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Published ahead of print on December 30, 2004, doi:10.1165/rcmb.2004-0226OC

Am. J. Respir. Cell Mol. Biol., Volume 32, Number 3, March 2005, 211-217

A more recent version of this article appeared on March 1, 2005
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Submitted on July 15, 2004
Revised on December 30, 2004

GENE TRANSFER MEDIATED BY NATIVE VERSUS FGF2-RETARGETED ADENOVIRAL VECTORS INTO LUNG CANCER CELLS

Min Qin1, Brian Escuadro1, Sherven Sharma1, and Raj K Batra1*

1 Department of Medicine, David Geffen School of Medicine at UCLA, GLAVAHS, and the Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

* To whom correspondence should be addressed. E-mail: rbatra{at}ucla.edu.

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.






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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2004 American Thoracic Society.