Skip Navigation

JNCI Journal of the National Cancer Institute 2005 97(20):1498-1506; doi:10.1093/jnci/dji311
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (89)
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Lyko, F.
Right arrow Articles by Brown, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lyko, F.
Right arrow Articles by Brown, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2005 Oxford University Press

REVIEW

DNA Methyltransferase Inhibitors and the Development of Epigenetic Cancer Therapies

Frank Lyko, Robert Brown

Affiliations of authors: Division of Epigenetics, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld, Heidelberg, Germany (FL); Centre for Oncology and Applied Pharmacology, CRUK Beatson Labs, Glasgow University, Glasgow, UK (RB)

Correspondence to: Frank Lyko, PhD, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany (e-mail: f.lyko{at}dkfz.de).

Epimutations, such as the hypermethylation and epigenetic silencing of tumor suppressor genes, play a role in the etiology of human cancers. In contrast to DNA mutations, which are passively inherited through DNA replication, epimutations must be actively maintained because they are reversible. In fact, the reversibility of epimutations by small-molecule inhibitors provides the foundation for the use of such inhibitors in novel cancer therapy strategies. Among the compounds that inhibit epigenetic processes, the most extensively studied are DNA methyltransferase inhibitors. In this review, we examine the literature on DNA methyltransferase inhibitors and discuss the efficacy of such compounds as antitumor agents, as evaluated in phase I–III clinical trials. We also discuss future areas of research, including the development of nonnucleoside inhibitors, the application of novel bioanalytical tools for DNA methylation analysis (which will be important for the clinical application of these compounds by allowing rational approaches to trial design), the need to optimize treatment schedules for maximal biologic effectiveness, and the need to define molecular endpoints so that changes induced by demethylating drugs in patients can be monitored during treatment. Assays for genome-wide and tumor-specific DNA methylation also need to be further developed to establish the pharmacodynamic parameters of DNA methyltransferase inhibitors in patients and to provide rational approaches to maximizing the therapeutic efficacy of these compounds.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 JCOHome page
V. Pistoia, C. Cocco, and I. Airoldi
Interleukin-12 Receptor {beta}2: From Cytokine Receptor to Gatekeeper Gene in Human B-Cell Malignancies
J. Clin. Oncol., October 1, 2009; 27(28): 4809 - 4816.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
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]

Home page
 EndocrinologyHome page
C. Balch, F. Fang, D. E. Matei, T. H.-M. Huang, and K. P. Nephew
Minireview: Epigenetic Changes in Ovarian Cancer
Endocrinology, September 1, 2009; 150(9): 4003 - 4011.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
K. E. Varley, D. G. Mutch, T. B. Edmonston, P. J. Goodfellow, and R. D. Mitra
Intra-tumor heterogeneity of MLH1 promoter methylation revealed by deep single molecule bisulfite sequencing
Nucleic Acids Res., August 1, 2009; 37(14): 4603 - 4612.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
Z. Liu, S. Liu, Z. Xie, R. E. Pavlovicz, J. Wu, P. Chen, J. Aimiuwu, J. Pang, D. Bhasin, P. Neviani, et al.
Modulation of DNA Methylation by a Sesquiterpene Lactone Parthenolide
J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 505 - 514.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
R. Plummer, L. Vidal, M. Griffin, M. Lesley, J. de Bono, S. Coulthard, J. Sludden, L. L. Siu, E. X. Chen, A. M. Oza, et al.
Phase I Study of MG98, an Oligonucleotide Antisense Inhibitor of Human DNA Methyltransferase 1, Given as a 7-Day Infusion in Patients with Advanced Solid Tumors
Clin. Cancer Res., May 1, 2009; 15(9): 3177 - 3183.
[Abstract] [Full Text] [PDF]

Home page
 aacredbookHome page
K. P. Nephew
In vivo Epigenetic Modulation after DNA Hypomethylation Therapy
Am. Assoc. Cancer Res. Educ. Book, April 18, 2009; 2009(1): 227 - 232.
[Full Text] [PDF]

Home page
 BloodHome page
T. Qin, J. Jelinek, J. Si, J. Shu, and J.-P. J. Issa
Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines
Blood, January 15, 2009; 113(3): 659 - 667.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
G. Lal, N. Zhang, W. van der Touw, Y. Ding, W. Ju, E. P. Bottinger, St. P. Reid, D. E. Levy, and J. S. Bromberg
Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells by DNA Methylation
J. Immunol., January 1, 2009; 182(1): 259 - 273.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
S. P. Garrison, J. R. Jeffers, C. Yang, J. A. Nilsson, M. A. Hall, J. E. Rehg, W. Yue, J. Yu, L. Zhang, M. Onciu, et al.
Selection against PUMA Gene Expression in Myc-Driven B-Cell Lymphomagenesis
Mol. Cell. Biol., September 1, 2008; 28(17): 5391 - 5402.
[Abstract] [Full Text] [PDF]

Home page
 Molecular Cancer TherapeuticsHome page
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]

Home page
 Phil Trans R Soc BHome page
N. D Allen
Temporal and epigenetic regulation of neurodevelopmental plasticity
Phil Trans R Soc B, January 12, 2008; 363(1489): 23 - 38.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
K. Appleton, H. J. Mackay, I. Judson, J. A. Plumb, C. McCormick, G. Strathdee, C. Lee, S. Barrett, S. Reade, D. Jadayel, et al.
Phase I and Pharmacodynamic Trial of the DNA Methyltransferase Inhibitor Decitabine and Carboplatin in Solid Tumors
J. Clin. Oncol., October 10, 2007; 25(29): 4603 - 4609.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
R Brown and R Glasspool
Epigenetic modulation of resistance to chemotherapy?
Ann. Onc., September 1, 2007; 18(9): 1429 - 1430.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. Filomeni, G. Cerchiaro, A. M. Da Costa Ferreira, A. De Martino, J. Z. Pedersen, G. Rotilio, and M. R. Ciriolo
Pro-apoptotic Activity of Novel Isatin-Schiff Base Copper(II) Complexes Depends on Oxidative Stress Induction and Organelle-selective Damage
J. Biol. Chem., April 20, 2007; 282(16): 12010 - 12021.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Ghochikyan, M. Mkrtichyan, D. Loukinov, G. Mamikonyan, S. D. Pack, N. Movsesyan, T. E. Ichim, D. H. Cribbs, V. V. Lobanenkov, and M. G. Agadjanyan
Elicitation of T Cell Responses to Histologically Unrelated Tumors by Immunization with the Novel Cancer-Testis Antigen, Brother of the Regulator of Imprinted Sites
J. Immunol., January 1, 2007; 178(1): 566 - 573.
[Abstract] [Full Text] [PDF]

Home page
 GutHome page
J J L Wong, N J Hawkins, and R L Ward
Colorectal cancer: a model for epigenetic tumorigenesis
Gut, January 1, 2007; 56(1): 140 - 148.
[Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
D. Iliopoulos, M. Fabbri, T. Druck, H. R. Qin, S.-Y. Han, and K. Huebner
Inhibition of Breast Cancer Cell Growth In vitro and In vivo: Effect of Restoration of Wwox Expression
Clin. Cancer Res., January 1, 2007; 13(1): 268 - 274.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
J. H. Beumer, J. L. Eiseman, R. A. Parise, E. Joseph, J. L. Holleran, J. M. Covey, and M. J. Egorin
Pharmacokinetics, Metabolism, and Oral Bioavailability of the DNA Methyltransferase Inhibitor 5-Fluoro-2'-Deoxycytidine in Mice
Clin. Cancer Res., December 15, 2006; 12(24): 7483 - 7491.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
J.M. Ordway, J.A. Bedell, R.W. Citek, A. Nunberg, A. Garrido, R. Kendall, J.R. Stevens, D. Cao, R.W. Doerge, Y. Korshunova, et al.
Comprehensive DNA methylation profiling in a human cancer genome identifies novel epigenetic targets
Carcinogenesis, December 1, 2006; 27(12): 2409 - 2423.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
D. S. Schrump, M. R. Fischette, D. M. Nguyen, M. Zhao, X. Li, T. F. Kunst, A. Hancox, J. A. Hong, G. A. Chen, V. Pishchik, et al.
Phase I Study of Decitabine-Mediated Gene Expression in Patients with Cancers Involving the Lungs, Esophagus, or Pleura.
Clin. Cancer Res., October 1, 2006; 12(19): 5777 - 5785.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
C. Stresemann, B. Brueckner, T. Musch, H. Stopper, and F. Lyko
Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines.
Cancer Res., March 1, 2006; 66(5): 2794 - 2800.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
S. Xi, K. F. Dyer, M. Kimak, Q. Zhang, W. E. Gooding, J. R. Chaillet, R. L. Chai, R. E. Ferrell, B. Zamboni, J. Hunt, et al.
Decreased STAT1 Expression by Promoter Methylation in Squamous Cell Carcinogenesis
J Natl Cancer Inst, February 1, 2006; 98(3): 181 - 189.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.