Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir

• Published in: The journal of gene medicine 2010-05, Vol.12 (5), p.435-445
• Main Authors: Diaconu, Iulia, Cerullo, Vincenzo, Escutenaire, Sophie, Kanerva, Anna, Bauerschmitz, Gerd J., Hernandez-Alcoceba, Ruben, Pesonen, Sari, Hemminki, Akseli
• Format: Article
• Language: English
• Subjects: Adenoviridae Infections - virology; Adenovirus; Adenoviruses, Human - drug effects; Adenoviruses, Human - physiology; Animal models; Animals; Biological Transport - drug effects; Carcinoma; Cell Death - drug effects; Cell Line; Cell Line, Tumor; Cell Nucleus - drug effects; Cell Nucleus - virology; Children; Chlorpromazine; Chlorpromazine - pharmacology; Cidofovir; Cricetinae; Cytarabine - pharmacology; Cytosine - analogs & derivatives; Cytosine - pharmacology; cytosine arabinoside; Drug development; Gene therapy; Gene transfer; Genomes; Human adenovirus; Humans; Immunocompetence - drug effects; Immunocompetence - immunology; Immunosuppressive agents; Liver; Mesocricetus - immunology; Mesocricetus - virology; Neoplasms - pathology; Neoplasms - virology; Oncolysis; Organ Specificity - drug effects; Organophosphonates - pharmacology; Replication; Side effects; Toxicity; Transduction, Genetic; Tumor cell lines; Tumor cells; Tumors; Virus Replication - drug effects
• ISSN: 1099-498X; 1521-2254; 1521-2254
• DOI: 10.1002/jgm.1453

Background Adenoviruses can cause severe toxicity in children and in immunocompromised adults, and therefore a means to abrogate replication would be useful. With regard to cancer treatment, replication competent oncolytic adenoviruses have been safe in humans, although their efficacy has been variable. Therefore, more effective agents are now entering clinical testing and, consequently, replication‐associated side effects remain a concern. Preclinical analysis of replication related toxicity has been hampered by a lack of permissive models. Therefore, it has been difficult to study modulation of human adenovirus replication in immune competent animals. Methods We investigated four different hamster carcinoma cell lines for transduction and cell killing potency in vitro and in vivo. Gene transfer was assessed using replication‐deficient adenoviruses expressing luciferase. Cell killing was studied in vitro and in vivo using an oncolytic adenovirus that kills tumor cells by viral replication. After the most promising animal model had been selected, abrogation of virus replication was assessed in vitro and in vivo using a TCID50 assay. Results The results obtained suggest wild‐type adenovirus replication in all four tested Syrian hamster cell lines and also normal organs. Virus replication could be abrogated with chlorpromazine, cidofovir and cytosine arabinoside, and the effect occurred subsequent to nuclear delivery of the viral genome. Attenuation of virus replication also was seen in vivo both in tumors and the liver. Conclusions Syrian hamsters may comprise a valuable immune competent model for evaluating anti‐adenoviral drugs. Furthermore, chlorpromazine or cidofovir might be useful in case of adenovirus replication‐associated symptoms in humans. Copyright © 2010 John Wiley & Sons, Ltd.