title: Inhibition of VEGF mRNA by 2'-O,4'-C-ethylene-bridged nucleic acids (ENA) antisense oligonucleotides and their influence on off-target gene expressions.
abstract: We investigated 2'-O,4'-C-ethylene-bridged nucleic acids (ENA) antisense oligonucleotides (AONs) for vascular endothelial growth factor (VEGF) in human lung carcinoma A549 cells. An ENA/DNA gapmer AON with RNase H-mediated activity was virtually stable in rat plasma and exhibited more than 90% inhibition of VEGF mRNA production. Moreover, 22 genes that are likely to bind to the AON were found in the GenBank database by BLAST and CLUSTAL W searches. Three of these genes were actually inhibited by the ENA AON. In shorter ENA AONs with fewer matched sequences of these genes, inhibitiory activities were decreased and off-target effects were improved. These results indicate that ENA AONs act in a sequence-specific manner and could be used as effective antisense drugs.
authors.affiliation: Pharmaceutical Development Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Morita
authors.forename: Koji
authors.initials: K
authors.lastname: Yamate
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Kurakata
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.forename: Makoto
authors.initials: M
authors.lastname: Koizumi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imanishi
mesh_terms: D000818:Animals; D001483:Base Sequence; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A