Use of a chemically modified antisense oligonucleotide library to identify and validate Eg5 (kinesin-like 1) as a target for antineoplastic drug development.

Abstract	A library of 2'-methoxyethyl-modified antisense oligonucleotides (2'MOE ASO) targeting 1,510 different genes has been developed, validated, and used to identify cell cycle regulatory genes. The most effective molecular target identified was Eg5 (kinesin-like-1), which when inhibited gave the largest increase in 4N DNA in various tumor cells. The Eg5 ASO reduced Eg5 levels, inhibited proliferation, increased apoptosis, and altered the expression of other cell cycle proteins, including survivin and Aurora-A. To examine the therapeutic utility of the Eg5 ASO, the compound was also evaluated in xenograft models. Treatment with Eg5 ASO produced a statistically significant reduction of tumor growth, reduction in Eg5 expression in the tumors, and changes in histone phosphorylation, consistent with a loss of Eg5 protein expression. These data show, for the first time, the utility of a 2'MOE ASO library for high-throughput cell culture-based functional assays and suggest that an Eg5 ASO also has potential in a therapeutic strategy.
Authors	Erich Koller, Stephanie Propp, Hong Zhang, Chenguang Zhao, Xiaokun Xiao, MingYi Chang, Scott A Hirsch, Peter J Shepard, Seongjoon Koo, Cain Murphy, Robert I Glazer, Nicholas M Dean
Journal	Cancer research (Cancer Res) Vol. 66 Issue 4 Pg. 2059-66 (Feb 15 2006) ISSN: 0008-5472 [Print] United States
PMID	16489005 (Publication Type: Journal Article)
Chemical References	Antineoplastic Agents DNA, Neoplasm KIF11 protein, human Oligonucleotides, Antisense RNA, Messenger Kinesins
Topics	Animals Antineoplastic Agents (pharmacology) Apoptosis (drug effects, genetics) Breast Neoplasms (drug therapy, genetics, pathology) Cell Growth Processes (drug effects, genetics) Cell Line, Tumor DNA, Neoplasm (genetics) Gene Library Glioma (drug therapy, genetics, pathology) HeLa Cells Humans Kinesins (antagonists & inhibitors, biosynthesis, genetics) Mice Mice, Nude Oligonucleotides, Antisense (genetics, pharmacology) RNA, Messenger (antagonists & inhibitors, biosynthesis, genetics) Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!