Survivin as a novel radiation/CIS platinum/tumor specific promoter for conditional oncolytic viral therapy

Abstract

1535 Background: Conditional oncolytic viral therapy (CRVT) is a novel approach in treatment of cancer. It implies using viral genetic modification to exploit the powerful oncolytic potency of competent virus strictly in tumor. Using recombinant adenovirus (Ad) with tissue specific promoter (TSP) as a vector, different clinical trial has utilized CRVT concept. Although most of these trials employed CRVT in combination with radio or chemotherapy, none of the vector delivered was originally designed for combination treatment. We hypothesize that; radiotherapy (RT)and/or chemotherapy may enhance the selectivity and level of induction of TSP leading to a powerful CRVT system Methods: We have constructing eligible radiation or cis platinum inducible promoter in context of Ad. including Survivin. Glioma cell lines, cervical cancer as well as prostate cancer cell lines were infected with different MOI of the TSP Ad or CMV Ad then cells were exposed to a RTor to cis platinum. FACS analysis and Luc assay was used to detect level of gene expression. Quantitative RTPCR to the corresponding genes was done from RNA isolated from RT or platinum treated cells. A replicative Ad driven by survivin promoter were constructed and tested in glioma cell lines. Results: Ad driven Survivin was made and shows specificity to glioma cell lines, prostate cell lines and cervical cell lines. RT increase the expression of gene expression by Cells treated with RT and Ad Luc driven by Survivin promoter up to 5-fold increase in expression after 2 Gy of RT in compare to non-irradiated cells. RNA analysis was done and has shown increase copy 30 fold for survivin. Cis-platinum treatment shown similar trend in primary cancer cervix cell. Replicative Ad driven by survivin promoter showed a significant enhancing oncolytic effect after treatment with RT in glioma cell lines. Conclusions: Replicative Ad vector employing survivin promoter is a promising tool that could lead to the enhancement of selectivity and specificity of CRVT in radiogenetic and chemotherapy context No significant financial relationships to disclose.