Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-?B.

ABSTRACT: Telomerase-specific replication-competent adenoviruses (Ads), i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver). We reported that inhibition of nuclear factor-?B (NF-?B) leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative I?B? (DNI?B?) expression cassette (TRAD-DNI?B?). Compared with a conventional TRAD, TRAD-DNI?B? showed hepatocyte-specific inhibition of NF-?B signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNI?B?. However, the replication profiles and oncolytic activities of TRAD-DNI?B? were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNI?B? expression cassette have improved safety profiles without inhibiting oncolytic activities.

SUBMITTER: Machitani M 

PROVIDER: S-EPMC5704103 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature