Decitabine

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Decitabine
Decitabine.svg
Clinical data
Trade namesDacogen
AHFS/Drugs.comMonograph
MedlinePlusa608009
License data
Pregnancy
category
  • D
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding<1%
Elimination half-life30 minutes
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.017.355 Edit this at Wikidata
Chemical and physical data
FormulaC8H12N4O4
Molar mass228.206 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Decitabine (trade name Dacogen), or 5-aza-2'-deoxycytidine, acts as an Nucleic Acid Synthesis Inhibitor.[1] It is a drug for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML).[2] Chemically, it is a cytidine analog.

Medical use[edit]

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 renal insufficiency, Batty and colleagues reported the first case series on the feasibility of therapy with hypomethylating agents in patients with renal insufficiency.[3]

It also has EU approval for acute myeloid leukemia (AML).[2]

Pharmacology[edit]

Decitabine is a hypomethylating agent.[4][5] 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-dependant, 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. In cancer cells, and more specifically in haematological malignancies, it seems that DNA hypermethylation is really critical for their development. 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 is blocking this type of methylation and has an anti-neoplastic effect.

Research – atherosclerosis[edit]

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 cytokines by macrophages.[6]

References[edit]

  1. ^ "Decitabine". National Center for Biotechnology Information. Retrieved September 24, 2016.
  2. ^ a b "EC Approves Marketing Authorization Of DACOGEN For Acute Myeloid Leukemia". 2012-09-28. Retrieved 28 September 2012.
  3. ^ Ravandi, F.; Kantarjian, J. E.; Issa, S.; Jabbour, S.; Santos, G.; McCue, D.; Garcia-Manero, F. P. S.; Pierce, E.; O'Brien, J. P.; Cortés, J. E.; Ravandi, F. (2010). "Feasibility of Therapy with Hypomethylating Agents in Patients with Renal Insufficiency". Clinical Lymphoma, Myeloma & Leukemia. 10 (3): 205–210. doi:10.3816/CLML.2010.n.032. PMC 3726276. PMID 20511166.
  4. ^ Kantarjian H, Issa JP, Rosenfeld CS, et al. (April 2006). "Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study". Cancer. 106 (8): 1794–1803. doi:10.1002/cncr.21792. PMID 16532500.
  5. ^ Kantarjian HM, O'Brien S, Cortes J, et al. (August 2003). "Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia". Cancer. 98 (3): 522–528. doi:10.1002/cncr.11543. PMID 12879469.
  6. ^ Dunn, J; Thabet, S; Jo, H (July 2015). "Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 35 (7): 1562–9. doi:10.1161/atvbaha.115.305042. PMC 4754957. PMID 25953647.

Further reading[edit]

External links[edit]