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An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy

An Erratum to this article was published on 01 December 2000

Abstract

Replication-selective oncolytic viruses constitute a rapidly evolving and new treatment platform for cancer. Gene-deleted viruses have been engineered for tumor selectivity, but these gene deletions also reduce the anti-cancer potency of the viruses. We have identified an E1A mutant adenovirus, dl922-947, that replicates in and lyses a broad range of cancer cells with abnormalities in cell-cycle checkpoints. This mutant demonstrated reduced S-phase induction and replication in non-proliferating normal cells, and superior in vivo potency relative to other gene-deleted adenoviruses. In some cancers, its potency was superior to even wild-type adenovirus. Intravenous administration reduced the incidence of metastases in a breast tumor xenograft model. dl922-947 holds promise as a potent, replication-selective virus for the local and systemic treatment of cancer.

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Figure 1: Relative S-phase induction efficiency and replication of dl922-947 and wild-type adenovirus in normal cells and tumor cells.
Figure 2: Cytopathic potency index for adenovirus E1A and E1B-55 kD mutants.
Figure 3: Kaplan-Meier survival curves following intratumoral or intravenous injection with dl922-947 versus vehicle, dl1520 or wild-type adenovirus in nude mouse-human tumor xenograft models.
Figure 4: Anti-tumor effects of intravenous administration of adenovirus mutants or wild type on the incidence of lung and lymph nodes metastases in a metastatic breast cancer model.
Figure 5: Replication of E1A mutant adenovirus in human tumor xenografts following intratumoral or intravenous administration.

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Acknowledgements

We thank O. Diri and Y. Dugan for preparation of this manuscript; S. Weber and M. Lemmon for animal studies; M. Propst for cell culture and viral assays; P. Roo for in situ hybridization; F. McCormick for inspiration and discussions; and P. Trown, E. Fearon, A. Balmain, E. Harlow, D. Hanahan, O. Witte and A. Fattaey for discussions.

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Correspondence to David Kirn.

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Heise, C., Hermiston, T., Johnson, L. et al. An adenovirus E1A mutant that demonstrates potent and selective systemic anti-tumoral efficacy. Nat Med 6, 1134–1139 (2000). https://doi.org/10.1038/80474

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