A plasmid-encoded VEGF siRNA reduces glioblastoma angiogenesis and its combination with interleukin-4 blocks tumor growth in a xenograft mouse model.
Angiogenesis is required for the development and biologic progression of glioblastoma multiform (GBM), which is the most malignant infiltrative astrocytoma. Vascular endothelial growth factor (VEGF) plays a predominant role in the increased vascularity and endothelial cell proliferation in GBMs driven by the expression of pro-angiogenic cytokines. In this study, we employed a vector-encoded VEGF siRNA to impair VEGF secretion from U87 human glioblastoma cells. The direct intra-tumor injection of a siRNA-encoding plasmid complexed with linear polyethylenimine (PEI) efficiently reduced the vascularization of treated tumors in xenografts established in SCID mice by subcutaneous inoculation of U87 cells, but was not able to reduce tumor growth. We then sought to strengthen the in vivo action of our siRNA by coupling it to a well known direct antiangiogenic agent, mouse interleukin 4 (mIL4). We infected U87 cells with a retroviral vector coexpressing the VEGF siRNA and mIL4 and produced stable cell lines that we used for an in vivo experiment of subcutaneous injection in SCID mice. In this setting, the concomitant expression of mIL4 and siRNA totally abolished the growth of subcutaneous tumors. These results suggest that our retroviral vector might be employed as a potential tool in future antiangiogenic gene therapy trials for glioblastoma.
Niola
Francesco
F
Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata", Rome, Italy.
Evangelisti
Cristina
C
Campagnolo
Luisa
L
Massalini
Simone
S
Buè
Maria Cristina
MC
Mangiola
Annunziato
A
Masotti
Andrea
A
Maira
Giulio
G
Farace
Maria Giulia
MG
Ciafrè
Silvia Anna
SA
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000628:therapy*; D003131:Combined Modality Therapy; D015536:Down-Regulation; D015316:Genetic Therapy; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000628:therapy*; D006801:Humans; D015847:Interleukin-4 / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D015847:Interleukin-4