Efficacy And Mechanism Of Bevacizumab Combined With Renin-Angiotensin System Inhibitors In The Treatment Of Colorectal Cancer

Colorectal cancer hasbecome the third common malignant tumor worldwide with about a quarter of patients have metastatic lesion when they are initial diagnosed.Guidelines recommend 5-fluorouracil(5-Fu),oxaliplatin(OX)and/or irinotecan(IR)in combination with Bevacizumab(Bev)for the treatment of metastatic colorectal cancer(mCRC).However,it remains unknown which is better between Bev-OX and Bev-IR regimens in terms of efficacy and safety.Bev-induced hypertension(Bev-HT)is a common adverse drug reaction.However,the references for the medication therapy management of Bev-HT are in limitation till now.At present,there is no guideline recommending the topchoice antihypertensive drug for Bev-HT,and the anti-tumor effect and mechanism of antihypertensive drugs and Bev is still unclear.1.A systematic review and Meta-analysis was performed to compare Bev-IR with Bev-OX regimens in terms of efficacy and safety.Studies from databases including MEDLINE,EMBASE,CENTRAL and conference papers were searched.According to predetermined inclusion and exclusion criteria followed by quality assessment,eligible studies were included.Eleven studies including 5,632 patients were identified in the systematic review and Meta-analysis.No difference was found in overall survival(OS)or overall response rate between BEV-OX and BEV-IR regimens.The pooled progression-free survival(PFS)was significantly longer in the Bev-IR group than the Bev-OX group(HR 0.92,95%CI 0.87-0.98,P=0.008).Compared with the Bev-OX group,the Bev-IR group was related to a higher risk of bleeding events(RR 0.80,95%CI 0.64-0.98,P=0.03),venous thromboembolism(RR 0.60,95%CI 0.46-0.79,P<0.001)and diarrhea(RR 0.71,95%CI 0.62-0.80,P<0.001).Conversely,the Bev-OX group was related to a higher risk of thrombocytopenia(RR 2.39,95%CI 1.67-3.42,P<0.001)and neuropathy(RR 3.80,95%CI 1.90-7.64,P<0.001).Bev-HT was the most common adverse drug reaction in the two groups.2.A retrospective study intended to verify the hypothesis that Bev-HT might be a predictor of efficacy,and to investigate the effect of Bev combined with different antihypertensive drugs on the survival and prognosis of mCRC patients.A total of 94 mCRC patients who were treated with Bev plus OX or IR-based chemotherapy from January 2013 to January 2020 at the General Hospital of Northern TheaterCommandHospital were eligible for the retrospective analysis.The patients were divided into Bev induced hypertension group(Bev-HT group,n=41)and non-HT group(n=53)according to the blood pressure fluctuations before and after Bev treatment.The PFS and OS were found to be significantly different between the Bev-HT group and the non-HT group(Median PFS 10.5 vs.5.5 month,HR 0.305,95%CI 0.181-0.514,P<0.001;Median OS 16.0 vs.11.0 month,HR 0.38,95%CI 0.216-0.668,P<0.001).The patients receiving RASIs were found to be significant for PFS and OS when compared withthe patients receiving calcium channel blockers(Median PFS 13.00 vs.7.0 month,HR 0.396,95%CI 0.175-0.895,P=0.03;Median OS 18.00 vs.11.00 month,HR 0.251,95%CI 0.107-0.593,P=0.002).Multivariate progression and survival analysis indicated thatthe RASIs using was found to be significant for survival improvement(PFS RR=0.31,P=0.02;OS RR=0.21,P<0.001).3.Anti-tumor effect and mechanism of angiotensin-converting enzyme inhibitor Lisnopril(Lis)and Bev were explored.Human colon cancer HCT116 xenograft mouse model was established and the inhibitory effect of Lis and Bev on subcutaneous tumors was investigated.5-Fu concentration in tumor tissues was measured with the Liquid chromatography tandem mass spectrometry(LC-MS/MS)system.The effect of the combination of Bev and Lis on the concentration of chemotherapeutic drugs in tumor tissues was investigated.The levels of VEGF-A in tumor tissues at different time points were investigated.The effects of Bev and Lis on the tumor blood vessel normalization were investigated by CD31 and α-SMA immunofluorescence double staining and calculated by microvessel density(MVD)and vascular maturity index(VMI).The mechanism of the combination of Bev and Lis on tumor tissue hypoxia,ECM deposition,and the expression of related proteins in the TGF-β/SMAD signaling pathways were further evaluated by Sirius Red staining,ELISA and Western blot assay.The result of study indicated that Bev and Lis synergistically inhibited the subcutaneous tumor growth on HCT116 xenografts.Compared with the control group and the monotherapy treatment groups,Bev and Lis synergistically increase 5-Fu concentrationin tumor tissues and inhibited the level of VEGF-A.However,the addition of Lis did not influence the vascular normalization effect promoted by Bev.Moreover,Lis significantly inhibited the high expression level of HIF-1α,α-SMA,collagen I,hyaluronic acid and collagen fibers deposition and down-regulated the TGF-β/SMAD signaling pathways to reversing the ECM remodeling by Bev.Bev-HT was the most common AEs in the treatment of Bev.In this study,Bev-HT might be as an efficacy predictor of anti-VEGF targeted therapy for mCRC patients was proved.The renin-angiotensin system inhibitors might be an optimal choice for bevacizumab-induced hypertension was comfirmed.Further rmore,the enhanced anti-tumor effect and mechanism ofRASIs and Bev were preliminarily explored.The study provided evidence-based and theory-based medication for the clinical treatment of Bev-HT.