Gene transfer mediated by native versus fibroblast growth factor-retargeted adenoviral vectors into lung cancer cells.
We compared native Adenoviral (Ad) vectors to a basic Fibroblast Growth Factor-retargeted Adenovirus (FGF2-Ad) for gene delivery into a diverse panel of lung cancer cells in vitro and xenografts in vivo. Cells were first evaluated for vector-specific receptor expression. Marked variations of surface coxsackie-adenovirus receptor (CAR), but relatively similar levels of alpha v integrin and FGF receptor expression were evident. Transduction efficiency by Ad directly correlated (R = 0.77, 95% CI 0.28-0.94, P = 0.0085) with CAR, but not with alpha v integrin expression. Transduction efficiency by FGF2-Ad did not correlate with the measured FGF receptor expression. Blocking studies indicated that gene transfer by FGF2-Ad occurred by a CAR-independent pathway, and could be inhibited by free FGF in a dose-dependent manner. Ad-antiserum inhibited FGF2-Ad gene transfer, suggesting that the Ad-component was needed for post-entry DNA-delivery. Soluble heparin sulfate proteoglycans (HSPG) or alpha v integrin blockers marginally decreased FGF2-Ad transduction. Both Ad and FGF2-Ad equally transduced CAR-positive non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells. By contrast, FGF2-Ad had a distinct transduction advantage in CAR-deficient NSCLC cells. This improvement in transduction of CAR-deficient cells by FGF2-Ad persisted in vivo. These data justify the need for an improved FGF2-Ad vector for clinical use in CAR-deficient lung cancer.
Qin
Min
M
David Geffen School of Medicine at UCLA and Division of Pulmonary and Critical Care Medicine, Veterans Administration Greater Los Angeles Health Care System, 111Q, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA.
Escuadro
Brian
B
Sharma
Sherven
S
Batra
Raj K
RK
D000256:Adenoviridae; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D011991:Receptors, Virus / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D007140:Immunoglobulin Fab Fragments; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2