Coxsackievirus adenovirus receptor expression predicts the efficiency of adenoviral gene transfer into non-small cell lung cancer xenografts.
OBJECTIVE
Current paradigms postulate that inefficient adenoviral (Ad) gene transfer is a consequence of poor Coxsackievirus adenovirus receptor (CAR) expression in tumors in vivo. To test whether exuberant CAR expression alone is sufficient to mediate efficient Ad gene transfer, we compared Ad gene transfer efficiency in a panel of non-small cell lung cancer (NSCLC) cell model systems in which we systematically measured CAR expression in vitro and in vivo.


METHODS
NSCLC cells were selected for study on the basis of (a) differences in Ad transduction, (b) identical requirements for growth in vitro, (c) capacity to grow as xenografts in immunocompromised mice, and (d) similar amounts of alpha(v) integrin expression as measured by flow cytometry. CAR expression and Ad transduction profiles of these NSCLC cells were generated in vitro and in vivo.


RESULTS
Ad transduction efficiency of NSCLC cells in vitro can be directly related to CAR expression at both the mRNA and protein level. CAR expression in vitro favorably predicts a comparable pattern of expression in transplanted NSCLC xenografts in vivo. Xenografts generated from NSCLC cells exhibiting increased CAR expression showed evidence of higher Ad gene transfer, although the efficiency of transduction was reduced compared with in vitro measurements. Thus, in NSCLC cells with high basal expression of CAR, Ad vector doses that enabled uniform transduction in vitro achieve a gene transfer efficiency ranging from 10% to 70% after a single intratumoral injection in the xenografts.


CONCLUSIONS
These studies indicate CAR expression is predictive for more efficient gene transfer into NSCLC cells in vitro and in vivo but is not sufficient to achieve uniform transduction by Group C Ad vectors in vivo.
Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90073, USA.
Min
M
Qin
Shuang
S
Chen
Tina
T
Yu
Brian
B
Escuadro
Sherven
S
Sharma
Raj K
RK
Batra
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D004770:Enterovirus / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D011991:Receptors, Virus / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D039564:Integrin alphaV; D012333:RNA, Messenger; D011991:Receptors, Virus; C085301:adenovirus receptor