Cancer Research and Treatment

Original Article

Increased Cytopathic Effect of Replicating Adenovirus Expressing Adenovirus Death Protein: Eunhee Kim, Joo Hang Kim, Taeyoung Koo, Joo Hyuk Sohn, Chae Ok Yun; Cancer Res Treat. 2003;35(5):425-432. Published online October 31, 2003; DOI: https://doi.org/10.4143/crt.2003.35.5.425

PURPOSE
Replication-competent adenoviruses (Ads) are promising new modalities for the treatment of cancer. Selective replication of a viral agent in tumor may lead to improved efficacy over non-replicating Ads due to viral multiplication, lysis of the infected cancer cell and spread to surrounding cells. In our previous studies it was shown that the E1B 55 kD-deleted Ad (YKL-1) exhibits tumor specific replication and cell lysis, but with reduced cytolytic effects compared to the wild type adenovirus (Int J Cancer 2000;88: 454-463). Thus, improving the potency of oncolytic Ads remains an important goal for cancer gene therapy. To increase the oncolytic ability of YKL-1, an adenovirus death protein (ADP) gene was reintroduced under the control of a CMV or MLP promoter at the E3 region of the YKL-1, generating an YKL-cADP and YKL-mADP, respectively.
MATERIALS AND METHODS
The in vitro cytolytic effect of ADP expressing Ads was evaluated by MTT assay, and the induction of apoptosis by ADP expressing Ads was examined by TUNEL analysis. Finally, the antitumor effect of ADP expressing Ads was demonstrated in C33A xenograft tumor model. RESULTS: The YKL-cADP exerted a markedly enhanced cytolytic effect against H460 and SK-Hep1 cancer cell lines. The TUNEL assay indicated that the ADP-mediated cytotoxicity was largely driven by apoptosis. Finally, the YKL-cADP showed a superior antitumor effect than the YKL-1 or YKL-mADP in C33A xenografts. CONCLUSION: These lines of evidence demonstrate that the YKL-cADP induces efficient cell lysis, which is critical for the addition of therapeutic value to replicating Ads in cancer gene therapy.

Citations

Citations to this article as recorded by

The Adenovirus Death Protein – a small membrane protein controls cell lysis and disease
Fanny Georgi, Urs F. Greber
FEBS Letters.2020; 594(12): 1861. CrossRef
A compendium of adenovirus genetic modifications for enhanced replication, oncolysis, and tumor immunosurveillance in cancer therapy
Aleksei A. Stepanenko, Vladimir P. Chekhonin
Gene.2018; 679: 11. CrossRef
Oncolytic viruses: adenoviruses
Julia Niemann, Florian Kühnel
Virus Genes.2017; 53(5): 700. CrossRef

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Original Article

Development of a Conditional Replication Competent Adenovirus, Controlled by the Human Telomerase Promoter (hTERT): Eunhee Kim, Joo Hang Kim, Ha Youn Shin, Han Saem Lee, Joo Hyuk Sohn, Jai Myung Yang, Jungho Kim, Chae Ok Yun; Cancer Res Treat. 2003;35(3):191-206. Published online June 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.3.191

Abstract PDF

PURPOSE
This study has been planned to generate a replication-competent adenovirus which replicates in a cancer cell-specific manner, thus minimizing the side effects and toxicity of cancer gene therapy. MATERIALS AND METHODS: we have generated an E1B 19 kD attenuated recombinant adenoviruses, Ad-TERT-delta19 and Ad-mTERT-delta19, which encode E1A gene driven by the wild type hTERT and modified m-hTERT promoter containing additional c-myc and Sp1 binding sites in the backbone of Ad-deltaE1B19. The in vitro efficacy and specificity of the hTERT and m-hTERT promoter have been evaluated by the comparison of viral replication and cytopathic effect in cancer cells and normal cell lines. To assess anti-tumor effect and safety of hTERT or m-hTERT promoter driven replication competent adenoviruses, tumor regression after subcutaneous injection in subcutaneous C33A xenografts and lacZ expression after systemic injection in organs were examined. RESULTS: The activation of hTERT or m-hTERT promoter was significantly up-regulated only in hTERT-positive cells, but not in hTERT-negative cells. Moreover, the activity of m-hTERT promoter was substantially increased in hTERT-positive cancer cells, but not in hTERT-negative cells. While Ad-TERT-delta19 replicated in and induced cytopathic effect in cancer and in some normal cell lines, Ad-mTERT-delta19 enhanced viral replication and cytopathic effect in cancer cells only. Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-mTERT-delta19. CONCLUSIONS: The use of m-hTERT promoter is not only useful in the regulation of therapeutic gene expression but also that replication-competent oncolytic adenovirus under the control of m-hTERT promoter may be a new promising tool for the treatment of human malignancies.

Citations

Citations to this article as recorded by

Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy
Hiroshi Tazawa, Joe Hasei, Shuya Yano, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara
Cancers.2020; 12(2): 478. CrossRef
Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer
Hiroshi Tazawa, Shinji Kuroda, Joe Hasei, Shunsuke Kagawa, Toshiyoshi Fujiwara
International Journal of Molecular Sciences.2017; 18(7): 1479. CrossRef

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