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Blood, 1 December 2003, Vol. 102, No. 12, pp. 3865-3870. Prepublished online as a Blood First Edition Paper on August 7, 2003; DOI 10.1182/blood-2003-05-1738. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1738v1 102/12/3865    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 Saunthararajah, Y. Articles by DeSimone, J. Search for Related Content PubMed PubMed Citation Articles by Saunthararajah, Y. Articles by DeSimone, J. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Red Cells Plenary Papers Cell Adhesion and Motility Gene Expression Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLENARY PAPERS Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease Yogen Saunthararajah, Cheryl A. Hillery, Don Lavelle, Robert Molokie, Louise Dorn, Linda Bressler, Stefana Gavazova, Yi-Hsiang Chen, Ronald Hoffman, and Joseph DeSimone From the University of Illinois at Chicago (UIC); Medical College of Wisconsin, Milwaukee; The Blood Center of Southeastern Wisconsin, Milwaukee; and Veterans Administration Chicago Health Care System, IL. Fetal hemoglobin (HbF) decreases polymerization of sickle hemoglobin (HbS) and improves outcomes in sickle cell disease (SSD). Therefore, a therapeutic goal in SSD is pharmacologic reactivation of HbF. Silencing of the -globin (HbF) gene is associated with DNA methylation. The cytosine analog 5-aza-2'-deoxycytidine (decitabine) hypomethylates DNA by inhibiting DNA methyltransferase. We examined if subcutaneous decitabine could increase HbF levels and improve SSD pathophysiology without cytotoxicity. Eight symptomatic SSD patients resistant or intolerant of standard treatment with hydroxyurea received decitabine 0.2 mg/kg subcutaneously 1 to 3 times per week in 2 cycles of 6-week duration. Treatment decreased neutrophils and increased mean HbF (6.5% to 20.4%, P < .0001) and mean total hemoglobin (76 to 96 g/L [7.6 to 9.6 g/dL], P < .001). Features of vaso-occlusive crisis pathophysiology such as red cell adhesion, endothelial damage, and coagulation pathway activity significantly improved. -Globin gene promoter methylation decreased, and platelets and the proportion of megakaryocytes and erythroid cells in the marrow increased without a decrease in marrow cellularity, consistent with a DNA hypomethylating, noncytotoxic mechanism of action. Weekly subcutaneous decitabine produces cumulative increases in HbF and total hemoglobin through a noncytotoxic mechanism of action. Chronic dosing and sustained increases in hemoglobin F and total hemoglobin levels may be possible. Further studies in SSD and thalassemia are indicated. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Lavelle, Y. Saunthararajah, and J. DeSimone DNA methylation and mechanism of action of 5-azacytidine Blood, February 15, 2008; 111(4): 2485 - 2485. [Full Text] [PDF] K. Appleton, H. J. Mackay, I. Judson, J. A. Plumb, C. McCormick, G. Strathdee, C. Lee, S. Barrett, S. Reade, D. Jadayel, et al. Phase I and Pharmacodynamic Trial of the DNA Methyltransferase Inhibitor Decitabine and Carboplatin in Solid Tumors J. Clin. Oncol., October 10, 2007; 25(29): 4603 - 4609. [Abstract] [Full Text] [PDF] R. Mabaera, C. A. Richardson, K. Johnson, M. Hsu, S. Fiering, and C. H. Lowrey Developmental- and differentiation-specific patterns of human {gamma}- and {beta}-globin promoter DNA methylation Blood, August 15, 2007; 110(4): 1343 - 1352. [Abstract] [Full Text] [PDF] M. J. Telen Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease Hematology, January 1, 2007; 2007(1): 84 - 90. [Abstract] [Full Text] [PDF] K. I. Ataga and N. S. Key Hypercoagulability in Sickle Cell Disease: New Approaches to an Old Problem Hematology, January 1, 2007; 2007(1): 91 - 96. [Abstract] [Full Text] [PDF] J. A. Gollob, C. J. Sciambi, B. L. Peterson, T. Richmond, M. Thoreson, K. Moran, H. K. Dressman, J. Jelinek, and J.-P. J. Issa Phase I Trial of Sequential Low-Dose 5-Aza-2'-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma Clin. Cancer Res., August 1, 2006; 12(15): 4619 - 4627. [Abstract] [Full Text] [PDF] H. Fathallah and G. F. Atweh Induction of Fetal Hemoglobin in the Treatment of Sickle Cell Disease Hematology, January 1, 2006; 2006(1): 58 - 62. [Abstract] [Full Text] [PDF] K. Ghoshal, J. Datta, S. Majumder, S. Bai, H. Kutay, T. Motiwala, and S. T. Jacob 5-Aza-Deoxycytidine Induces Selective Degradation of DNA Methyltransferase 1 by a Proteasomal Pathway That Requires the KEN Box, Bromo-Adjacent Homology Domain, and Nuclear Localization Signal Mol. Cell. Biol., June 1, 2005; 25(11): 4727 - 4741. [Abstract] [Full Text] [PDF] M. H. Steinberg Sickle cell disease and hydroxyurea: the good, the bad, and the future Blood, January 15, 2005; 105(2): 441 - 441. [Full Text] [PDF] A. Pujol, I. Ferrer, C. Camps, E. Metzger, C. Hindelang, N. Callizot, M. Ruiz, T. Pampols, M. Giros, and J. L. Mandel Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy Hum. Mol. Genet., December 1, 2004; 13(23): 2997 - 3006. [Abstract] [Full Text] [PDF] G. R. Buchanan, M. R. DeBaun, C. T. Quinn, and M. H. Steinberg Sickle Cell Disease Hematology, January 1, 2004; 2004(1): 35 - 47. [Abstract] [Full Text] [PDF]

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