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A tumor-specific conditionally replicative adenovirus vector expressing TRAIL for gene therapy of hepatocellular carcinoma

Cancer Gene Therapy volume 13, pages 159–168 (2006)Cite this article

Abstract

We constructed a novel hepatocellular carcinoma-specific conditionally replicative adenovirus (CRAd). This adenovirus, designated Ad.HS4.AFP.E1A/TRAIL, expresses E1A to mediate viral replication and TRAIL to enhance HCC-killing efficacy under the control of a modified AFP promoter. An insulator HS-4 was placed in front of the AFP promoter to enhance the fidelity of the heterologous promoter. This virus was shown to have specific cytolytic activity in AFP-expressing HCC cells in vitro. Furthermore, the replication efficiency of Ad.HS4.AFP.E1A/TRAIL correlated well with AFP expression of the host cells, showing a 100-fold and 1 000 000-fold decrease in the low-and non-AFP-expressing HCC cells, respectively, compared to the high AFP-expressing HCC cells. An increase in mRNA of TRAIL and the elevated Caspase-3 activity were also observed in Ad.HS4.AFP.E1A/TRAIL-infected HCC cells. These results indicated that TRAIL expression from the viral vector activated the Caspase-3 enzymatic capacity and the HCC cells were sensitive to TRAIL. In vivo, Ad.HS4.AFP.E1A/TRAIL effectively prevented the growth of low AFP-expressing BEL-7404 xenografts. These results indicate that Ad.HS4.AFP.E1A/TRAIL could provide a new strategy of gene therapy for HCC.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

CRAd:

conditionally replicative adenovirus

IRES:

internal ribosome entry site

HCC:

hepatocellular carcinoma

AFP:

α-fetoprotein

TNF:

tumor necrosis factor

TRAIL:

TNF-related apoptosis inducing ligand

MTS:

3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

MOI:

multiplicity of infection

PFU:

plaque-forming units

RT-PCR:

reverse transcrption-PCR

CAR:

coxsackie-adenovirus receptor

Ad5.WT:

wild-type adenovirus 5

CPE:

cytopathic effect

DDP:

cis-diamminedichloroplatinum

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Acknowledgements

We thank Andre Lieber for providing Ad5.WT. We also thank Pavel Sova and Chang-Xing Shi for helpful discussion and thank Chen Wang and Mihoko Kato for critically reviewing the manuscript. The work was supported in part by National 863 Program of China Grant 2001AA217131 and 2004AA217051.

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Author notes

  1. X-W Ren and M Liang: These two authors contributed equally to this work.

Authors and Affiliations

  1. Shanghai Sunway Biotech Co., Ltd, Pudong, Shanghai, China

    X-W Ren, M Liang, X Meng, X Ye, H Ma, Y Zhao, J Guo, N Cai & F Hu

  2. Liver Cancer Institute/ZhongShan Hospital, Fudan University, Shanghai, China

    M Liang & S-L Ye

  3. Department of Pharmacology, Shanghai Second Medical University, Shanghai, China

    X Ye & H-Z Chen

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  1. X-W Ren
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Correspondence to F Hu.

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Ren, XW., Liang, M., Meng, X. et al. A tumor-specific conditionally replicative adenovirus vector expressing TRAIL for gene therapy of hepatocellular carcinoma. Cancer Gene Ther 13, 159–168 (2006). https://doi.org/10.1038/sj.cgt.7700868

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