Document Detail


Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo.
MedLine Citation:
PMID:  18176556     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Transcription factors are important targets for the treatment of a variety of malignancies but are extremely difficult to inhibit, as they are located in the cell's nucleus and act mainly by protein-DNA and protein-protein interactions. The transcriptional regulators Id1 and Id3 are attractive targets for cancer therapy as they are required for tumor invasiveness, metastasis and angiogenesis. We report here the development of an antitumor agent that downregulates Id1 effectively in tumor endothelial cells in vivo. Efficient delivery and substantial reduction of Id1 protein levels in the tumor endothelium were effected by fusing an antisense molecule to a peptide known to home specifically to tumor neovessels. In two different tumor models, systemic delivery of this drug led to enhanced hemorrhage, hypoxia and inhibition of primary tumor growth and metastasis, similar to what is observed in Id1 knockout mice. Combination with the Hsp90 inhibitor 17-(allylamino)-17-demethoxygeldanamycin yielded virtually complete growth suppression of aggressive breast tumors.
Authors:
Erik Henke; Jonathan Perk; Jelena Vider; Paola de Candia; Yvette Chin; David B Solit; Vladimir Ponomarev; Luca Cartegni; Katia Manova; Neal Rosen; Robert Benezra
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-01-06
Journal Detail:
Title:  Nature biotechnology     Volume:  26     ISSN:  1546-1696     ISO Abbreviation:  Nat. Biotechnol.     Publication Date:  2008 Jan 
Date Detail:
Created Date:  2008-01-09     Completed Date:  2008-02-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9604648     Medline TA:  Nat Biotechnol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  91-100     Citation Subset:  IM    
Affiliation:
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1270 York Ave., New York, New York 10021, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Breast Neoplasms / genetics*,  pathology*
Cell Line, Tumor
Gene Targeting / methods*
Mice
Neoplasm Proteins / genetics*
Oligonucleotides, Antisense / administration & dosage,  genetics*
Peptides / administration & dosage,  genetics*
Transcription Factors / genetics*
Chemical
Reg. No./Substance:
0/Neoplasm Proteins; 0/Oligonucleotides, Antisense; 0/Peptides; 0/Transcription Factors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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