Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy
Murali Ramachandra, Amena Rahman, Aihua Zou, Mei Vaillancourt, John A. Howe, Douglas Antelman, Barry Sugarman, G. William Demers, Heidrun Engler, Duane Johnson
& Paul Shabram
Canji, Inc. 3525 John Hopkins Court, San Diego, CA 92121.
Replicating adenoviruses may prove to be effective anticancer agents if they can be engineered to selectively destroy tumor cells. We have constructed a virus (01/PEME) containing a novel regulatory circuit in which p53-dependent expression of an antagonist of the E2F transcription factor inhibits viral replication in normal cells. In tumor cells, however, the combination of p53 pathway defects and deregulated E2F allows replication of 01/PEME at near wild-type levels. The re-engineered virus also showed significantly enhanced efficacy compared with extensively studied E1b-deleted viruses such as dl1520 in human xenograft tumor models.
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