This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 McGuffie, E. M. Articles by Catapano, C. V. Search for Related Content PubMed PubMed Citation Articles by McGuffie, E. M. Articles by Catapano, C. V.

Antigene and Antiproliferative Effects of a c-myc-targeting Phosphorothioate Triple Helix-forming Oligonucleotide in Human Leukemia Cells¹

Department of Experimental Oncology and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425

The c-myc gene is frequently deregulated and overexpressed in human cancers, and strategies designed to inhibit c-myc expression in cancer cells may have considerable therapeutic value. The purpose of the present work was to characterize the antigene and antiproliferative activity of a triple helix-forming oligonucleotide (TFO) targeted to a homopurine-homopyrimidine sequence in the P2 promoter of the c-myc gene. The TFO was synthesized with phosphorothioate (PS) internucleotide linkages to confer resistance to intra- and extracellular nucleases. This property is required of oligonucleotides designed for in vivo testing and therapeutic applications. The PS-TFO was found to form triplex DNA with affinity and specificity comparable with that of the corresponding phosphodiester TFO, as shown by gel mobility shift and footprinting assays. Fluorescence microscopy and polyacrylamide gel analysis showed that the fluorescein-labeled PS-TFO accumulated in nuclei of CEM leukemia cells and remained intact for at least 72 h. Incubation of CEM cells with PS-TFO reduced c-myc RNA and protein levels. A single exposure of leukemia cells to the PS-TFO was sufficient to induce dose-dependent growth inhibitory effects. Growth inhibition correlated with accumulation of cells in S phase and with induction of cell death by apoptosis. The PS-TFO was also effective in other leukemia and lymphoma cell lines. Control oligonucleotides had minimal effects in all assays. These data indicate that the c-myc-targeted PS-TFO is an effective antigene and antiproliferative agent, with potential for testing in vivo as a novel approach to cancer therapy.

This article has been cited by other articles:

				Y.-J. Han and P. de Lanerolle Naturally Extended CT {middle dot} AG Repeats Increase H-DNA Structures and Promoter Activity in the Smooth Muscle Myosin Light Chain Kinase Gene Mol. Cell. Biol., January 15, 2008; 28(2): 863 - 872. [Abstract] [Full Text] [PDF]

				S. Napoli, U. Negri, F. Arcamone, M. L. Capobianco, G. M. Carbone, and C. V. Catapano Growth inhibition and apoptosis induced by daunomycin-conjugated triplex-forming oligonucleotides targeting the c-myc gene in prostate cancer cells Nucleic Acids Res., January 30, 2006; 34(2): 734 - 744. [Abstract] [Full Text] [PDF]

				A. Hachem and R. B. Gartenhaus Oncogenes as molecular targets in lymphoma Blood, September 15, 2005; 106(6): 1911 - 1923. [Full Text] [PDF]

				G. M. Carbone, S. Napoli, A. Valentini, F. Cavalli, D. K. Watson, and C. V. Catapano Triplex DNA-mediated downregulation of Ets2 expression results in growth inhibition and apoptosis in human prostate cancer cells Nucleic Acids Res., August 16, 2004; 32(14): 4358 - 4367. [Abstract] [Full Text] [PDF]

				G. M. Carbone, E. McGuffie, S. Napoli, C. E. Flanagan, C. Dembech, U. Negri, F. Arcamone, M. L. Capobianco, and C. V. Catapano DNA binding and antigene activity of a daunomycin-conjugated triplex-forming oligonucleotide targeting the P2 promoter of the human c-myc gene Nucleic Acids Res., April 30, 2004; 32(8): 2396 - 2410. [Abstract] [Full Text] [PDF]

				J. A. Jackson, A. V. Trevino, M. C. Herzig, T. S. Herman, and J. M. Woynarowski Matrix attachment region (MAR) properties and abnormal expansion of AT island minisatellites in FRA16B fragile sites in leukemic CEM cells Nucleic Acids Res., November 1, 2003; 31(21): 6354 - 6364. [Abstract] [Full Text] [PDF]

				G. M. Carbone, E. M. McGuffie, A. Collier, and C. V. Catapano Selective inhibition of transcription of the Ets2 gene in prostate cancer cells by a triplex-forming oligonucleotide Nucleic Acids Res., February 1, 2003; 31(3): 833 - 843. [Abstract] [Full Text] [PDF]

				E. M. McGuffie and C. V. Catapano Design of a novel triple helix-forming oligodeoxyribonucleotide directed to the major promoter of the c-myc gene Nucleic Acids Res., June 15, 2002; 30(12): 2701 - 2709. [Abstract] [Full Text] [PDF]