|
|
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.
Previous Article | Table of Contents | Next Article 
CLINICAL TRIALS AND OBSERVATIONS
Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias
Ivana Gojo1,
Anchalee Jiemjit2,
Jane B. Trepel3,
Alex Sparreboom3,
William D. Figg3,
Sandra Rollins1,
Michael L. Tidwell1,
Jacqueline Greer2,
Eun Joo Chung3,
Min-Jung Lee3,
Steven D. Gore2,
Edward A. Sausville1,
James Zwiebel3, and
Judith E. Karp2
1 University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD;
2 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD;
3 National Cancer Institute, Bethesda, MD
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.

CiteULike Connotea Del.icio.us Digg Reddit Technorati What's this?
This article has been cited by other articles:

|
 |

|
 |
 
A. A. Lane and B. A. Chabner
Histone Deacetylase Inhibitors in Cancer Therapy
J. Clin. Oncol.,
November 10, 2009;
27(32):
5459 - 5468.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
X. Huang, L. Gao, S. Wang, C.-K. Lee, P. Ordentlich, and B. Liu
HDAC Inhibitor SNDX-275 Induces Apoptosis in erbB2-Overexpressing Breast Cancer Cells via Down-regulation of erbB3 Expression
Cancer Res.,
November 1, 2009;
69(21):
8403 - 8411.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Q. Li, D. L. Bartlett, M. C. Gorry, M. E. O'Malley, and Z. S. Guo
Three Epigenetic Drugs Up-Regulate Homeobox Gene Rhox5 in Cancer Cells through Overlapping and Distinct Molecular Mechanisms
Mol. Pharmacol.,
November 1, 2009;
76(5):
1072 - 1081.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. E. Fandy, J. G. Herman, P. Kerns, A. Jiemjit, E. A. Sugar, S.-H. Choi, A. S. Yang, T. Aucott, T. Dauses, R. Odchimar-Reissig, et al.
Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies
Blood,
September 24, 2009;
114(13):
2764 - 2773.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. Stimson, V. Wood, O. Khan, S. Fotheringham, and N. B. La Thangue
HDAC inhibitor-based therapies and haematological malignancy
Ann. Onc.,
August 1, 2009;
20(8):
1293 - 1302.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. M. Prince, M. J. Bishton, and S. J. Harrison
Clinical Studies of Histone Deacetylase Inhibitors
Clin. Cancer Res.,
June 15, 2009;
15(12):
3958 - 3969.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. L. Piekarz and S. E. Bates
Epigenetic Modifiers: Basic Understanding and Clinical Development
Clin. Cancer Res.,
June 15, 2009;
15(12):
3918 - 3926.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. E. Witta, R. Dziadziuszko, K. Yoshida, K. Hedman, M. Varella-Garcia, P. A. Bunn Jr, and F. R. Hirsch
ErbB-3 expression is associated with E-cadherin and their coexpression restores response to gefitinib in non-small-cell lung cancer (NSCLC)
Ann. Onc.,
April 1, 2009;
20(4):
689 - 695.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
P. Munster, D. Marchion, E. Bicaku, M. Lacevic, J. Kim, B. Centeno, A. Daud, A. Neuger, S. Minton, and D. Sullivan
Clinical and Biological Effects of Valproic Acid as a Histone Deacetylase Inhibitor on Tumor and Surrogate Tissues: Phase I/II Trial of Valproic acid and Epirubicin/FEC
Clin. Cancer Res.,
April 1, 2009;
15(7):
2488 - 2496.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
O. M. Odenike, S. Alkan, D. Sher, J. E. Godwin, D. Huo, S. J. Brandt, M. Green, J. Xie, Y. Zhang, D. H. Vesole, et al.
Histone Deacetylase Inhibitor Romidepsin Has Differential Activity in Core Binding Factor Acute Myeloid Leukemia
Clin. Cancer Res.,
November 1, 2008;
14(21):
7095 - 7101.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. Laubach and A. V. Rao
Current and Emerging Strategies for the Management of Acute Myeloid Leukemia in the Elderly
Oncologist,
October 1, 2008;
13(10):
1097 - 1108.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y.-S. Lee, K.-H. Lim, X. Guo, Y. Kawaguchi, Y. Gao, T. Barrientos, P. Ordentlich, X.-F. Wang, C. M. Counter, and T.-P. Yao
The Cytoplasmic Deacetylase HDAC6 Is Required for Efficient Oncogenic Tumorigenesis
Cancer Res.,
September 15, 2008;
68(18):
7561 - 7569.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
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]
|
 |
|

|
 |

|
 |
 
S. Liu, H. Cheng, W. Kwan, J. M. Lubieniecka, and T. O. Nielsen
Histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in clear cell sarcoma models
Mol. Cancer Ther.,
June 1, 2008;
7(6):
1751 - 1761.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Bonfils, A. Kalita, M. Dubay, L. L. Siu, M. A. Carducci, G. Reid, R. E. Martell, J. M. Besterman, and Z. Li
Evaluation of the Pharmacodynamic Effects of MGCD0103 from Preclinical Models to Human Using a Novel HDAC Enzyme Assay
Clin. Cancer Res.,
June 1, 2008;
14(11):
3441 - 3449.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. M.W. Verheul, B. Salumbides, K. Van Erp, H. Hammers, D. Z. Qian, T. Sanni, P. Atadja, and R. Pili
Combination Strategy Targeting the Hypoxia Inducible Factor-1{alpha} with Mammalian Target of Rapamycin and Histone Deacetylase Inhibitors
Clin. Cancer Res.,
June 1, 2008;
14(11):
3589 - 3597.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Hadnagy, R. Beaulieu, and D. Balicki
Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics
Mol. Cancer Ther.,
April 1, 2008;
7(4):
740 - 748.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. Garcia-Manero, H. Yang, C. Bueso-Ramos, A. Ferrajoli, J. Cortes, W. G. Wierda, S. Faderl, C. Koller, G. Morris, G. Rosner, et al.
Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes
Blood,
February 1, 2008;
111(3):
1060 - 1066.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|
|