DT-Web

DB00928 - Azacitidine


Identification
Name Azacitidine
Accession Number DB00928 (APRD00809)
Type small molecule
Description A pyrimidine nucleoside analogue that inhibits DNA methyltransferase, impairing DNA methylation. It is also an antimetabolite of cytidine, incorporated primarily into RNA. Azacytidine has been used as an antineoplastic agent. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 244.2047
Groups approved
Monoisotopic Weight 244.080769514
Pharmacology
Indication For treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (now classified as acute myelogenous leukemia with multilineage dysplasia), and chronic myelomonocytic leukemia.
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.
Absorption Azacitidine is rapidly absorbed after subcutaneous administration. The bioavailability of subcutaneous azacitidine relative to IV azacitidine is approximately 89%, based on area under the curve.
Protein binding Not Available
Biotransformation An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. The potential of azacitidine to inhibit cytochrome P450 (CYP) enzymes is not known.
Route of elimination Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over three days. Mean excretion of radioactivity in urine following SC administration of 14C-azacitidine was 50%.
Toxicity One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea, nausea, and vomiting after receiving a single IV dose of approximately 290 mg/m2, almost 4 times the recommended starting dose.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available

Targets


DNA (cytosine-5)-methyltransferase 1
Name DNA (cytosine-5)-methyltransferase 1
Gene Name DNMT1
Pharmacological action yes
Actions inhibitor
References
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
  • Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. - Pubmed
  • Cataldo VD, Cortes J, Quintas-Cardama A: Azacitidine for the treatment of myelodysplastic syndrome. Expert Rev Anticancer Ther. 2009 Jul;9(7):875-84. - Pubmed
  • Leone G, Voso MT, Teofili L, Lubbert M: Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS. Clin Immunol. 2003 Oct;109(1):89-102. - Pubmed
  • Ghoshal K, Bai S: DNA methyltransferases as targets for cancer therapy. Drugs Today (Barc). 2007 Jun;43(6):395-422. - Pubmed
  • Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15;20(10):2429-40. - Pubmed
  • Fenaux P: Inhibitors of DNA methylation: beyond myelodysplastic syndromes. Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S36-44. - Pubmed
  • Silverman LR: Targeting hypomethylation of DNA to achieve cellular differentiation in myelodysplastic syndromes (MDS). Oncologist. 2001;6 Suppl 5:8-14. - Pubmed
  • O'Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. - Pubmed
  • Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. - Pubmed
  • Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. - Pubmed
DTHybrid score 0.7824
RNA
Name RNA
Gene Name Not Available
Pharmacological action yes
Actions other
References
  • Muller A, Florek M: 5-Azacytidine/Azacitidine. Recent Results Cancer Res. 2010;184:159-70. - Pubmed
  • Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. - Pubmed
  • Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. - Pubmed
  • Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. - Pubmed
  • Cihak A, Vesely J, Skoda J: Azapyrimidine nucleosides: metabolism and inhibitory mechanisms. Adv Enzyme Regul. 1985;24:335-54. - Pubmed
  • Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. - Pubmed
DTHybrid score Not Available
DNA
Name DNA
Gene Name Not Available
Pharmacological action yes
Actions other
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Allen A: Epigenetic alterations and cancer: New targets for therapy. IDrugs. 2007 Oct;10(10):709-12. - Pubmed
  • Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R: FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist. 2005 Mar;10(3):176-82. - Pubmed
  • O'Dwyer K, Maslak P: Azacitidine and the beginnings of therapeutic epigenetic modulation. Expert Opin Pharmacother. 2008 Aug;9(11):1981-6. - Pubmed
  • Muller A, Florek M: 5-Azacytidine/Azacitidine. Recent Results Cancer Res. 2010;184:159-70. - Pubmed
  • Hollenbach PW, Nguyen AN, Brady H, Williams M, Ning Y, Richard N, Krushel L, Aukerman SL, Heise C, MacBeth KJ: A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010 Feb 2;5(2):e9001. - Pubmed
  • Glover AB, Leyland-Jones B: Biochemistry of azacitidine: a review. Cancer Treat Rep. 1987 Oct;71(10):959-64. - Pubmed
  • Cihak A, Vesely J, Skoda J: Azapyrimidine nucleosides: metabolism and inhibitory mechanisms. Adv Enzyme Regul. 1985;24:335-54. - Pubmed
  • Dapp MJ, Clouser CL, Patterson S, Mansky LM: 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol. 2009 Nov;83(22):11950-8. Epub 2009 Sep 2. - Pubmed
DTHybrid score Not Available

Enzymes


Cytidine deaminase
Name Cytidine deaminase
Gene Name CDA
Actions substrate
References
  • -
  • Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S: A pilot pharmacokinetic study of oral azacitidine. Leukemia. 2008 Sep;22(9):1680-4. Epub 2008 Jun 12. - Pubmed
DTHybrid score 0.8034

Predictions


Id Partner name Gene Name Score
3611 Cytidine deaminase cdd 0.8034
3707 Cytidine deaminase cdd 0.8034
24 Thymidylate synthase TMP1 0.2102
359 Thymidylate synthase TYMS 0.2102
2626 Thymidylate synthase thyA 0.2102
2729 Thymidylate synthase thyA 0.2102
5352 Thymidylate synthase THYA 0.2102
4773 Deoxycytidine kinase DCK 0.1802
2222 Equilibrative nucleoside transporter 1 SLC29A1 0.0486
3639 Thymidine phosphorylase deoA 0.0419
3936 Thymidine phosphorylase TYMP 0.0419
6148 Multidrug resistance-associated protein 7 ABCC10 0.0401
1302 Dihydropyrimidine dehydrogenase [NADP+] DPYD 0.0371
1830 5'-nucleotidase NT5E 0.0344
125 DNA polymerase beta POLB 0.0333
6144 Solute carrier family 22 member 2 SLC22A2 0.0325
6145 Solute carrier family 22 member 1 SLC22A1 0.0313
702 UMP-CMP kinase CMPK1 0.0294
360 Ribonucleoside-diphosphate reductase large subunit RRM1 0.0282
4604 Liver carboxylesterase 1 CES1 0.0278
6171 Solute carrier family 28 member 3 SLC28A3 0.0275
6147 Solute carrier family 22 member 3 SLC22A3 0.0201
833 Organic cation/carnitine transporter 1 SLC22A4 0.02
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0199
118 Organic cation/carnitine transporter 2 SLC22A5 0.0175
3923 Cholinesterase BCHE 0.0171
4757 Cytochrome P450 2C9 CYP2C9 0.016
4119 Cytochrome P450 2D6 CYP2D6 0.0124
1588 Multidrug resistance protein 1 ABCB1 0.0107
4512 Cytochrome P450 3A4 CYP3A4 0.0094
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