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Transcatheter arterial embolization combined with hypoxia-replicative oncolytic adenovirus perfusion enhances the therapeutic effect of hepatic carcinoma

Authors Zhang H, Xiong F, Qian K, Liu Y, Liang B, Xiong B, Yang F, Zheng C

Received 29 September 2018

Accepted for publication 6 December 2018

Published 23 January 2019 Volume 2019:11 Pages 981—996

DOI https://doi.org/10.2147/CMAR.S189208

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Professor Nakshatri


Hongsen Zhang, Fu Xiong, Kun Qian, Yiming Liu, Bin Liang, Bin Xiong, Fan Yang, Chuansheng Zheng

Department of Radiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Purpose: Transcatheter arterial embolization or transcatheter arterial chemoembolization has become a critical therapy for unresectable hepatocarcinoma. 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-1α 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 eliminate the surviving tumor cells, which expressed HIF-1α.
Materials and 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 therapeutic effect of transcatheter arterial embolization combined with HYAD perfusion under digital subtraction angiography. 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-1α expression or hypoxia. Compared with wild adenovirus type 5 (WT), HYAD expressed much more under hypoxia, which was the main principle of HYAD killing surviving tumor cells posttransarterial embolization. In vivo experiment of VX2 models, HYAD perfusion combined with polyvinyl alcohol (PVA) embolization achieved the highest expression quantity and the longest expression duration compared with simple HYAD perfusion, WT perfusion combined with PVA embolization, and simple WT perfusion. Because adenovirus expression protein E1A had the properties of promoting apoptosis, inhibiting invasion, and inhibiting metastasis, HYAD perfusion combined with PVA embolization group efficiently repressed tumor growth and intrahepatic metastases compared to other processing groups.
Conclusion: HYAD can overcome the hypoxic tumor microenvironment postembolization and target the surviving tumor cells with specificity. In turn, HYAD perfusion combined with PVA embolization can bring out the best effect in each other.

Keywords: transcatheter arterial embolization, hepatocarcinoma, hypoxia, oncolytic adenovirus


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