Hypomethylating agent
{{Short description|Drug type for epigenetic therapy}}
A hypomethylating agent (or demethylating agent{{cite journal |author=Garcia-Manero G |title=Demethylating agents in myeloid malignancies |journal=Curr Opin Oncol |volume=20 |issue=6 |pages=705–10 |date=November 2008 |pmid=18841054 |pmc=3873866 |doi=10.1097/CCO.0b013e328313699c }}) 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.{{cite journal |vauthors=Hambach L, Ling KW, Pool J, etal |title=Hypomethylating drugs convert HA-1 negative solid tumors into targets for stem cell based immunotherapy |journal=Blood |volume=113 |issue=12 |pages=2715–22 |date=December 2008 |pmid=19096014 |doi=10.1182/blood-2008-05-158956 |doi-access=free }}
Clinical use
Two hypomethylating agents are approved for the treatment of myelodysplastic syndrome by the United States FDA{{cite web |url=http://www.cancer.gov/about-cancer/treatment/drugs/azacitidine |title=Azacitadine - National Cancer Institute |date=September 17, 2014 |website=NCI}}{{cite web |url=http://www.cancer.gov/about-cancer/treatment/drugs/decitabine |title=Decitabine - National Cancer Institute |date=May 19, 2011 |website=NCI}}
- decitabine{{cite journal |vauthors=Aribi A, Borthakur G, Ravandi F, etal |title=Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia |journal=Cancer |volume=109 |issue=4 |pages=713–7 |date=February 2007 |pmid=17219444 |doi=10.1002/cncr.22457|doi-access=free }}{{cite journal |vauthors=De Padua Silva L, de Lima M, Kantarjian H, etal |title=Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome |journal=Bone Marrow Transplant. |volume= 43|issue= 11|pages= 839–43|date=January 2009 |pmid=19151791 |doi=10.1038/bmt.2008.400|doi-access= }} Also has EU approval for acute myeloid leukemia (AML).{{cite news|title=EC Approves Marketing Authorization Of DACOGEN For Acute Myeloid Leukemia|url=http://www.rttnews.com/1973982/ec-approves-marketing-authorization-of-dacogen-for-acute-myeloid-leukemia.aspx?type=qf|access-date=28 September 2012|date=2012-09-28}}
- azacitidine{{cite journal |vauthors=Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S |title=A pilot pharmacokinetic study of oral azacitidine |journal=Leukemia |volume=22 |issue=9 |pages=1680–4 |date=September 2008 |pmid=18548103 |doi=10.1038/leu.2008.145|doi-access= }}
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.{{cite journal|pmid=14627790|year=2003|last1=Herman|first1=J. G.|title=Gene silencing in cancer in association with promoter hypermethylation|journal=New England Journal of Medicine|volume=349|issue=21|pages=2042–54|last2=Baylin|first2=S. B.|doi=10.1056/NEJMra023075}}
See also
References
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{{Intracellular chemotherapeutic agents}}
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