Azacitidine
|
| Systematic (IUPAC) name |
|
4-Amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
|
| Clinical data |
| Trade names |
Vidaza, Azadine |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a607068 |
Pregnancy
category |
|
| Legal status |
|
Routes of
administration |
SubQ, IV |
| Pharmacokinetic data |
| Metabolism |
possible hepatic metabolism, mostly urinary excretion |
| Biological half-life |
4 hr.[1] |
| Identifiers |
| CAS Number |
320-67-2 Y |
| ATC code |
L01BC07 |
| PubChem |
CID: 9444 |
| IUPHAR/BPS |
6796 |
| DrugBank |
DB00928 Y |
| ChemSpider |
9072 Y |
| UNII |
M801H13NRU Y |
| KEGG |
D03021 Y |
| ChEBI |
CHEBI:2038 Y |
| ChEMBL |
CHEMBL1489 Y |
| Synonyms |
5-azacytidine |
| Chemical data |
| Formula |
C8H12N4O5 |
| Molecular 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 Y
-
Key:NMUSYJAQQFHJEW-KVTDHHQDSA-N Y
|
| (verify) |
Azacitidine (INN; 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
- 1 Uses
- 2 Mechanism of action
- 3 Incorporation of azanucleosides into nucleic acids and DNA demethylation.
- 4 See also
- 5 References
- 6 External links
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]
Azacitidine induces tumor regression on IDH1 mutant glioma xenografts in mice.[6]
In research, 5-azacytidine is commonly used for promoting cardiomyocyte differentiation of adult stem cells, however it is suggested that this drug has a compromised efficacy as a cardiac differentiation factor as it promotes the transdifferentiation of cardiac cells to skeletal myocytes. [7]
Mechanism of action
The mechanism of action of azacitidine is not yet fully understood. Azacitidine 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[8] and HTLV.[9]
Incorporation of azanucleosides into nucleic acids and DNA demethylation.
After azanucleosides such as 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.[10]
See also
- DNA methylation, the phenomenon that azacitidine is known to interfere with
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; Farrell; Wang; Sridhara; Pazdur (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)
- ^ kaur, keerat (2014). "5-azacytidine promotes the transdifferentiation of cardiac cells to skeletal myocytes." (PDF). cellular reprogramming 16: 324–30. doi:10.1089/cell.2014.0021. PMID 25090621.
- ^ Dapp, M. J.; Clouser, C. L.; Patterson, S; Mansky, L. M. (2009). "5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1". Journal of Virology 83 (22): 11950–8. doi:10.1128/JVI.01406-09. PMC 2772699. PMID 19726509.
- ^ Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations
- ^ Stresemann, C.; Lyko, F. (2008). "Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine". Int. J. Cancer 123 (1): 8–13. doi:10.1002/ijc.23607. PMID 18425818.
External links
- 5-Aza-2'-Deoxycytidine information and protocols to study DNA methylation
