Azacitidine

Azacitidine

Systematic (IUPAC) name
4-amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
Clinical data
Trade names	Vidaza
AHFS/Drugs.com	monograph
MedlinePlus	a607068
Pregnancy cat.	D (US), X (Aus)
Legal status	?
Routes	SubQ, IV
Pharmacokinetic data
Metabolism	possible hepatic metabolism, mostly urinary excretion
Half-life	4 hr. [1]
Identifiers
CAS number	320-67-2 Y
ATC code	L01BC07
PubChem	CID 9444
DrugBank	DB00928
ChemSpider	9072 Y
UNII	M801H13NRU Y
KEGG	D03021 Y
ChEBI	CHEBI:2038 Y
ChEMBL	CHEMBL1489 Y
Synonyms	5-azacytidine
Chemical data
Formula	C8H12N4O5
Mol. mass	244.205 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C8H12N4O5/c9-7-10-2-12(8(16)11-7)6-5(15)4(14)3(1-13)17-6/h2-6,13-15H,1H2,(H2,9,11,16)/t3-,4-,5-,6-/m1/s1 Y Key:NMUSYJAQQFHJEW-KVTDHHQDSA-N Y
Y (what is this?)  (verify)

Azacitidine (INN) or 5-azacytidine, sold under the trade name Vidaza, is a chemical analogue of cytidine, a nucleoside present in DNA and RNA. Azacitidine and its deoxy derivative, decitabine (also known as 5-aza-2′deoxycytidine), are used in the treatment of myelodysplastic syndrome. Both drugs were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.^[2]

Azacitidine has also been used as an experimental treatment in clinical trials involving cases of acute myeloid leukemia, where the patient has suffered more than one relapse- in these cases, standard chemotherapy, hematopoietic stem cell transplantation, and other mainline treatments have failed.

Uses

Azacitidine is mainly used in the treatment of myelodysplastic syndrome (MDS), for which it received approval by the U.S. Food and Drug Administration on May 19, 2004; it is marketed as Vidaza.^[3] In a randomized controlled trial comparing azacitidine to supportive treatment of MDS, around 16% of people receiving the drug had a complete or partial response—blood cell counts and bone marrow morphology returning to normal—and 2/3 patients who required blood transfusions before the study no longer needed them after receiving azacitidine.^[4]

It can also be used in vitro to remove methyl groups from DNA. This may weaken the effects of gene silencing mechanisms that occurred prior to the methylation. Methylation events are therefore believed to secure the DNA in a silenced state. Demethylation may reduce the stability of silencing signals and thus confer relative gene activation.^[5]

Mechanism of action

Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside used in DNA and RNA. Azacitidine is thought to induce antineoplastic activity via two mechanisms; inhibition of DNA methyltransferase at low doses, causing hypomethylation of DNA, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA at high doses, resulting in cell death. As azacitidine is a ribonucleoside, it incoporates into RNA to a larger extent than into DNA. The incorporation into RNA leads to the dissembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of protein. Its incorporation into DNA leads to a covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequent cytotoxicity.

See also

• DNA methylation, the phenomenon that azacitidine is known to interfere with

References

1. ^ Deglin, Judith, & Vallerand, April. (2009). Davis's drug guide for nurses. Philadelphia: F.A. Davis Company. pg. 204-206
2. ^ Cihák A (1974). "Biological effects of 5-azacytidine in eukaryotes". Oncology 30 (5): 405–22. doi:10.1159/000224981. PMID 4142650. 
3. ^ Vidaza web site.
4. ^ Kaminskas E, Farrell AT, Wang Y-C, Sridhara R, Pazdur R (2005). "FDA Drug Approval Summary: Azacitidine (5-azacytidine, Vidaza) for Injectable Suspension". The Oncologist 10 (3): 176–82. doi:10.1634/theoncologist.10-3-176. PMID 15793220. 
5. ^ Whitelaw E and Garrick D (2005), The Epigenome, Chapter 7, In: Mammalian Genomics, Ed: Ruvinsky A & Marshall Graves JA, CABI Publishing, Wallingford, UK, ISBN 0-85199-910-7.

External links

• Vidaza / Azacitidine Virtual Cancer Centre
• 5-Aza-2'-Deoxycytidine information and protocols to study DNA methylation

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