Development of recombinant adeno-associated virus and adenovirus cocktail system for efficient hTERTC27 polypeptide-mediated cancer gene therapy.
The low in vivo transduction efficiency of recombinant adeno-associated virus (rAAV) and the undesirably strong immunogenicity of adenovirus (rAdv) have limited their clinical utilization in cancer gene therapy. We have previously demonstrated that intratumoral injection of rAAV expressing a C-terminal polypeptide of human telomerase reverse transcriptase (rAAV-hTERTC27) effectively inhibits the growth of glioblastoma xenografts in nude mice. To further improve its efficacy, we combined rAAV-hTERTC27 with rAdv and investigated the efficiency of the cocktail vectors in vivo. At a nontherapeutic dose (1 x 10(8) plaque-forming units (PFUs)), rAdv-null and rAdv-hTERTC27 were equipotent in enhancing the therapeutic efficacy of rAAV-hTERTC27 (1.5 x 10(11) v.g.), and complete tumor regression was achieved in 25% of the treated animals. Importantly, the combination of rAAV-hTERTC27 and a therapeutic dose (2.5 x 10(9) PFU) of rAdv-hTERTC27 significantly augmented the therapeutic effects and led to a 38% complete tumor regression rate. In vivo optical imaging also showed that rAAV-luc/rAdv-luc cocktail vectors could synergistically enhance the early transient and latent sustained expression of luciferase, as compared to rAdv-luc and rAAV-luc alone. These findings suggest that the combination of rAAV-hTERTC27 and a therapeutic dose of rAdv-hTERTC27 is potentially a promising treatment for glioblastoma, and the rAAV/rAdv cocktail vector system warrants further development for cancer gene therapy.
Gao
Y
Y
Department of Chemistry, Institute of Molecular Biology, The University of Hong Kong, Pokfulam, Hong Kong, China.
Ng
S S M
SS
Chau
D H W
DH
Yao
H
H
Yang
C
C
Man
K
K
Huang
P T
PT
Huang
C
C
Huang
J J
JJ
Kung
H-F
HF
Lin
M C
MC
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017931:DNA Primers / Q000235:genetics; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008156:Luciferases; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics*; D014161:Transduction, Genetic / Q000379:methods
D017931:DNA Primers; D008156:Luciferases; C509186:TERT protein, human; D019098:Telomerase