This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koller, E. Articles by Dean, N. M. Search for Related Content PubMed PubMed Citation Articles by Koller, E. Articles by Dean, N. M.

Use of a Chemically Modified Antisense Oligonucleotide Library to Identify and Validate Eg5 (Kinesin-Like 1) as a Target for Antineoplastic Drug Development

¹ Department of Functional Genomics, Isis Pharmaceuticals, Carlsbad, California and ² Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia

Requests for reprints: Erich Koller, Department of Functional Genomics, Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, CA 92008. Phone: 760-603-2618; Fax: 760-268-4989; E-mail: ekoller{at}isisph.com or Nicholas M. Dean, Phone: 760-603-2364; E-mail: ndean{at}isisph.com.

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. (Cancer Res 2006; (66)4: 2059-66)

This article has been cited by other articles:

				M. Taniwaki, A. Takano, N. Ishikawa, W. Yasui, K. Inai, H. Nishimura, E. Tsuchiya, N. Kohno, Y. Nakamura, and Y. Daigo Activation of KIF4A as a Prognostic Biomarker and Therapeutic Target for Lung Cancer Clin. Cancer Res., November 15, 2007; 13(22): 6624 - 6631. [Abstract] [Full Text] [PDF]

				B. Rebacz, T. O. Larsen, M. H. Clausen, M. H. Ronnest, H. Loffler, A. D. Ho, and A. Kramer Identification of Griseofulvin as an Inhibitor of Centrosomal Clustering in a Phenotype-Based Screen Cancer Res., July 1, 2007; 67(13): 6342 - 6350. [Abstract] [Full Text] [PDF]

				R. Fujii, C. Zhu, Y. Wen, H. Marusawa, B. Bailly-Maitre, S.-i. Matsuzawa, H. Zhang, Y. Kim, C. F. Bennett, W. Jiang, et al. HBXIP, Cellular Target of Hepatitis B Virus Oncoprotein, Is a Regulator of Centrosome Dynamics and Cytokinesis. Cancer Res., September 15, 2006; 66(18): 9099 - 9107. [Abstract] [Full Text] [PDF]

				E. Koller, S. Propp, H. Murray, W. Lima, B. Bhat, T. P. Prakash, C. R. Allerson, E. E. Swayze, E. G. Marcusson, and N. M. Dean Competition for RISC binding predicts in vitro potency of siRNA Nucleic Acids Res., September 11, 2006; 34(16): 4467 - 4476. [Abstract] [Full Text] [PDF]

				S. Davis, B. Lollo, S. Freier, and C. Esau Improved targeting of miRNA with antisense oligonucleotides. Nucleic Acids Res., January 1, 2006; 34(8): 2294 - 2304. [Abstract] [Full Text] [PDF]