The Mechanism Exploration And Efficacy Assessment Of Hypoxia-replicative Oncolytic Adenovirus Perfusion Combined With Transcatheter Arterial Embolization For Hepatocellular Carcinoma

Purpose: Transcatheter arterial embolization(TAE)or transcatheter arterial chemoembolization(TACE)has become a critical therapy for unresectable hepatocarcinoma(HCC).Although hypoxia caused by embolization can induce apoptosis and necrosis of the majority of tumor cells,a small proportion of cells can survive with hypoxia and chemotherapy resistance.HIF-1? induced by hypoxia is the key factor rendering surviving tumor cells invasive and metastatic properties.Thus,we generated a synthetic hypoxia-replicative oncolytic adenovirus(HYAD)expecting to further eliminated the surviving tumor cells which expressed HIF-1?.methods: In our study,we detected protein expression,proliferation,apoptosis and necrosis of hepatic tumor cell line when infected with HYAD under hypoxia and normoxia.And we constructed VX2 hepatic cancer rabbit models to explore the combination treatment effect of transcatheter arterial embolization with HYAD perfusion under Digital Subtraction Angiography(DSA).Inhibition of tumor growth and invasion was detected by histopathological examination and contrast-enhanced CT scan.Results: Experiments in vitro verified that HYAD expressed and replicated along with HIF-1? expression or hypoxia.Compared with wild adenovirus type 5(WT),HYAD expressed more higher under hypoxia,which was the main principle of HYAD killing surviving tumor cells post transarterial embolization.In vivo experiment of VX2 models,the combination treatment of HYAD perfusion with PVA embolization achieved the highest expression quantity and the longest expression duration compared with simple HYAD perfusion,the combination treatment of WT perfusion with PVA embolization and simple WT perfusion.Adenovirus expression protein E1 A had the properties of promoting apoptosis,inhibiting invasion and inhibiting metastasis.Therefore,the combination treatment of HYAD perfusion with PVA embolization group efficiently repressed tumor growth and intrahepatic metastases compared to other processing groups.Conclusion: HYAD can overcome the hypoxic tumor microenvironment post-embolization and target the surviving tumor cells with specificity.In turn,the combination treatment of HYAD perfusion with PVA embolization can bring out the best effect in each other.