Chlorpromazine and apigenin reduce adenovirus replication and decrease replication associated toxicity.
BACKGROUND
Adenoviruses can cause severe toxicity in immunocompromised individuals. Although clinical trials have confirmed the potency and safety of selectively oncolytic adenoviruses for treatment of advanced cancers, increasingly effective agents could result in more toxicity and therefore it would be useful if replication could be abrogated if necessary.


METHODS
We analyzed the effect of chlorpromazine, an inhibitor of clathrin-dependent endocytosis and apigenin, a cell cycle regulator, on adenovirus replication and toxicity. First, we evaluated the in vitro replication of a tumor targeted Rb-p16 pathway selective oncolytic adenovirus (Ad5/3-Delta24) and a wild-type adenovirus in normal cells, fresh liver samples and in ovarian cancer cell lines. Further, we analyzed the in vitro cell killing efficacy of adenoviruses in the presence and absence of the substances. Moreover, the effect on in vivo efficacy, replication and liver toxicity of the adenoviruses was evaluated.


RESULTS
We demonstrate in vitro and in vivo reduction of adenovirus replication and associated toxicity with chlorpromazine and apigenin. Effective doses were well within what would be predicted safe in humans.


CONCLUSIONS
Chlorpromazine and apigenin might reduce the replication of adenovirus, which could provide a safety switch in case replication-associated side effects are encountered in patients. In addition, these substances could be useful for the treatment of systemic adenoviral infections in immunosuppressed patients.
Kanerva
Anna
A
Cancer Gene Therapy Group, Rational Drug Design Program and Haartman Institute, University of Helsinki, Finland.
Raki
Mari
M
Ranki
Tuuli
T
Särkioja
Merja
M
Koponen
Jarmo
J
Desmond
Renee A
RA
Helin
Aija
A
Stenman
Ulf-Håkan
UH
Isoniemi
Helena
H
Höckerstedt
Krister
K
Ristimäki
Ari
A
Hemminki
Akseli
A
D000230:Adenocarcinoma / Q000188:drug therapy / Q000821:virology; D000256:Adenoviridae / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D002746:Chlorpromazine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000821:virology; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
D047310:Apigenin; D002746:Chlorpromazine