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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.
 Previous Article | Table of Contents | Next Article 
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
A phase 1 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
From the Department of Internal Medicine and Division of Hematology-Oncology, The Ohio State University, Columbus; the Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus; the College of Pharmacy, The Ohio State University, Columbus; the Division of Human Cancer Genetics, The Ohio State University, Columbus; the Department of Medicine and Division of Cardiology, The Ohio State University, Columbus; and the Cancer Therapy and Evaluation Program, National Cancer Institute, Washington, DC.
Preclinical 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 at which 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 patients with CLL and 10 patients with AML 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 antitumor 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.
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