TY - JOUR
T1 - Modifications of the fiber in adenovirus vectors increase tropism for malignant glioma models
AU - Staba, Mary Jane
AU - Wickham, Thomas J.
AU - Kovesdi, Imre
AU - Hallahan, Dennis E.
N1 - Funding Information:
This work was supported by grants from the Children’s Research Foundation (to M.-J.S.) and by National Institutes of Health Grants CA58508, CA70937, and CA66132 (to D.E.H.). M.-J.S. was supported by a postdoctoral fellowship from the American Association for Cancer Research.
PY - 2000
Y1 - 2000
N2 - Recombinant adenovirus (Ad) vectors provide a means of local, therapeutic gene 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 titers and multiple dosages. In an attempt to improve Ad vector gene transfer, we studied human (U87, D54) and rodent (GL261, C6) malignant glioma cell lines transfected with various doses of unmodified Ad vectors (ADZ), Ad vectors that contain an alteration of the fiber-coat protein and that direct virus binding to heparan sulfate receptors (AdZ.F(pK7)), and Ad vectors with modifications of the fiber-coat protein that direct virus binding to α(υ) integrin cellular receptors (AdZ.F(RGD)). AdZ.F(pK7) increased the frequency of cells expressing the reporter gene, β- galactosidase, and improved transduction 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(RGD) increased gene expression in C6 xenografts compared with AdZ, but had reduced transduction compared with the C6 xenografts of AdZ in all other glioma tumors. These findings suggest that the increased tropisms resulting from alterations of the Ad vector fiber-coat protein as in AdZ. F(pK7) and AdZ. F(RGD) offer a feasible approach to improving in vitro and in vivo transduction efficiencies in certain malignant glioma cell lines.
AB - Recombinant adenovirus (Ad) vectors provide a means of local, therapeutic gene 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 titers and multiple dosages. In an attempt to improve Ad vector gene transfer, we studied human (U87, D54) and rodent (GL261, C6) malignant glioma cell lines transfected with various doses of unmodified Ad vectors (ADZ), Ad vectors that contain an alteration of the fiber-coat protein and that direct virus binding to heparan sulfate receptors (AdZ.F(pK7)), and Ad vectors with modifications of the fiber-coat protein that direct virus binding to α(υ) integrin cellular receptors (AdZ.F(RGD)). AdZ.F(pK7) increased the frequency of cells expressing the reporter gene, β- galactosidase, and improved transduction 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(RGD) increased gene expression in C6 xenografts compared with AdZ, but had reduced transduction compared with the C6 xenografts of AdZ in all other glioma tumors. These findings suggest that the increased tropisms resulting from alterations of the Ad vector fiber-coat protein as in AdZ. F(pK7) and AdZ. F(RGD) offer a feasible approach to improving in vitro and in vivo transduction efficiencies in certain malignant glioma cell lines.
KW - Adenovirus
KW - Fiber
KW - Gene therapy
KW - Gliomas
UR - http://www.scopus.com/inward/record.url?scp=0033961964&partnerID=8YFLogxK
U2 - 10.1038/sj.cgt.7700104
DO - 10.1038/sj.cgt.7700104
M3 - Article
C2 - 10678351
AN - SCOPUS:0033961964
SN - 0929-1903
VL - 7
SP - 13
EP - 19
JO - Cancer gene therapy
JF - Cancer gene therapy
IS - 1
ER -