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Blood, 1 February 2005, Vol. 105, No. 3, pp. 959-967. Prepublished online as a Blood First Edition Paper on October 5, 2004; DOI 10.1182/blood-2004-05-1693. This Article Full Text (PDF) All Versions of this Article: 2004-05-1693v1 105/3/959    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 Byrd, J. C Articles by Grever, M. R Search for Related Content PubMed PubMed Citation Articles by Byrd, J. C Articles by Grever, M. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 6, 2004 Accepted September 10, 2004 A phase I and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia John C Byrd*, Guido Marcucci, Mark R Parthun, Jim J Xiao, Rebecca B Klisovic, Mollie Moran, Thomas S Lin, Shujun Liu, Amy R Sklenar, Melanie E Davis, David M Lucas, Beth Fischer, Roshini Shank, Sooraj L Tejaswi, Philip Binkley, John Wright, Kenneth K Chan, and Michael R Grever Department of Internal Medicine and Division of Hematology-Oncology, The Ohio State University, Columbus, Ohio, USA; College of Pharmacy, The Ohio State University, Columbus, Ohio, USA Department of Internal Medicine and Division of Hematology-Oncology, The Ohio State University, Columbus, Ohio, USA; Division of Human Cancer Genetics, The Ohio State University, Columbus, Ohio, USA Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio, USA College of Pharmacy, The Ohio State University, Columbus, Ohio, USA Department of Internal Medicine and Division of Hematology-Oncology, The Ohio State University, Columbus, Ohio, USA Department of Medicine and Division of Cardiology, The Ohio State University, Columbus, Ohio, USA Cancer Therapy and Evaluation Program, National Cancer Institute, Washington, DC, USA * Corresponding author; email: byrd-3{at}medctr.osu.edu. Pre-clinical studies with the histone deacetylase (HDAC) inhibitor depsipeptide (FK228) in Chronic Lymphocytic Leukemia (CLL) and Acute Myeloid Leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations where HDAC inhibition occurs. We initiated a Minimum Effective Pharmacologic Dose study of depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten CLL and ten AML patients were treated with 13 mg/m2 depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of anti-tumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein and 1D10 antigen expression. We conclude that depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with depsipeptide should examine alternative administration schedules. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Garcia-Manero, S. Assouline, J. Cortes, Z. Estrov, H. Kantarjian, H. Yang, W. M. Newsome, W. H. Miller Jr, C. Rousseau, A. Kalita, et al. Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia Blood, August 15, 2008; 112(4): 981 - 989. [Abstract] [Full Text] [PDF] L. Gore, M. L. Rothenberg, C. L. O'Bryant, M. K. Schultz, A. B. Sandler, D. Coffin, C. McCoy, A. 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