title: Potent and long-term antiangiogenic efficacy mediated by FP3-expressing oncolytic adenovirus.
abstract: Various ways to inhibit vascular endothelial growth factor (VEGF), a key facilitator in tumor angiogenesis, are being developed to treat cancer. The soluble VEGF decoy receptor (FP3), due to its high affinity to VEGF, is a highly effective and promising strategy to disrupt VEGF signaling pathway. Despite potential advantage and potent therapeutic efficacy, its employment has been limited by very poor in vivo pharmacokinetic properties. To address this challenge, we designed a novel oncolytic adenovirus (Ad) expressing FP3 (RdB/FP3). To demonstrate the VEGF-specific nature of RdB/FP3, replication-incompetent Ad expressing FP3 (dE1/FP3) was also generated. dE1/FP3 was highly effective in reducing VEGF expression and functionally elicited an antiangiogeneic effect. Furthermore, RdB/FP3 exhibited a potent antitumor effect compared with RdB or recombinant FP3. Consistent with these data, RdB/FP3 was shown to greatly decrease VEGF expression level and vessel density and increase apoptosis in both tumor endothelial and tumor cells, verifying potent suppressive effects of RdB/FP3 on VEGF-mediated tumor angiogenesis in vivo. Importantly, the therapeutic mechanism of antitumor effect mediated by RdB/FP3 is associated with prolonged VEGF silencing efficacy and enhanced oncolysis via cancer cell-specific replication of oncolytic Ad. Taken together, RdB/FP3 provides a new promising therapeutic approach in the treatment of cancer and angiogenesis-related diseases.
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-Gu, Seoul, Korea.
authors.forename: Il-Kyu
authors.initials: IK
authors.lastname: Choi
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-Gu, Seoul, Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Shin
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-Gu, Seoul, Korea.
authors.forename: Eonju
authors.initials: E
authors.lastname: Oh
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-Gu, Seoul, Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-Gu, Seoul, Korea.
authors.forename: June Kyu
authors.initials: JK
authors.lastname: Hwang
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-Gu, Seoul, Korea.
authors.forename: Kyungsub
authors.initials: K
authors.lastname: Shin
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: De-Chao
authors.initials: DC
authors.lastname: Yu
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-Gu, Seoul, Korea.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; C557495:FP3 VEGF receptor Fc-fusion protein; D011993:Recombinant Fusion Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: angiogenesis inhibitors: endogenous and synthetic; animal models of cancer; lung cancer; targeting strategies; vector systems