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Abstract：
Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug (NO: Y2020046 retrospectively registered). An experiment of HCT116 colon cancer cell xenografts in mice confirmed that combined treatment of Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-β1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary extracellular matrix components. In conclusion, RASIs and Bev have synergistic effect in the treatment of colorectal cancer and RASIs might be an optimal choice for the treatment of Bev-induced HT.
摘要：
贝伐单抗（Bev）是一种人源化血管内皮生长因子单克隆抗体，与化疗药物一起用于治疗转移性结直肠癌（mCRC）。Bev诱发的高血压（HT）是临床实践中最常见的不良反应。然而,目前,对于Bev诱导的HT，没有合适的抗高血压药物。在这项研究中,对接受肾素-血管紧张素系统抑制剂(RASIs)的mCRC患者的临床数据进行回顾性分析,结果显示,与接受钙通道阻滞剂(CCBs)的患者和未接受抗高血压药物的患者相比,在总生存期(OS)和无进展生存期(PFS)方面有显著的生存获益(NO:Y2020046回顾性注册).小鼠HCT116结肠癌细胞异种移植物的实验证实，Bev和赖诺普利（Lis）联合治疗，ARASI,协同抑制皮下肿瘤生长并提高肿瘤组织中5-氟尿嘧啶（5-Fu）的浓度。我们的结果表明，添加Lis不会干扰Bev促进的血管正常化效果，但也抑制胶原蛋白和透明质酸（HA）沉积，并显着下调TGF-β1和下游SMAD信号传导成分的表达，最终重塑主要的细胞外基质成分。总之,RASI和Bev在结直肠癌的治疗中具有协同作用，RASI可能是治疗Bev诱导的HT的最佳选择。
