DNA demethylating agents synergize with oncolytic HSV1 against malignant gliomas
Menée in vitro et in vivo, cette étude suggère l'intérêt de combiner un agent déméthylant (5-azacytidine) avec un virus oncolytique (rQNestin34.5) pour le traitement d'un gliome malin
Purpose:Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being utilized in clinical trials for a variety of cancers. The OV, rQNestin34.5, utilizes a nestin promoter/enhancer to selectively drive robust viral replication in malignant glioma cells. We have discovered that this promoter becomes extensively methylated in infected glioma cells, reducing OV efficacy. Experimental Design:We utilized demethylating drugs (5-azacytidine), Decitabine or Valproic Acid (VPA) in both in vitro and in vivo malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy. Results:Utilization of demethylating agents, such as 5-azacytidine (5-Aza), improved OV replication and tumor cell lysis in vitro and, in fact, synergized pharmacologically by Chou-Talalay analysis. In vivo the combination of the demethylating agents, 5-Aza or Decitabine, with rQNestin34.5 significantly prolonged the survivorship of athymic mice harboring intracranial human glioma xenografts over single agent alone. Conclusions:These results thus provide further justification for the exploration of demethylating agents when combined with the OV, rQNestin34.5, in preclinical therapeutics and possibly clinical trials for malignant glioma.