Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir.
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.
Diaconu
Iulia
I
Cancer Gene Therapy Group, Molecular Cancer Biology Program & Transplantation Laboratory & Haartman Institute & Finnish Institute for Molecular Medicine, University of Helsinki, Haartmaninkatu 8, Helsinki, Finland.
Cerullo
Vincenzo
V
Escutenaire
Sophie
S
Kanerva
Anna
A
Bauerschmitz
Gerd J
GJ
Hernandez-Alcoceba
Ruben
R
Pesonen
Sari
S
Hemminki
Akseli
A
D000257:Adenoviridae Infections / Q000821:virology; D000260:Adenoviruses, Human / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000821:virology; D002746:Chlorpromazine / Q000494:pharmacology*; D000077404:Cidofovir; D006224:Cricetinae; D003561:Cytarabine / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007121:Immunocompetence / Q000187:drug effects / Q000276:immunology*; D008647:Mesocricetus / Q000276:immunology / Q000821:virology*; D009369:Neoplasms / Q000473:pathology / Q000821:virology; D009928:Organ Specificity / Q000187:drug effects; D063065:Organophosphonates / Q000494:pharmacology*; D014161:Transduction, Genetic; D014779:Virus Replication / Q000187:drug effects*
D063065:Organophosphonates; D003561:Cytarabine; D003596:Cytosine; D000077404:Cidofovir; D002746:Chlorpromazine