Hypomethylating agent

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A hypomethylating agent (or demethylating agent[1]) is a drug that inhibits DNA methylation: the modification of DNA nucleotides by addition of a methyl group. Because DNA methylation affects cellular function through successive generations of cells without changing the underlying DNA sequence, treatment with a hypomethylating agent is considered a type of epigenetic therapy.

Currently available hypomethylating agents block the activity of DNA methyltransferase (DNA methyltransferase inhibitors / DNMT inhibitors). Currently two members of the class, azacitidine and decitabine, are FDA-approved for use in the United States in myelodysplastic syndrome and are being investigated for use in a number of tumors.[2]

Clinical use

Two hypomethylating agents are approved for the treatment of myelodysplastic syndrome by the United States FDA[3][4]

Mechanism of action

DNA methylation is the modification of DNA nucleotides by addition of a methyl group. These methyl groups are associated with changes in the ability of the corresponding DNA to be used. Patterns of DNA methylation are stable during cellular division. Methylation of tumor suppressor genes in some cancers contributes to the growth and survival of the cancer. Hypomethylating agents decrease the amount of cellular DNA methylation, allowing for tumor suppressor gene expression.[9]

See also


  1. ^ Garcia-Manero G (November 2008). "Demethylating agents in myeloid malignancies". Curr Opin Oncol. 20 (6): 705–10. doi:10.1097/CCO.0b013e328313699c. PMC 3873866. PMID 18841054.
  2. ^ Hambach L, Ling KW, Pool J, et al. (December 2008). "Hypomethylating drugs convert HA-1 negative solid tumors into targets for stem cell based immunotherapy". Blood. 113 (12): 2715–22. doi:10.1182/blood-2008-05-158956. PMID 19096014. Archived from the original on 2013-04-14.
  3. ^ "Azacitadine - National Cancer Institute". NCI. September 17, 2014.
  4. ^ "Decitabine - National Cancer Institute". NCI. May 19, 2011.
  5. ^ Aribi A, Borthakur G, Ravandi F, et al. (February 2007). "Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia". Cancer. 109 (4): 713–7. doi:10.1002/cncr.22457. PMID 17219444.
  6. ^ De Padua Silva L, de Lima M, Kantarjian H, et al. (January 2009). "Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome". Bone Marrow Transplant. 43 (11): 839–43. doi:10.1038/bmt.2008.400. PMID 19151791.
  7. ^ "EC Approves Marketing Authorization Of DACOGEN For Acute Myeloid Leukemia". 2012-09-28. Retrieved 28 September 2012.
  8. ^ Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S (September 2008). "A pilot pharmacokinetic study of oral azacitidine". Leukemia. 22 (9): 1680–4. doi:10.1038/leu.2008.145. PMID 18548103.
  9. ^ Herman, J. G.; Baylin, S. B. (2003). "Gene silencing in cancer in association with promoter hypermethylation". New England Journal of Medicine. 349 (21): 2042–54. doi:10.1056/NEJMra023075. PMID 14627790.