Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer.
Current clinical success rates of adenoviral vector (Adv)-based gene therapy of squamous cell carcinoma (SCC) of the head and neck remain unsatisfactory. A major problem with this approach is thought to be related to low Adv transduction efficiency due to weak expression of the adenovirus receptor, coxsackie-adenovirus receptor (CAR), in SCC. To improve the limited infectivity of Adv in oral SCC, we constructed mutated Adv incorporating the integrin-binding motif, RGD, in the HI loop of the fiber knob. The mutated Adv infected target cells through integrins commonly expressed in oral SCC. LacZ marker gene expression after infection with this mutated Adv (Adv-F/RGD) in oral SCC cell lines that showed reduced expression of CAR was approximately 5-10 times higher than that obtained with the parental Adv containing wild-type fiber knob (Adv-F/wt). In an in vitro study, transduction of oral cancer cell lines with Adv-F/RGD expressing human IL-2 (AxCAhIL2-F/RGD) resulted in greater production of cytokine than AxCAhIL2-F/wt infection. In an in vivo therapeutic xenograft model of oral SCC in nude mice, AxCAhIL2-F/RGD demonstrated antitumor effects superior to those of AxCAhIL2-F/wt. These data suggest that exploitation of genetically altered adenovirus vectors with integrin-binding motifs may offer significant improvements in oral SCC gene therapy.
Dehari
Hironari
H
Department of Oral Surgery, Sapporo Medical University, S1W17, Chuo-ku, Japan.
Ito
Yoshinori
Y
Nakamura
Takafumi
T
Kobune
Masayoshi
M
Sasaki
Katsunori
K
Yonekura
Noriyuki
N
Kohama
Geniku
G
Hamada
Hirofumi
H
D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009842:Oligopeptides / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D017931:DNA Primers; D007376:Interleukin-2; D009842:Oligopeptides; D011991:Receptors, Virus; D011994:Recombinant Proteins; C047981:arginyl-glycyl-aspartic acid