Human telomerase reverse transcriptase promoter-driven oncolytic adenovirus with E1B-19 kDa and E1B-55 kDa gene deletions.
We constructed an oncolytic adenovirus, Adeno-hTERT-E1A, with deletions of the viral E1B, E3A, and E3B regions and insertion of a human telomerase reverse transcriptase (hTERT) promoter-driven early viral 1A (E1A) cassette that confers high transcriptional activity in multiple human tumor cell lines. The oncolytic potential of Adeno-hTERT-E1A was characterized in comparison with that of the E1B-55 kDa- and E3B-region-deleted oncolytic adenovirus ONYX-015. Tumor cells infected with Adeno-hTERT-E1A expressed dramatically higher levels of E1A oncoprotein, underwent enhanced lysis, and displayed an earlier and higher apoptotic index than cells infected with ONYX-015. Despite the increase in virus-induced apoptotic death, Adeno-hTERT-E1A replicated and produced functional progeny leading to viral spread, but with reduced efficiency compared with ONYX-015, in particular in A549 cells. Virus-induced E1A expression, host cell apoptosis, viral hexon protein production, and DNA synthesis were markedly reduced in primary human hepatocytes after infection with Adeno-hTERT-E1A as compared with ONYX-015. The strong oncolytic activity of Adeno-hTERT-E1A in tumor cell culture translated into superior antitumor activity in vivo in an MDA-MB-231 solid tumor xenograft model. Adeno-hTERT-E1A thus has strong therapeutic potential and an improved safety profile compared with ONYX-015, which may lead to reduced toxicity in the clinic.
Doloff
Joshua C
JC
Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA.
Waxman
David J
DJ
Jounaidi
Youssef
Y
D000256:Adenoviridae / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D017353:Gene Deletion; D006801:Humans; D050130:Oncolytic Virotherapy; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*
D017501:Adenovirus E1B Proteins; D017931:DNA Primers; D019098:Telomerase
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