Bevacizumab疗效有限性和"促癌作用"之不足刚被认识，我们推测分别与用药后有氧糖酵解关键酶PKM2上调和缺氧加重有关。基于我们前期发现bevacizumab有效治疗肠癌的同时也有促转移风险，糖酵解与肠癌生物学行为相关，也是有效的抗癌靶点；预试验发现肿瘤在缺氧环境下侵袭性增强；bevacizumab促转移和增强局部浸润力；肠癌高表达PKM2，并在bevacizumab治疗后明显升高，但细胞凋亡却有减少趋势；Adenosine显著上调红细胞内2,3-DPG（纠正缺氧）。我们拟通过抑制PKM2来增强疗效，可能机制是增加ROS介导的细胞凋亡；通过上调2,3-DPG纠正缺氧，克服"促癌作用"；同步干预因为协同作用而效果最好；在Ⅲ期临床实验资料中验证促转移风险及探讨PKM2与其疗效的关系。旨在探讨制约bevacizumab疗效的原因及其解决办法，找出疗效预测指标，为提高其临床疗效提供理论基础。

The limited anticancer capability of bevacizumab and its risk of promoting cancer (pro-cancer risk) included promoting metasitasis and enhancing local invasion had been recognized recently. Either upregulation of PKM2, the key enzyme of aerobic glycolysis, or increasing tumor hypoxia after administeration of bevacizumab was postulated to contribute respectively to the abovementioned pro-cancer phenomenon. Our previous studies found that bevacizumab real increased the risk of distant metastasis in mCRC patients, though it improved survival of mCRC patients; also found that GAPDH, another key enzyme of aerobic glycolysis, is a potential target for its treatment since it related to biological behavior of colorectal cancer. Furthermore, in the pilot experiments, we found that tumor became more aggressive under hypoxia condition; bevacizumab promoted liver metastasis and enhanced local invasion; colorectal cancer cell lines expressed PKM2, and its expression abviously increased after delivering bevacizumab when compared with tumor before becacizumab treatment, however, the appotosis maybe decrease after bevacizumab application; adenosine increased the concentration of 2,3-DPG in mouse RBC. We plan to improve efficacy of bevacizumab by inhibiting PKM2 since more apoptosis mediated by ROS may be induced; to overcome hypoxia via increasing of 2,3-DPG by adenosine which will prevent the pro-cancer effect of bevacizumab; simultaneous interference of 2,3-DPG and PKM2 will be more effective since the synergic effect. In addition, we plan to validate the pro-cancer risk of bevacizumab and to investage the correlation between PKM2 and its efficacy based on phase Ⅲ clinical trail (ARTIST) where bevacizuamb combined with IFL to treat mCRC in first line. The aim of study is to find the reasons of limited efficacy of bevacizumab and its solution strategy; to find efficacy predictor of bevacizumab. Finally, to resolve the problems that bevacizumab is facing in clinical practice.