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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]

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]

Borodovsky, et al. describe the dramatic effect of 5-azacytidine on IDH1 mutant glioma xenografts in mice.^[6]

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 incorporates 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. Being a ribonucleoside, it has been shown effective against HIV ^[7] and HTLV.^[8]

Incorporation of azanucleosides (Azacitidine) into nucleic acids and DNA demethylation.

After azanucleosides (Azacitidine) have been metabolized to 5-aza-2′-deoxycytidine-triphosphate, they can become substrates for the DNA replication machinery and will be incorporated into DNA, where azacytosine can substitute for cytosine. Azacytosine-guanine dinucleotides are recognized by the DNA methyltransferases as natural substrate and the enzymes will initiate the methylation reaction by a nucleophilic attack. This results in the establishment of a covalent bond between the carbon-6 atom of the cytosine ring and the enzyme. The bond is normally resolved by beta-elimination through the carbon-5 atom, but the reaction is blocked with azacytosine, where carbon-5 is substituted by nitrogen. Thus, the enzyme remains covalently bound to DNA and its DNA methyltransferase function is blocked. In addition, the covalent protein adduction also compromises the functionality of DNA and triggers DNA damage signaling, resulting in the degradation of trapped DNA methyltransferases. As a consequence, methylation marks become lost during DNA replication.^[9]

References

^ Deglin, Judith, & Vallerand, April. (2009). Davis's drug guide for nurses. Philadelphia: F.A. Davis Company. pg. 204-206
^ Cihák A (1974). "Biological effects of 5-azacytidine in eukaryotes". Oncology 30 (5): 405–422. doi:10.1159/000224981. PMID 4142650.
^ Vidaza web site.
^ 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): 176–182. doi:10.1634/theoncologist.10-3-176. PMID 15793220.
^ 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.
^ Borodovsky, A, et al., "5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft", Oncotarget Advance Publications (2013)
^ 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1
^ Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations
^ Stresemann, C. and Lyko, F. (2008), Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer, 123: 8–13. doi:10.1002/ijc.23607.

External links

5-Aza-2'-Deoxycytidine information and protocols to study DNA methylation

UpToDate Contents

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1. 高齢者における急性骨髄性白血病の治療 treatment of acute myeloid leukemia in older adults
2. 中等度～低リスクまたは極めて低リスクの骨髄異形成症候群の治療 treatment of intermediate low or very low risk myelodysplastic syndromes
3. 高リスクまたは極めて高リスクの骨髄異形成症候群の治療 treatment of high or very high risk myelodysplastic syndromes
4. 鎌状赤血球症に対するヒドロキシ尿素治療または疾患修飾療法 hydroxyurea and other disease modifying therapies in sickle cell disease
5. 慢性骨髄単球性白血病 chronic myelomonocytic leukemia

English Journal

Hypermethylation of Wnt antagonist gene promoters and activation of Wnt pathway in myelodysplastic marrow cells.

Masala E, Valencia A, Buchi F, Nosi D, Spinelli E, Gozzini A, Sassolini F, Sanna A, Zecchi S, Bosi A, Santini V.SourceUF Ematologia, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy.
Leukemia research.Leuk Res.2012 Oct;36(10):1290-5. Epub 2012 Jun 27.
We observed aberrant gene methylation of Wnt antagonists: sFRP1, sFRP2, sFRP4, sFRP5 and DKK1 in marrow cells of 55 MDS cases. Methylation of Wnt antagonist genes was associated with activation of the Wnt signaling pathway, consistent with the up-regulation of the Wnt downstream genes TCF1 and LEF1.
PMID 22742816

Deferasirox treatment for myelodysplastic syndromes: "real-life" efficacy and safety in a single-institution patient population.

Breccia M, Finsinger P, Loglisci G, Federico V, Santopietro M, Colafigli G, Petrucci L, Salaroli A, Serrao A, Latagliata R, Alimena G.SourceDepartment of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy, breccia@bce.uniroma1.it.
Annals of hematology.Ann Hematol.2012 Sep;91(9):1345-9. Epub 2012 May 9.
We here describe a single-institution experience on 40 patients with myelodysplastic syndromes (MDS) consecutively treated with deferasirox at the dose of 10-30 mg/kg/day according to Consensus Guidelines on Iron Chelation Therapy, outside of clinical trials. Serum ferritin (SF) was measured monthl
PMID 22569854

Japanese Journal

Mechanisms of neurotoxicity induced in the developing brain of mice and rats by DNA-damaging chemicals

DOI Kunio
Journal of toxicological sciences 36(6), 695-712, 2011-12-01
… This paper reviews the mechanisms of neurotoxicity induced in the developing brain of mice and rats by six chemicals (ethylnitrosourea, hydroxyurea, 5-azacytidine, cytosine arabinoside, 6-mercaptopurine and etoposide), which cause DNA damage in different ways, especially from the viewpoints of apoptosis and cell cycle arrest in neural progenitor cells. …
NAID 10030036432

Synthesis of O[2]- and N[3]-(2-phosphonomethoxy)ethyl derivatives of 6-phenyl- and 6-pyridinyl-5-azacytosine

Otmar Miroslav,Dracinsky Martin,Krecmerova Marcela [他]
Heterocycles 83(4), 797-813, 2011-04-01
NAID 40018733653

Related Pictures

Changzhou ComWin Fine Chemicals Co.,Ltd. is a member of COMWIN INTERNATIONAL CO.,LTD. 5-Azacytidine | STEMCELL Technologies 5-Azacytidine - Arbor Assays - P012 - DNA Methyltransferase Inhibitor | Arbor Assays 5-Azacytidine | CAS# 320-67-2 | 1854 | BioVision, Inc. 5-Azacytidine products - China products exhibition,reviews - Hisupplier.com Intracellular methabolic pathways of azacitidine and decitabine. After | Download Comparison of structures of cytidine, 5-aza-2-deoxycytidine,

★リンクテーブル★

リンク元	「5-アザシチジン」「azacitidine」「azacytosine」
関連記事	「azacytidine」

「5-アザシチジン」

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.
Identifiers
CAS number	320-67-2
ATC code	L01BC07
PubChem	CID 9444
DrugBank	DB00928
ChemSpider	9072
UNII	M801H13NRU
KEGG	D03021
ChEBI	CHEBI:2038
ChEMBL	CHEMBL1489
Synonyms	5-azacytidine
Chemical data
Formula	C8H12N4O5
Mol. mass	244.205 g/mol
	SMILES O=C1/N=C(\N=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)CO)N;
	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 ; Key:NMUSYJAQQFHJEW-KVTDHHQDSA-N ;
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