AdΔ24 and the p53-expressing variant AdΔ24-p53 achieve potent anti-tumor activity in glioma when combined with radiotherapy

Background: The conditionally replicating adenovirus (CRAd) AdΔ24-p53 replicates selectively in Rb mutant cells, and encodes the p53 suppressor protein. It has shown improved oncolytic potency compared to the parental control AdΔ24. As exogenous p53 has been shown to enhance radiosensitivity, the combination of AdΔ24-p53 and AdΔ24 with radiotherapy was assessed in vitro and in vivo against the therapy resistant gliomas. Methods: In glioma cells, multicellular spheroids and animal xenografts the efficacy of combination therapy was assessed. P53 phosphorylation, induction of apoptosis and viral replication were determined following single or combination therapies. Results: In vitro, AdΔ24-p53 was more effective against glioma cells than the control AdΔ24. Addition of irradiation equally increased the efficacy of both AdΔ24-p53 and AdΔ24 resulting in improved oncolysis compared to single agent treatment. Radiotherapy did not significantly change the replication kinetics of AdΔ24-p53 or AdΔ24. No detectable increase in p53 phosphorylation was observed but combination of radiotherapy and AdΔ24-p53 caused an increase in the percentage of apoptotic cells. In vivo, combination therapy with either AdΔ24 or AdΔ24-p53 significantly increased the number of mice demonstrating tumor regression (100%) as well as long-term survival (50%). No differences between viruses were noted. Conclusions: Exogenous p53 expression does not appear to increase the synergistic interaction of CRAds combined with radiotherapy. These results however do indicate that radiotherapy provides the time frame in which AdΔ24 and AdΔ24-p53 can eradicate established tumors that would otherwise escape treatment, and establishes the need to combine these modalities to form an effective anti-cancer treatment. Copyright

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