-11节律化疗联合贝伐单抗治疗结肠癌的疗效优于MTD治疗。CEP的连续测定可能是结肠癌节律治疗疗效的预测因素和最佳剂量的决定因素。

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.