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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
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