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Conditionally Replicative Adenovirus Expressing p53 Exhibits Enhanced Oncolytic Potency¹

Division of Gene Therapy, Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands [V. W. v. B., P. B. v. d. D., J. G., H. M. P., W. R. G.], and Department of Pediatrics and Laboratory of Pharmacotoxicology and Pharmacogenetics, Institut Gustave Roussy, 94 805 Villejuif, France [J. G.]

Conditionally replicative adenoviruses (CRAds) hold promise as anticancer agents. Their potency depends on their replication efficiency in cancer cells and their capacity to destroy these cells by oncolysis. In this regard, a critical determinant is the capacity of CRAds to induce cell death at late stages of infection to release their progeny. One of the cell death pathways that are exploited by adenoviruses involves the tumor suppressor protein p53. Unfortunately, many cancer cells have a nonfunctional p53 pathway and thus do not effectively support CRAd-induced cell death. We hypothesized that restoration of the p53-dependent cell death pathway in cancer cells would promote CRAd-induced cell lysis. Exogenous expression of p53 in human cancer cells during adenovirus replication accelerated cell death by several days and augmented early virus progeny release. The p53-enhanced oncolysis occurred independent of E1A binding to pRb and independent of E3 functions. On the basis of these findings, we constructed a new CRAd, Ad24-p53. This virus expressed functional p53 while replicating in cancer cells. Most importantly, Ad24-p53 exhibited enhanced oncolytic potency on 80% of tested human cancer cell lines of various tissue origins and with different p53 status. CRAd potency was increased up to >100-fold by p53 expression. We conclude that CRAds expressing p53 are promising new agents for more effective treatment of many human cancers.

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