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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2781-2790. Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-05-021873. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-021873v1 109/7/2781    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gojo, I. Articles by Karp, J. E Search for Related Content PubMed PubMed Citation Articles by Gojo, I. Articles by Karp, J. E Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 9, 2006 Accepted November 1, 2006 Phase 1 and pharmacological study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias Ivana Gojo*, Anchalee Jiemjit, Jane B Trepel, Alex Sparreboom, William D Figg, Sandra Rollins, Michael L Tidwell, Jacqueline Greer, Eun Joo Chung, Min-Jung Lee, Steven D Gore, Edward A Sausville, James Zwiebel, and Judith E Karp University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD National Cancer Institute, Bethesda, MD * Corresponding author; email: igojo{at}umm.edu. MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 39 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly x 2, repeated every 4 weeks from 4 to 8 mg/m2, and after 13 patients were treated, once weekly x 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum tolerated dose was 8 mg/m2 at weekly x 4 every 6 weeks schedule. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested preferably in patients with less advanced disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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