Abstract |
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 38 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 weekly for 4 weeks every 6 weeks. 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.
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Authors | 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, Judith E Karp |
Journal | Blood
(Blood)
Vol. 109
Issue 7
Pg. 2781-90
(Apr 01 2007)
ISSN: 0006-4971 [Print] United States |
PMID | 17179232
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Benzamides
- Enzyme Inhibitors
- Histone Deacetylase Inhibitors
- Histones
- Neoplasm Proteins
- Pyridines
- entinostat
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Topics |
- Acetylation
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents
(administration & dosage, pharmacokinetics, therapeutic use)
- Benzamides
(administration & dosage, pharmacokinetics, therapeutic use)
- Enzyme Inhibitors
(administration & dosage, pharmacokinetics, therapeutic use)
- Female
- Histone Deacetylase Inhibitors
- Histones
(metabolism)
- Humans
- Leukemia
(drug therapy, metabolism)
- Male
- Middle Aged
- Neoplasm Proteins
(metabolism)
- Pyridines
(administration & dosage, pharmacokinetics, therapeutic use)
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