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Azacitidine

 

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
MedlinePlus
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  YesY
ATC code L01
PubChem
DrugBank
ChemSpider  YesY
UNII  YesY
KEGG  YesY
ChEBI  YesY
ChEMBL  YesY
Synonyms 5-azacytidine
Chemical data
Formula C8H12N4O5 
Mol. mass 244.205 g/mol
 YesY   

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]

Contents

  • Uses 1
  • Mechanism of action 2
  • Incorporation of azanucleosides (Azacitidine) into nucleic acids and DNA demethylation. 3
  • See also 4
  • References 5
  • External links 6

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]

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): 405–422.  
  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): 176–182.  
  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.
  6. ^ 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)
  7. ^ 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1
  8. ^ Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations
  9. ^ 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
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