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Oncolytic Activity of p53-Expressing Conditionally Replicative Adenovirus Ad24-p53 against Human Malignant Glioma

Department of ¹ Pediatrics, ² Pharmacology and New Treatments in Cancer, and ³ Vectorology and Gene Transfer, Institut Gustave Roussy, Villejuif, France, and ⁴ Department of Neurosurgery, and ⁵ Division of Gene TherapyDepartment of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands

Prognosis of malignant glioma is poor, and results of treatment remain mediocre. Conditionally replicative adenoviruses hold promise as alternative anticancer agents for the treatment of malignant glioma. Here, we evaluated the conditionally replicative adenovirus Ad24 and its recently developed derivative Ad24-p53, which expresses functional p53 tumor suppressor protein while replicating in cancer cells, for treatment of malignant glioma. In comparison to its parent Ad24, Ad24-p53 killed most malignant glioma cell lines and primary glioblastoma multiforme short-term cultures more effectively, irrespective of their p53 status. Moreover, Ad24-p53 caused more frequent regression and more delayed growth of IGRG121 xenografts derived from a glioblastoma multiforme in vivo. Five intratumoral injections of 10⁷ pfu Ad24 gave 24 days median tumor growth delay (P < 0.01), 30% tumor regressions, and 30% animals surviving >120 days tumor-free or with a minimal tumor residual. The same dose of Ad24-p53 caused >113 days of median tumor growth delay (P < 0.001), 70% tumor regressions, and 60% animals surviving >120 days tumor-free or with a minimal tumor residual. Antitumor effects in vivo were associated with extensive conditionally replicative adenovirus replication, apoptosis induction, and tumor morphology changes, including dissociation, inflammatory cell infiltration, and necrosis. We conclude that conditionally replicative adenoviruses expressing p53 are promising new agents for treatment of malignant glioma.

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