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Published on: November 24, 2014
Significant antitumor activity of oncolytic adenovirus expressing human interferon-beta for hepatocellular carcinoma
Ling Feng He1, Jin Fa Gu, Wen Hao Tang
1Laboratory of Cancer Therapy, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Background:
Human interferon-beta (IFN-beta) has been widely used in gene therapy for its antitumor activity but its therapeutic effect is limited. The conditionally replicative adenovirus ONYX-015 (a E1B-55-kDa-deleted adenovirus) targets well to tumor cells, but is not potent enough to cause significant tumor regression. To solve these problems, a tumor-selective replicating adenovirus expressing IFN-beta was constructed in this study.
Methods:
The oncolytic adenoviruses were generated by homologous recombination in packaging cells. The expression of the IFN-beta protein was detected by enzyme-linked immunosorbent assay (ELISA). The antitumor efficacy of ZD55-IFN-beta was evaluated in cell lines and human hepatocellular carcinoma xenografts in nude mice.
Results:
ZD55-IFN-beta can express much more IFN-beta than Ad-IFN-beta because of the replication of the ZD55 vector. Our data showed that ZD55-IFN-beta could exert a strong cytopathic effect on tumor cells (about 100-fold higher than Ad-IFN-beta or ONYX-015). Moreover, no obvious cytotoxic or apoptotic effects were detected in normal cells infected with ZD55-IFN-beta.
Conclusions:
The antitumor efficacy of IFN-beta could be significantly improved due to the increased gene expression level from the tumor-selective replicating vector. The oncolytic adenovirus expressing IFN-beta may provide a novel approach for cancer gene therapy.
Insights
A new oncolytic adenovirus, ZD55-IFN-beta, enhances the antitumor activity of human interferon-beta (IFN-beta) by replicating within tumor cells. This novel therapy shows significant tumor cell killing with no observed toxicity in normal cells.
Area of Science:
- Oncolytic virology
- Gene therapy
- Cancer research
Background:
- Human interferon-beta (IFN-beta) shows antitumor activity but has limited therapeutic effects.
- Conditionally replicative adenovirus ONYX-015 targets tumor cells but lacks sufficient potency for significant tumor regression.
Purpose of the Study:
- To construct a tumor-selective replicating adenovirus expressing IFN-beta to overcome limitations of existing therapies.
- To evaluate the antitumor efficacy of the novel construct, ZD55-IFN-beta.
Main Methods:
- Oncolytic adenoviruses were generated using homologous recombination.
- IFN-beta expression was quantified using enzyme-linked immunosorbent assay (ELISA).
- Antitumor efficacy was assessed in tumor cell lines and human hepatocellular carcinoma xenografts in mice.
Main Results:
- ZD55-IFN-beta demonstrated significantly higher IFN-beta expression compared to Ad-IFN-beta due to vector replication.
- ZD55-IFN-beta exhibited a potent cytopathic effect on tumor cells, approximately 100-fold greater than Ad-IFN-beta or ONYX-015.
- No significant cytotoxic or apoptotic effects were observed in normal cells infected with ZD55-IFN-beta.
Conclusions:
- The tumor-selective replicating vector significantly enhances the antitumor efficacy of IFN-beta through increased gene expression.
- Oncolytic adenovirus expressing IFN-beta represents a promising novel strategy for cancer gene therapy.
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