Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice
Pei-Hsin Cheng1, Xiao-Mei Rao2, Stephen L Wechman3,4
1Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. paisin.paisin@gmail.com.
Background:
Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads.
Methods:
Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies.
Results:
Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment.
Conclusion:
Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor.
Insights
Oncolytic adenovirus therapy shows promise in mouse models by targeting cyclin E overexpression. However, capsule formation around treated cells may limit viral spread, impacting overall efficacy.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Gene therapy
Background:
- Preclinical models using human tumor xenografts may overestimate adenovirus (Ad)-mediated oncolytic therapy efficacy.
- Human Ad replication is dependent on cyclin E dysregulation or overexpression in cancer cells.
- ED-1 cells, derived from mouse lung adenocarcinomas with human cyclin E overexpression, serve as a model for oncolytic Ad studies.
Purpose of the Study:
- To investigate the antitumor efficacy of oncolytic adenovirus therapy targeting cyclin E overexpression in a syngeneic mouse model.
- To evaluate the replication of human Ad in ED-1 cells and its effect on tumor growth.
Main Methods:
- Utilized Ad-cycE to target cyclin E overexpression in ED-1 cells.
- Administered Ad-cycE in a syngeneic mouse model to assess tumor growth repression.
- Observed viral replication and tumor cell response in immunocompetent FVB mice.
Main Results:
- Murine ED-1 cells supported human Ad replication.
- Ad-cycE successfully repressed ED-1 tumor growth in vivo.
- Oncolytic Ads induced destruction of ED-1 cells within capsule-like structures, limiting spread to surrounding cells.
Conclusions:
- Ad-cycE effectively targets cyclin E-overexpressing cancer cells and inhibits tumor growth in syngeneic models.
- Capsule formation post-intratumoral Ad injection may impede viral particle dissemination throughout the tumor, affecting treatment reach.
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