Prodrug bioactivation and oncolysis of diffuse liver @entity3 by a XXXX mutant that expresses the CYP2B1 transgene.

@entity1 @entity11670 @entity137 @entity99 @entity5 @entity19 @entity786 @entity694 @entity1014 @entity3 @entity35 @entity4540 @entity3307
BACKGROUND: @entity3307 ) infection of @entity5 cells results in viral replication with cell destruction and liberation of progeny virion that infect adjacent @entity5 cells. rRp450 is a novel replication-conditional @entity3307 mutant that expresses both the endogenous herpes viral @entity1014 kinase gene and the @entity35 @entity11670 CYP2B1 transgene; @entity11670 bioactivates such @entity5 prodrugs as @entity786 . METHODS: @entity137 and replication assays were performed in @entity694 cells as well as primary @entity1 hepatocytes. For in vivo studies, diffuse liver @entity3 were generated by inoculating MC26 cells into the portal system of BALB/c @entity19 . @entity19 were treated with control media, rRp450, or rRp450 plus @entity786 . RESULTS: Cytopathic effects induced by rRp450 replication in @entity694 cells were equivalent to those induced by wild type @entity3307 in vitro. Assays developed to separate @entity137 mediated by viral replication from @entity137 mediated by chemotherapy confirmed that @entity3307 @entity1014 kinase bioactivates @entity4540 and CYP2B1 bioactivates @entity786 in rRp450-infected cells. rRp450 mediated @entity137 in the presence of @entity786 was increased by 21% to 30% above that achieved by viral replication alone. @entity786 bioactivation produced bystander killing of @entity694 cells but not hepatocytes. In contrast to these effects of @entity786 , rRp450 mediated @entity137 was reduced in the presence of @entity4540 . These findings are explained by further experiments showing that bioactivation of @entity786 only minimally affected @entity3307 replication in @entity694 cells, whereas bioactivation of @entity4540 markedly attenuated @entity3307 replication. In vivo studies revealed a substantial decrease in @entity99 burden in all rRp450-treated animals compared to controls. The addition of @entity786 augmented rRp450's in vivo anti-neoplastic effect. CONCLUSIONS: The rRp450 mutant @entity3307 is highly oncolytic against @entity694 cells both in vitro and in vivo. rRp450 displays preferential replication in @entity694 cells compared to normal hepatocytes. Activation of @entity786 by the @entity11670 transgene augmented the anti-neoplastic effects of rRp450 without simultaneously decreasing viral replication. Oncolysis induced by @entity3307 replication combined with @entity786 prodrug activation warrants further investigation as a potential therapy for @entity694 liver @entity3 .
