Oligonucleotide NX1838 inhibits VEGF165-mediated cellular responses in vitro |
| |
Authors: | Carol Bell Eric Lynam Darla J Landfair Nebojsa Janjic Marc E Wiles |
| |
Institution: | (1) Cell Biology/Life Sciences, NeXstar Pharmaceuticals, Inc., 2860 Wilderness Place, 80301 Boulder, Colorado |
| |
Abstract: | Summary VEGF (vascular endothelial growth factor) overproduction has been identified as a major factor underlying pathological angiogenesis
in vivo, including such conditions as psoriasis, macular degeneration, and tumor proliferation. Endothelial cell tyrosine
kinase receptors, KDR and Flt-1, have been implicated in VEGF responses including cellular migration, proliferation, and modulation
of vascular permeability. Therefore, agents that limit VEGF-cellular interaction are likely therapeutic candidates for VEGF-mediated
disease states (particularly agents blocking activity of VEGF165, the most frequently occurring VEGF isoform). To that end, a nuclease-resistant, VEGF165-specific aptamer NX1838 (2′-fluoropyrimidine, RNA-based oligonucleotide/40-kDa-PEG) was developed. We have assessed NX1838
inhibition of a variety of cellular events associated with VEGF, including cellular binding, signal transduction, calcium
mobilization, and induction of cellular proliferation. Our data indicate that NX1838 inhibits binding of VEGF to HUVECs (human
umbilical vein endothelial cells) and dose-dependently prevents VEGF-mediated phosphorylation of KDR and PLCγ, calcium flux,
and ultimately VEGF-induced cell proliferation. NX1838-inhibition of VEGF-mediated cellular events was comparable to that
observed with anti-VEGF monoclonal antibody, but was ineffective as an inhibitor of VEGF121-induced HUVEC proliferation. These findings, coupled with nuclease stability of the molecule, suggest that NX1838 may provide
therapeutic utility in vivo. |
| |
Keywords: | VEGF oligonucleotide cell signaling signal transduction |
本文献已被 SpringerLink 等数据库收录! |
|