Enhancement of glioblastoma cell killing by combination treatment with temozolomide and tamoxifen or hypericin
Abstract
OBJECT: Adenovirus transduction in gene therapy is dependent on the expression of the coxsackie virus-adenovirus receptor (CAR) for initial binding and on the integrin receptors (avb3, avb5) for viral internalization. Low and variable expression of CAR may be responsible for the low transduction rates seen with native adenoviral vectors. The goal of this study was to demonstrate increased transduction efficiency by retargeting the adenovirus with a fibroblast growth factor (FGF) ligand, FGF-2. METHODS: The retargeted adenoviruses were used to transduce human glioblastoma multiforme (GBM)-derived ECs (tumor-associated brain endothelial cells [TuBECs]), in which there is minimal CAR expression but a high expression of FGF receptor (FGFR). The results demonstrate that the transduction efficiency of TuBECs can reach as high as 80% when one uses an FGF2-conjugated adenovirus containing green fluorescent protein (FGF2-AdGFP) yet be only 5% when one uses the native adenovirus (AdGFP). The TuBECs were transduced with either a native adenovirus (AdHSV-TK) or a retargeted adenovirus (FGF2-AdHSV-TK), both of which carry the suicide herpes simplex virus-thymidine kinase (HSV-TK) gene. Administered as a cytotoxic prodrug, ganciclovir induced a significant decline in the proliferation rate and increased apoptosis in TuBECs treated with the retargeted adenovirus, compared with its effect on TuBECs treated with the native adenovirus. Increased transduction efficiency was determined by…
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