Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo Journal Article
| Authors: | Henke, E.; Perk, J.; Vider, J.; De Candia, P.; Chin, Y.; Solit, D. B.; Ponomarev, V.; Cartegni, L.; Manova, K.; Rosen, N.; Benezra, R. |
| Article Title: | Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo |
| Abstract: | 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. © 2008 Nature Publishing Group. |
| Keywords: | cancer chemotherapy; controlled study; unclassified drug; human cell; nonhuman; mouse; animals; mice; gene targeting; mus; metastasis; breast cancer; neoplasm proteins; animal experiment; animal model; in vivo study; drug structure; cell line, tumor; breast neoplasms; oncology; cancer model; transcription factors; hypoxia; cancer invasion; endothelium cell; transcription regulation; tumors; peptides; transcription; heat shock protein 90 inhibitor; tanespimycin; tumor growth; patient treatment; tumor vascularization; tumor bleeding; drug conjugation; knockout mouse; regulator protein; oligonucleotides; oligonucleotides, antisense; peptide derivative; antisense oligodeoxynucleotide; medical problems; peptide-conjugated antisense oligonucleotides; protein-protein interactions; protein ld1; protein ld3 |
| Journal Title: | Nature Biotechnology |
| Volume: | 26 |
| Issue: | 1 |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2008-01-01 |
| Start Page: | 91 |
| End Page: | 100 |
| Language: | English |
| DOI: | 10.1038/nbt1366 |
| PUBMED: | 18176556 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 37" - "Export Date: 17 November 2011" - "CODEN: NABIF" - "Source: Scopus" |
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