Effective high-capacity gutless adenoviral vectors mediate transgene expression in human glioma cells.
Glioblastoma multiforme (GBM) is the most common subtype of primary malignant brain tumor. Although serotype 5 adenoviral vectors (Ads) have been used successfully in clinical trials for GBM, the capacity of Ads to infect human glioma cells and the expression of adenoviral receptors in GBM cells have been challenged. In this report, we studied the expression of three molecules that have been shown to mediate adenoviral entry into cells, i.e., coxsackie and adenovirus receptor (CAR), integrin alphavbeta3 (INT), and major histocompatibility complex class I (MHCI), in rodent glioma cell lines and low-passage primary cultures and cell lines from human GBM. We correlated levels of expression of CAR, INT, and MHCI with transduction efficiency elicited by several high-capacity helper-dependent adenoviral vectors (HC-Ads). Expression levels of adenoviral receptors were variable among the different GBM cells studied. HC-Ad-mediated therapeutic gene expression was efficient, ranging between 20 and 80% of the total target cells expressing the encoded transgenes. Our results show no correlation between the levels of CAR, INT, or MHCI molecules and the levels of transgene expression or the number of GBM cells transduced. We conclude that expression levels of adenoviral receptors do not predict their transduction efficiency or biological function.
Candolfi
Marianela
M
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90048, USA.
Curtin
James F
JF
Xiong
Wei-Dong
WD
Kroeger
Kurt M
KM
Liu
Chunyan
C
Rentsendorj
Altan
A
Agadjanian
Hasmik
H
Medina-Kauwe
Lali
L
Palmer
Donna
D
Ng
Philip
P
Lowenstein
Pedro R
PR
Castro
Maria G
MG
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003587:Cytomegalovirus / Q000235:genetics; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D005805:Genes, MHC Class I / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D005909:Glioblastoma / Q000628:therapy*; D005910:Glioma / Q000628:therapy; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic; D011991:Receptors, Virus / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes / Q000235:genetics*
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D039302:Integrin alphaVbeta3; D011991:Receptors, Virus; D015774:Ganciclovir