MICRO RNA BASED STRATEGY FOR ENHANCING THE EFFECT OF ONCOLYTIC HSV-1 VIRUS THERAPY

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Abstract

BACKGROUND: G47Δ is a third generation, genetically engineered, oncolytic herpes simplex virus type 1 (HSV-1) that is currently used in a clinical trial for patients with refractory glioblastomas. Genetic modifications in the γ34.5, ICP6 and α47 genes make G47Δ replicate selectively in tumor cells. Most tumor cell lines support the replication of G47Δ well and are susceptible to the therapy, but some cell lines are relatively resistant to oncolytic HSV-1. Micro RNA (miR) -199a-3p and miR-214 are reported to suppress wild type HSV-1 replication in murine cell lines. We investigated if these micro RNAs also have effect on the replication of onoclytic HSV-1. METHODS: Four human glioma cell lines were tested for the susceptibility for G47Δ, and A172 and T98G were found to be relatively resistant. Micro RNA expression levels were examined in real-time reverse transcription polymerase chain reaction (RT-PCR) assay, and both miR-199a-3p and miR-214 levels were high in these G47Δ resistant cell lines. Using tough decoy (TuD) microRNA suppression system, A172 and T98G with low miR-199a-3p and miR-214 expression were created. RESULTS: G47Δ replication and cytopathic effect were better in A172 and T98G miR-199a-3p low, miR-214 low cells than A172 and T98G cells which were transfected with control TuD, expressing original levels of miR-199a-3p and miR-214. CONCLUSIONS: These results suggest that expression level of some microRNA may have effects on oncolytic HSV-1 replication. Modulation of some specific micro RNA expression may enhance the anti-tumor effect of oncolytic HSV-1 therapy, and the micro RNA based strategy may be a useful tool to improve the efficacy of oncolytic HSV-1 therapy for malignant glioma. SECONDARY CATEGORY: n/a.

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