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Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy

Abstract

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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Figure 1: Components to confer selective replication.
Figure 2: p53-dependent E2F antagonist expression selectively attenuates an adenovirus vector.
Figure 3: Overexpression of E3-11.6K in vectors encoding p53-regulated E2F antagonist.
Figure 4: 01/PEME is selectively attenuated in normal cells.
Figure 5: Survival of animals in PC-3 intraperitoneal tumor model.
Figure 6: 01/PEME is efficacious in xenograft tumor models.

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Acknowledgements

We thank Drs. Arnie Berk (UCLA) and Stan Bayley (McMaster) for providing dl1520 and dl1101, respectively; Drs. Robert Ralston, Ken Wills, Wendy Hancock, Shu Fen Wen, Dan Maneval, and Stephen Chang for helpful discussions; Mark Horn, Daniel Giroux, and Anastasia Sofianos for virus purification; and Stuart Perry, Todd Machemer, Susan Miller, Margarita Nodelman, Elaine Hurney, Erlinda Quijano, and Henry Kikunaga for technical assistance.

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Correspondence to Murali Ramachandra.

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Ramachandra, M., Rahman, A., Zou, A. et al. Re-engineering adenovirus regulatory pathways to enhance oncolytic specificity and efficacy. Nat Biotechnol 19, 1035–1041 (2001). https://doi.org/10.1038/nbt1101-1035

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