Abstract
<div>Abstract<p><b>Purpose:</b> Oncolytic viruses (OV) based on herpes simplex virus type 1 (HSV1) are being used in clinical trials for a variety of cancers. The OV, rQNestin34.5, uses 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.</p><p><b>Experimental Design:</b> We used demethylating drugs [5-azacytidine (5-Aza)], decitabine, or valproic acid (VPA) in both <i>in vitro</i> and <i>in vivo</i> malignant glioma models to determine if they improved the efficacy of rQNestin34.5 therapy.</p><p><b>Results:</b> The use of demethylating agents, such as 5-Aza, improved OV replication and tumor cell lysis <i>in vitro</i> and, in fact, synergized pharmacologically on Chou–Talalay analysis. <i>In vivo</i>, 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.</p><p><b>Conclusion:</b> 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. <i>Clin Cancer Res; 19(21); 5952–9. ©2013 AACR</i>.</p></div>
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