Targeted cytotoxic gene delivery to malignant gliomas via the fibroblast growth factor receptor

Abstract

Object. The use of gene therapy for the treatment of malignant gliomas has been disappointing. In an effort to increase the viral transduction efficiency in delivering cytotoxic genes to malignant gliomas, the authors have used a novel retargeting schema that redirects the adenovirus to fibroblast growth factor receptors present on the cell surface of both proliferating glioma cells and glioma endothelial cells. Methods.Using this targeted adenovirus, the authors demonstrated an increase in expression of the luciferase mark- er gene in human glioma cells and glioma endothelial cells. Transduction with the herpes simplex thymidine kinase gene resulted in greater cytotoxicity when treated with ganciclovir for both cell types. This increased cytotoxity was sustained for up to 6 days after administration of ganciclovir. Conclusions. The mechanism of cytotoxicity was determined to be apoptosis by using the terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay. Increasing the specificity of adenovirus tar- geting may be crucial to decrease the number of adenoviral vectors necessary to create adequate levels of gene trans- fer in malignant gliomas, thus reducing the risk of vector-related immunogenicity and toxicity, as well as increasing the overall effectiveness of cytotoxic gene therapy.