| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; 2 James Cancer Center of Ohio State University, Columbus, Ohio; 3 Medizinische Klinik IV, Universitaetsklinikum Aachen, Rheinisch-Westfaelische Technische Hochschule Aachen, Aachen, Germany; and 4 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland
Requests for reprints: Steven D. Gore, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, Baltimore, MD 21287. Phone: 410-955-8781; Fax: 410-614-1005; E-mail: gorest{at}jhmi.edu.
Optimal reexpression of most genes silenced through promoter methylation requires the sequential application of DNA methyltransferase inhibitors followed by histone deacetylase inhibitors in tumor cell cultures. Patients with myelodysplastic syndrome or acute myeloid leukemia (AML) were treated with the methyltransferase inhibitor 5-azacitidine (aza-CR) followed by the histone deacetylase inhibitor sodium phenylbutyrate. Major responses associated with cytogenetic complete response developed in patients receiving prolonged dosing schedules of aza-CR. Bisulfite sequencing of the p15 promoter in marrow DNA during the first cycle of treatment showed heterogeneous allelic demethylation in three responding patients, suggesting ongoing demethylation within the tumor clone, but no demethylation in two nonresponders. Six of six responding patients with pretreatment methylation of p15 or CDH-1 promoters reversed methylation during the first cycle of therapy (methylation-specific PCR), whereas none of six nonresponders showed any demethylation. Gene demethylation correlated with the area under the aza-CR plasma concentration-time curve. Administration of both drugs was associated with induction of acetylation of histones H3 and H4. This study provides the first demonstration that molecular mechanisms responsible for responses to DNA methyltransferase/histone deacetylase inhibitor combinations may include reversal of aberrant epigenetic gene silencing. The promising percentage of major hematologic responses justifies the testing of such combinations in prospective randomized trials. (Cancer Res 2006; 66(12): 6361-9)
This article has been cited by other articles:
|
|
 |
|
  C. Stresemann, I. Bokelmann, U. Mahlknecht, and F. Lyko Azacytidine causes complex DNA methylation responses in myeloid leukemia Mol. Cancer Ther., September 1, 2008; 7(9): 2998 - 3005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. P. Vaughan and J. E. Karp The Long Road to a Cure for Acute Myelocytic Leukemia: From Intensity to Specificity J. Clin. Oncol., July 20, 2008; 26(21): 3475 - 3477. [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]
|
|
|
|
 |
|
 S. D. Nimer Myelodysplastic syndromes Blood, May 15, 2008; 111(10): 4841 - 4851. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-P. J Issa DNA Methylation as a Therapeutic Target in Cancer Am. Assoc. Cancer Res. Educ. Book, April 12, 2008; 2008(1): 643 - 649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Klimek, S. Fircanis, P. Maslak, I. Guernah, M. Baum, N. Wu, K. Panageas, J. J. Wright, P. P. Pandolfi, and S. D. Nimer Tolerability, Pharmacodynamics, and Pharmacokinetics Studies of Depsipeptide (Romidepsin) in Patients with Acute Myelogenous Leukemia or Advanced Myelodysplastic Syndromes Clin. Cancer Res., February 1, 2008; 14(3): 826 - 832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Palii, B. O. Van Emburgh, U. T. Sankpal, K. D. Brown, and K. D. Robertson DNA Methylation Inhibitor 5-Aza-2'-Deoxycytidine Induces Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by DNA Methyltransferases 1 and 3B Mol. Cell. Biol., January 15, 2008; 28(2): 752 - 771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. R. Fantin and V. M. Richon Mechanisms of Resistance to Histone Deacetylase Inhibitors and Their Therapeutic Implications Clin. Cancer Res., December 15, 2007; 13(24): 7237 - 7242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. O. Soriano, H. Yang, S. Faderl, Z. Estrov, F. Giles, F. Ravandi, J. Cortes, W. G. Wierda, S. Ouzounian, A. Quezada, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome Blood, October 1, 2007; 110(7): 2302 - 2308. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Blum, R. B. Klisovic, B. Hackanson, Z. Liu, S. Liu, H. Devine, T. Vukosavljevic, L. Huynh, G. Lozanski, C. Kefauver, et al. Phase I Study of Decitabine Alone or in Combination With Valproic Acid in Acute Myeloid Leukemia J. Clin. Oncol., September 1, 2007; 25(25): 3884 - 3891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Napieralski, K. Ott, M. Kremer, K. Becker, A.-L. Boulesteix, F. Lordick, J. R. Siewert, H. Hofler, and G. Keller Methylation of Tumor-Related Genes in Neoadjuvant-Treated Gastric Cancer: Relation to Therapy Response and Clinicopathologic and Molecular Features Clin. Cancer Res., September 1, 2007; 13(17): 5095 - 5102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Shi, Y. Zhao, T. Ishii, W. Hu, S. Sozer, W. Zhang, E. Bruno, V. Lindgren, M. Xu, and R. Hoffman Effects of Chromatin-Modifying Agents on CD34+ Cells from Patients with Idiopathic Myelofibrosis Cancer Res., July 1, 2007; 67(13): 6417 - 6424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Merimi, P. Klener, M. Szynal, Y. Cleuter, P. Kerkhofs, A. Burny, P. Martiat, and A. Van den Broeke Suppression of Viral Gene Expression in Bovine Leukemia Virus-Associated B-Cell Malignancy: Interplay of Epigenetic Modifications Leading to Chromatin with a Repressive Histone Code J. Virol., June 1, 2007; 81(11): 5929 - 5939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Carraway and S. D. Gore Addition of Histone Deacetylase Inhibitors in Combination Therapy J. Clin. Oncol., May 20, 2007; 25(15): 1955 - 1956. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Huang, E. Greene, T. Murray Stewart, A. C. Goodwin, S. B. Baylin, P. M. Woster, and R. A. Casero Jr Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes PNAS, May 8, 2007; 104(19): 8023 - 8028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. J. Issa DNA Methylation as a Therapeutic Target in Cancer Clin. Cancer Res., March 15, 2007; 13(6): 1634 - 1637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Garcia-Manero Modifying the Epigenome as a Therapeutic Strategy in Myelodysplasia Hematology, January 1, 2007; 2007(1): 405 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Ting, K. M. McGarvey, and S. B. Baylin The cancer epigenome--components and functional correlates Genes & Dev., December 1, 2006; 20(23): 3215 - 3231. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
