Rodents Versus Pig Model for Assessing the Performance of Serotype Chimeric Ad5/3 Oncolytic Adenoviruses
| Autor: | Julia Davydova, Matthew Glen Robertson, Lisa Koodie, Michele Dunning, Richard W. Bianco, Malavika Chandrashekar, G. R. Ruth |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oncolytic adenovirus pig Cancer Research replication viruses serotype 3 Biology lcsh:RC254-282 Virus Article 03 medical and health sciences Transduction (genetics) 0302 clinical medicine preclinical model Tropism animal model biochemical phenomena metabolism and nutrition lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens porcine Virology syrian hamsters 3. Good health Oncolytic virus oncolytic adenovirus 030104 developmental biology Oncology Viral replication Cell culture 030220 oncology & carcinogenesis Cancer cell Species B Ad5/3 |
| Zdroj: | Cancers Cancers, Vol 11, Iss 2, p 198 (2019) Volume 11 Issue 2 |
| ISSN: | 2072-6694 |
| Popis: | Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor (Coxsackie and Adenovirus Receptor, CAR) on cancer cells. Engineering serotype chimeric vectors (Ad5/3) to utilize Adenovirus type 3 (Ad3) receptors has greatly improved their oncolytic potential. Clinical translation of these infectivity-enhanced vectors has been challenging due to a lack of replication permissive animal models. In this study, we explored pigs as a model to study the performance of fiber-modified Ad5/3 chimeric vectors. As a control, the Ad5 fiber-unmodified virus was used. We analyzed binding, gene transfer, replication, and cytolytic ability of Ad5 and Ad5/3 in various non-human cell lines (murine, hamster, canine, porcine). Among all tested cell lines only porcine cells supported active binding and replication of Ad5/3. Syrian hamster cells supported Ad5 replication but showed no evidence of productive viral replication after infection with Ad5/3 vectors. Transduction and replication ability of Ad5/3 in porcine cells outperformed Ad5, a phenomenon often observed in human cancer cell lines. Replication of Ad5 and Ad5/3 was subsequently evaluated in vivo in immunocompetent pigs. Quantitative PCR analyses 7 days post infection revealed Ad5 and Ad5/3 DNA and replication-dependent luciferase activity in the swine lungs and spleen indicating active replication in these tissues. These studies demonstrated the flaws in using Syrian hamsters for testing serotype chimeric Ad5/3 vectors. This is the first report to validate the pig as a valuable model for preclinical testing of oncolytic adenoviruses utilizing Adenovirus type 3 receptors. We hope that these data will help to foster the clinical translation of oncolytic adenoviruses including those with Ad3 retargeted tropism. |
| Databáze: | OpenAIRE |
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