SEARCH:   Advanced

Blood, 15 February 2005, Vol. 105, No. 4, pp. 1742-1749. Prepublished online as a Blood First Edition Paper on October 26, 2004; DOI 10.1182/blood-2003-12-4322. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-12-4322v1 105/4/1742    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by El-Daly, H. Articles by Martens, U. M. Search for Related Content PubMed PubMed Citation Articles by El-Daly, H. Articles by Martens, U. M. Related Collections Neoplasia Cell Cycle Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532 Hesham El-Daly, Miriam Kull, Stefan Zimmermann, Milena Pantic, Cornelius F. Waller, and Uwe M. Martens From the Freiburg University Medical Center, Department of Hematology/Oncology, Freiburg, Germany; and the Albert-Ludwigs-University, Department of Biology, Freiburg, Germany. Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a nonnucleosidic small molecule inhibitor, BIBR1532 (2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid), has been identified that is highly selective for inhibition of telomerase, resulting in delayed growth arrest of tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) in short-term culture assays. We observed a dose-dependent direct cytotoxicity in concentrations ranging from 30 to 80 µM. Interestingly, cell death was not dependent on the catalytic activity of telomerase but was delayed in cells with very long telomeres. We observed time-dependent individual telomere erosion, which was associated with loss of telomeric repeat binding factor 2 (TRF2) and increased phosphorylation of p53. Importantly, the proliferative capacity of normal CD34+ cells from cord blood and leukapheresis samples was not affected by treatment with BIBR1532. We conclude that using this class of telomerase inhibitor at higher concentrations exerts a direct cytotoxic effect on malignant cells of the hematopoietic system, which appears to derive from direct damage of the structure of individual telomeres and must be dissected from telomerase-suppressed overall telomere shortening. (Blood. 2005; 105:1742-1749) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. M. Raynaud, S. J. Jang, P. Nuciforo, S. Lantuejoul, E. Brambilla, N. Mounier, K. A. Olaussen, F. Andre, L. Morat, L. Sabatier, et al. Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions Ann. Onc., November 1, 2008; 19(11): 1875 - 1881. [Abstract] [Full Text] [PDF] D. Poncet, A. Belleville, C. t'Kint de Roodenbeke, A. Roborel de Climens, E. Ben Simon, H. Merle-Beral, E. Callet-Bauchu, G. Salles, L. Sabatier, J. Delic, et al. Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia Blood, February 15, 2008; 111(4): 2388 - 2391. [Abstract] [Full Text] [PDF] R. J. Ward and C. Autexier Pharmacological Telomerase Inhibition Can Sensitize Drug-Resistant and Drug-Sensitive Cells to Chemotherapeutic Treatment Mol. Pharmacol., September 1, 2005; 68(3): 779 - 786. [Abstract] [Full Text] [PDF]

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020