Modifications of the fiber in adenovirus vectors increase tropism for malignant glioma models

Recombinant adenovirus (Ad) vectors provide a means of local, therapeutic g ene delivery to a wide range of neoplasms. Ad-mediated gene therapy trials in malignant glioma models have been limited by the need for high viral tit ers and multiple dosages. In an attempt to improve Ad vector gene transfer, we studied human (U87, D54) and rodent (GL261, C6) malignant glioma cell l ines transfected with various doses of unmodified Ad vectors (AdZ), Ad vect ors that contain an alteration of the fiber-coat protein and that direct vi rus binding to heparan sulfate receptors (AdZ.F(pK7)), and Ad vectors with modifications of the fiber-coal protein that direct virus binding to oc, in tegrin cellular receptors (AdZ.F(RGD)). AdZ.F(pK7) increased the frequency of cells expressing the reporter gene, beta-galaclosidase, and improved tra nsduction by 2- to 20-fold compared with AdZ in U87, D54, and GL261 cells. In U87, D54, GL261, and C6 tumors, AdZ.F(pK7) increased gene transfer by 10 - to 100-fold compared with AdZ. AdZ.F(RCD) increased gene expression in C6 xenografts compared with AdZ, but had reduced transduction compared with t he C6 xenografts of AdZ in all other glioma tumors. These findings suggest that the increased tropisms resulting from alterations of the Ad vector fib er-coal protein as in AdZ.F(pK7) and AdZ.F(RCD) offer a feasible approach t o improving in vitro and in vivo transduction efficiencies in certain malig nant glioma cell lines.