Decitabine: Difference between revisions

{{Short description|Medication for the treatment of conditions where certain blood cells are dysfunctional,}}

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| tradename = Dacogen, Demylocan

| DailyMedID = Decitabine

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

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| ATC_prefix = L01

| ATC_suffix = BC08

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| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Summary Basis of Decision (SBD) for Dacogen | website=[[Health Canada]] | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00452&lang=en | access-date=29 May 2022}}</ref><ref>{{cite web | title=Summary Basis of Decision (SBD) for Demylocan | website=[[Health Canada]] | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00436&lang=en | access-date=29 May 2022}}</ref>

| legal_US = Rx-only

| legal_US_comment =

| legal_EU = Rx-only

| legal_EU_comment = <ref>{{cite web | title=Dacogen EPAR | website=[[European Medicines Agency]] (EMA) | date=8 June 2006 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/dacogen | access-date=4 June 2024}}</ref>

| legal_status = Rx-only

| IUPHAR_ligand = 6805

| CAS_number_Ref = {{cascite|correct|??}}

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1201129

| synonyms = 5-aza-2'-deoxycytidine

| IUPAC_name = 4-Amino-1-(2-deoxy-β-<small>D</small>-erythro-pentofuranosyl)-1,3,5-triazin-2(1''H'')-one

| C=8 | H=12 | N=4 | O=4

'''Decitabine''' (i.e., '''5-aza-2′-deoxycytidine'''), sold under the brand name '''Dacogen''' among others, acts as a nucleic acid synthesis inhibitor.<ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/451668|title=Decitabine|website=National Center for Biotechnology Information|access-date=September 24, 2016}}</ref> It is a [[pharmaceutical drug|medication]] for the treatment of [[myelodysplastic syndromes]], a class of conditions where certain blood cells are dysfunctional, and for [[acute myeloid leukemia]] (AML).<ref name=EC-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}}</ref> Chemically, it is a [[cytidine]] [[analog (chemistry)|analog]].

==Medical uses==

Decitabine is used to treat [[myelodysplastic syndromes]] (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes ([[refractory anemia]], [[refractory anemia with ringed sideroblasts]], [[refractory anemia with excess blasts]], [[refractory anemia with excess blasts in transformation]], and [[chronic myelomonocytic leukemia]]) and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System groups. In patients with chronic kidney disease, Batty and colleagues reported the first case series on the feasibility of therapy with hypomethylating agents in patients with chronic kidney disease.<ref>{{cite journal | vauthors = Batty GN, Kantarjian H, Issa JP, Jabbour E, Santos FP, McCue D, Garcia-Manero G, Pierce S, O'Brien S, Cortés JE, Ravandi F | display-authors = 6 | title = Feasibility of therapy with hypomethylating agents in patients with renal insufficiency | journal = Clinical Lymphoma, Myeloma & Leukemia | volume = 10 | issue = 3 | pages = 205–210 | date = June 2010 | pmid = 20511166 | pmc = 3726276 | doi = 10.3816/CLML.2010.n.032 }}</ref>

It also has EU approval for [[acute myeloid leukemia]] (AML).<ref name=EC-AML/>

==Pharmacology==

{{refimprove section|date=December 2018}}

Decitabine is a [[hypomethylating agent]].<ref name="pmid16532500">{{cite journal | vauthors = Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R, Shen L, Nimer SD, Leavitt R, Raza A, Saba H | display-authors = 6 | title = Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study | journal = Cancer | volume = 106 | issue = 8 | pages = 1794–1803 | date = April 2006 | pmid = 16532500 | doi = 10.1002/cncr.21792 | s2cid = 9556660 | doi-access = free }}</ref><ref name="pmid12879469">{{cite journal | vauthors = Kantarjian HM, O'Brien S, Cortes J, Giles FJ, Faderl S, Issa JP, Garcia-Manero G, Rios MB, Shan J, Andreeff M, Keating M, Talpaz M | display-authors = 6 | title = Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia | journal = Cancer | volume = 98 | issue = 3 | pages = 522–528 | date = August 2003 | pmid = 12879469 | doi = 10.1002/cncr.11543 | s2cid = 1149318 | doi-access = free }}</ref> It hypomethylates DNA by inhibiting [[DNA methyltransferase]].

It functions in a similar manner to [[azacitidine]], although decitabine can only be incorporated into DNA strands while azacitidine can be incorporated into both DNA and RNA chains.

It incorporates into DNA strands upon replication, and then when DNA methyltransferases (DNMTs) such as DNMT1, are engaged to bind the DNA and to replicate the methylation to the daughter strand, DNMTs are bound to decitabine irreversibly and cannot disengage. Therefore, the action of decitabine is division-dependent, meaning the cells have to divide in order for the pharmaceutical to act.

Therefore, cancer cells which divide much more rapidly than most other cells in the body will be more severely affected by decitabine just because they replicate more. It seems that DNA hypermethylation is critical for development of cancer cells, and specifically for haematological malignancies. Methylation of CpG islands upstream of tumor suppressor genes in order to silence them seems to be critical for these type of cancers. Thus at optimal doses, decitabine blocks this type of methylation and has an anti-[[Neoplasm|neoplastic]] effect.

== Research ==

===Atherosclerosis===

A number of investigators have shown a relationship between [[atherosclerosis]] and disturbed blood flow. This upregulates DNA [[methyltransferase]] expression, which leads to genome-wide DNA methylation alterations and global gene expression changes. These studies have revealed several mechanosensitive genes, such as HoxA5, Klf3, and Klf4, whose promoters were hypermethylated by disturbed blood flow, but rescued by DNA methyltransferases inhibitors such as 5-aza-2'-deoxycytidine. It has been found that use of this DNA methyltranferase inhibitor prevents atherosclerosis lesion formation and reduces the production of inflammatory [[cytokine]]s by [[macrophages]].<ref>{{cite journal | vauthors = Dunn J, Thabet S, Jo H | title = Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 35 | issue = 7 | pages = 1562–1569 | date = July 2015 | pmid = 25953647 | pmc = 4754957 | doi = 10.1161/atvbaha.115.305042 }}</ref>

== References ==

== Further reading ==

* {{cite journal | vauthors = Moon C, Kim SH, Park KS, Choi BK, Lee HS, Park JB, Choi GS, Kwan JH, Joh JW, Kim SJ | display-authors = 6 | title = Use of epigenetic modification to induce FOXP3 expression in naïve T cells | journal = Transplantation Proceedings | volume = 41 | issue = 5 | pages = 1848–1854 | date = June 2009 | pmid = 19545742 | doi = 10.1016/j.transproceed.2009.02.101 }}

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