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Low-Dose Radiation Enhances Survivin-Mediated Virotherapy against Malignant Glioma Stem Cells

¹ The Brain Tumor Center and ² Department of Medicine, The University of Chicago, Chicago, Illinois and ³ Division of Human Gene Therapy, University of Alabama at Birmingham, Birmingham, Alabama

Requests for reprints: Maciej S. Lesniak, Section of Neurosurgery, The University of Chicago Pritzker School of Medicine, 5841 South Maryland Avenue, M/C 3026, Chicago, IL 60637. Phone: 773-834-4757; Fax: 773-834-2608; E-mail: mlesniak{at}surgery.bsd.uchicago.edu.

Key Words: Glioblastoma multiforme (GBM) • Conditionally replicating adenovirus (CRAd) • Radiotherapy • Survivin • CD133 • Stem cells • Radioinducible promoters

To improve the efficacy and selectivity of virotherapy for malignant glioma, we designed a strategy to amplify adenoviral replication in conjunction with radiotherapy using a radioinducible promoter. First, we compared the radiation-inducible activity of FLT-1, vascular endothelial growth factor, DR5, Cox2, and survivin. We then examined the capacity of the optimal promoter to modulate transgene expression followed by E1A activity in vitro and in vivo in a glioma stem cell model. In the presence of radiation, survivin mRNA activity increased 10-fold. Luciferase transgene expression was dose dependent and optimal at 2 Gy. A novel oncolytic adenovirus, CRAd-Survivin-pk7, showed significant toxicity and replication against a panel of passaged and primary CD133⁺ glioma stem cells. On delivery of radiation, the toxicity associated with CRAd-Survivin-pk7 increased by 20% to 50% (P < 0.05). At the same time, the level of E1A activity increased 3- to 10-fold. In vivo, treatment of U373MG CD133⁺ stem cells with CRAd-Survivin-pk7 and radiation significantly inhibited tumor growth (P < 0.05). At the same time, the level of E1A activity was 100-fold increased versus CRAd-Survivin-pk7 alone. Selected genes linked to radioinducible promoters whose expression can be regulated by ionizing radiation may improve the therapeutic ratio of virotherapy. In this study, we have identified a new radioinducible promoter, survivin, which greatly enhances the activity of an oncolytic adenovirus in the presence of low-dose radiotherapy. [Cancer Res 2008;68(14):5778–84]