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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2099-2106. Prepublished online as a Blood First Edition Paper on September 23, 2004; DOI 10.1182/blood-2004-06-2205. This Article Full Text (PDF) All Versions of this Article: 2004-06-2205v1 105/5/2099    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shanafelt, T. D Articles by Kay, N. E Search for Related Content PubMed PubMed Citation Articles by Shanafelt, T. D Articles by Kay, N. E Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 14, 2004 Accepted August 24, 2004 Adaphostin-induced apoptosis in CLL B-cells is associated with induction of oxidative stress and exhibits synergy with fludarabine Tait D Shanafelt*, Yean K Lee, Nancy D Bone, Ann K Strege, Ven L Narayanan, Edward A Sausville, Susan M Geyer, Scott H Kaufmann, and Neil E Kay Department of Medicine, Division of Hematology, Division of Oncology Research, and Division of Biostatistics, Mayo Clinic, Rochester, MN, USA Developmental Therapeutics Program (V.L.N.), Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA Greenebaum Cancer Center (E.A.S), University of Maryland, Baltimore, MD, USA * Corresponding author; email: shanafelt.tait{at}mayo.edu. B-cell chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal lymphocytes resistant to apoptosis. We evaluated the ability of the investigational antileukemic agent adaphostin to induce apoptosis in CLL B-cells and synergize with fludarabine in vitro. Analysis by Annexin V/propidium iodide (PI) staining revealed that the mean IC50 for adaphostin at 24 hours was 4.2 µM (range 1.10 µM - 11.25 M; median = 4.25; n = 29) for CLL isolates and >10 µM for B and T-cells from normal donors. Immunoblots demonstrated adaphostin-induced PARP cleavage and cleavage of caspase 3 substrates, suggesting that adaphostin induces apoptosis. Adaphostin increased the level of reactive oxygen species (ROS) within CLL B-cells; and the antioxidant N-acetylcysteine blocked both adaphostin-induced ROS generation and apoptosis. Adaphostin also caused a decrease in the level of the anti-apoptotic protein Bcl-2. When adaphostin was combined with fludarabine (F-ARA-AMP), a synergistic effect on cell death was observed in all 10 CLL samples. These findings not only indicate that adaphostin induces apoptosis selectively in CLL B-cells through a mechanism that involves ROS generation, but also demonstrate its ability to augment the effects of fludarabine. Further preclinical development of adaphostin as a novel agent for the treatment of CLL appears warranted. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. M. Evens, W. G. Spies, I. B. Helenowski, D. Patton, S. Spies, B. D. Jovanovic, S. Miyata, E. Hamilton, D. Variakojis, J. Chen, et al. The Novel Expanded Porphyrin, Motexafin Gadolinium, Combined with [90Y]Ibritumomab Tiuxetan for Relapsed/Refractory Non-Hodgkin's Lymphoma: Preclinical Findings and Results of a Phase I Trial Clin. Cancer Res., October 15, 2009; 15(20): 6462 - 6471. [Abstract] [Full Text] [PDF] A. Veldurthy, M. Patz, S. Hagist, C. P. Pallasch, C.-M. Wendtner, M. Hallek, and G. 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