PMID- 9361904
OWN - NLM
STAT- MEDLINE
DCOM- 19971218
LR  - 20151119
IS  - 1087-2906 (Print)
IS  - 1087-2906 (Linking)
VI  - 7
IP  - 5
DP  - 1997 Oct
TI  - Sequence-specific inhibition of the tumor necrosis factor-alpha receptor I gene 
      by oligodeoxynucleotides containing N7 modified 2'-deoxyguanosine.
PG  - 447-59
AB  - Tumor necrosis factor-alpha (TNF-alpha) is a highly pleiotropic cytokine produced 
      mainly by activated macrophages. This cytokine has been found to mediate the 
      growth of certain tumors, the replication of HIV-1, septic shock, cachexia, 
      graft-versus-host disease, and autoimmune diseases. The binding of TNF-alpha to 
      the p55 tumor necrosis factor receptor type I (TNFRI) is considered one of the 
      initial steps responsible for the multiple physiologic effects mediated by 
      TNF-alpha. The role of TNF-alpha as an inflammatory mediator through TNFRI makes 
      both of these genes attractive targets for intervention in both acute and chronic 
      inflammatory diseases. We have designed antisense oligodeoxynucleotides (ODNs) 
      containing chemically modified purine and pyrimidine bases that specifically 
      inhibit TNFRI expression and functions. These ODNs were designed to hybridize to 
      the 3'-polyadenylation signal region of the TNFRI gene. In cell-based assays, 
      gene-specific antisense inhibition occurred in a dose-dependent fashion at 
      submicromolar concentrations in the presence of cellular uptake enhancing agents. 
      Within ODN sets with a common pattern of stabilizing backbone substitution, the 
      inhibition of the gene expression is found to be correlated with the affinity of 
      the ODNs for their cognate mRNA target sites, providing direct evidence for an 
      antisense mechanism of action. In addition, events triggered by the binding of 
      TNF-alpha to TNFRI, such as the production of IL-6 and IL-8, were significantly 
      reduced by treatment of cells with the anti-TNFRI ODN. Therefore, antisense ODNs 
      can be used to control biologic processes mediated by TNF-alpha and may be useful 
      as therapeutic agents to treat conditions resulting from overproduction of 
      TNF-alpha.
FAU - Ojwang, J O
AU  - Ojwang JO
AD  - Aronex Pharmaceuticals, Inc., Woodlands, TX 77380, USA.
FAU - Lewis, A F
AU  - Lewis AF
FAU - Revankar, G R
AU  - Revankar GR
FAU - Walker, D
AU  - Walker D
FAU - Akiyama, T
AU  - Akiyama T
FAU - Hogan, M E
AU  - Hogan ME
FAU - Rando, R F
AU  - Rando RF
LA  - eng
GR  - 5RO1AI32894/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Antisense Nucleic Acid Drug Dev
JT  - Antisense & nucleic acid drug development
JID - 9606142
RN  - 0 (Antigens, CD)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - G9481N71RO (Deoxyguanosine)
RN  - TPY09G7XIR (Fluorescein)
SB  - IM
MH  - Antigens, CD/*genetics
MH  - Cell Line
MH  - Deoxyguanosine/*analysis
MH  - Fluorescein
MH  - Gene Expression/*drug effects
MH  - Humans
MH  - Oligonucleotides, Antisense/chemistry/*pharmacology
MH  - RNA, Messenger/genetics
MH  - Receptors, Tumor Necrosis Factor/*genetics
MH  - Receptors, Tumor Necrosis Factor, Type I
MH  - Structure-Activity Relationship
MH  - Thermodynamics
EDAT- 1997/11/15 00:00
MHDA- 1997/11/15 00:01
CRDT- 1997/11/15 00:00
PHST- 1997/11/15 00:00 [pubmed]
PHST- 1997/11/15 00:01 [medline]
PHST- 1997/11/15 00:00 [entrez]
AID - 10.1089/oli.1.1997.7.447 [doi]
PST - ppublish
SO  - Antisense Nucleic Acid Drug Dev. 1997 Oct;7(5):447-59. doi: 
      10.1089/oli.1.1997.7.447.