VEGF-specific short hairpin RNA-expressing oncolytic adenovirus elicits potent inhibition of angiogenesis and tumor growth.
RNA interference is being developed to treat cancer. Although highly target specific, its use has been limited by its short duration of expression. To overcome this shortcoming, we constructed an oncolytic adenovirus (Ad)-based short hairpin RNA (shRNA) expression system (Ad-DeltaB7-shVEGF) against vascular endothelial growth factor (VEGF), a key mediator in angiogenesis. To demonstrate the VEGF-specific nature of this Ad-based shRNA, replication-incompetent Ad expressing VEGF-specific shRNA (Ad-DeltaE1-shVEGF) was also generated. Ad-DeltaE1-shVEGF was highly effective in reducing VEGF expression, and elicited an antiangiogenic effect in vitro and in vivo. Similarly, Ad-DeltaB7-shVEGF exhibited potent antiangiogenic effects in the matrigel plug assay. Moreover, Ad-DeltaB7-shVEGF demonstrated a greater antitumor effect and enhanced survival compared to the cognate control oncolytic Ad, Ad-DeltaB7. Ad-DeltaB7-shVEGF induced significant reduction in tumor vasculature, verifying the antiangiogenic mechanism. Furthermore, both the duration and magnitude of gene silencing by Ad-DeltaB7-shVEGF was greater than Ad-DeltaE1-shVEGF. These results suggest that the combined effects of oncolytic viral therapy and cancer cell-specific expression of VEGF-targeted shRNA elicits greater antitumor effect than an oncolytic Ad alone.
Yoo
Ji Young
JY
Brain Korea 21 Project for Medical Science, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
Kim
Joo-Hang
JH
Kwon
Young-Guen
YG
Kim
Eok-Cheon
EC
Kim
Nam Kyu
NK
Choi
Hye Jin
HJ
Yun
Chae-Ok
CO
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014779:Virus Replication / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A