Dependence of efficient adenoviral gene delivery in malignant glioma cells on the expression levels of the Coxsackievirus and adenovirus receptor.
OBJECTIVE
Recombinant adenovirus is used as a competent vector in a wide spectrum of cancer gene therapies because of its high efficiency in gene delivery. To study the feasibility of gene therapy in malignant gliomas, the authors examined the antiproliferative effect of the adenovirally transduced wild-type p53 tumor suppressor gene by using 15 different high-grade glioma cell lines.


METHODS
Although growth suppression in association with a high adenoviral p53 transduction efficiency was seen in five of 15 cell lines, it was not observed in the remaining 10 cell lines. To clarify the underlying mechanism, we examined the expression levels of the Coxsackievirus and adenovirus receptor (CAR), which is the primary receptor for adenovirus, and of the integrins alpha vbeta3 and alpha vbeta5, which promote adenoviral internalization. The expression level of the CAR gene showed a close correlation to adenoviral gene transduction efficiency in the tested cell lines, whereas the expression levels of the integrins did not. The CAR expression was decreased by wild-type p53 transduction in U251MG cells harboring mutant p53 and increased by antisense inhibition of p53 in LN443 cells with endogenous wild-type p53.


CONCLUSIONS
The results of this study indicate that CAR expression is a critical determinant of transduction efficiencies in adenovirus-based gene therapy for human malignant gliomas.
Asaoka
K
K
Department of Neurosurgery, Cancer Institute, Hokkaido University School of Medicine, Sapporo, Japan.
Tada
M
M
Sawamura
Y
Y
Ikeda
J
J
Abe
H
H
D000256:Adenoviridae / Q000235:genetics*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics*; D019030:Receptors, Vitronectin / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016023:Integrins; D012333:RNA, Messenger; D011991:Receptors, Virus; D019030:Receptors, Vitronectin; D016159:Tumor Suppressor Protein p53; C064660:integrin alphaVbeta5