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 TCID(50) 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 (c) 2010 John Wiley & Sons, Ltd.
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 TCID(50) 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 (c) 2010 John Wiley & Sons, Ltd.
Authors: Vincenzo Cerullo; Iulia Diaconu; Lotta Kangasniemi; Maria Rajecki; Sophie Escutenaire; Anniina Koski; Valentina Romano; Noora Rouvinen; Tamara Tuuminen; Leena Laasonen; Kaarina Partanen; Satu Kauppinen; Timo Joensuu; Minna Oksanen; Sirkka-Liisa Holm; Elina Haavisto; Aila Karioja-Kallio; Anna Kanerva; Sari Pesonen; Petteri T Arstila; Akseli Hemminki Journal: Mol Ther Date: 2011-06-14 Impact factor: 11.454
Authors: Marko T Ahonen; Iulia Diaconu; Sari Pesonen; Anna Kanerva; Marc Baumann; Suvi T Parviainen; Brad Spiller; Vincenzo Cerullo; Akseli Hemminki Journal: PLoS One Date: 2010-09-30 Impact factor: 3.240
Authors: Otto Hemminki; Suvi Parviainen; Juuso Juhila; Riku Turkki; Nina Linder; Johan Lundin; Matti Kankainen; Ari Ristimäki; Anniina Koski; Ilkka Liikanen; Minna Oksanen; Dirk M Nettelbeck; Kalevi Kairemo; Kaarina Partanen; Timo Joensuu; Anna Kanerva; Akseli Hemminki Journal: Oncotarget Date: 2015-02-28