Azacitidine

Azacitidine is indicated for the treatment of myelodysplastic syndrome, for which it received approval by the U.S. Food and Drug Administration (FDA) on 19 May 2004.{{cite web | title=Drug Approval Package: Vidaza (Azacitidine) NDA #050794 | website=U.S. Food and Drug Administration (FDA) | date=14 July 2004 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/50-794_Vidaza.cfm | access-date=26 September 2020}}{{cite web|title=Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations|url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=050794&TABLE1=OB_Rx|website=fda.gov|publisher=U.S. Food and Drug Administration (FDA)|access-date=20 May 2016}} In two randomized controlled trials comparing azacitidine to supportive treatment, 16% of subjects with myelodysplastic syndrome who were randomized to receive azacitidine had a complete or partial normalization of blood cell counts and bone marrow morphology, compared to none who received supportive care, and about two-thirds of patients who required blood transfusions no longer needed them after receiving azacitidine.{{cite journal | vauthors = Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R | title = FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension | journal = The Oncologist | volume = 10 | issue = 3 | pages = 176–82 | date = March 2005 | pmid = 15793220 | doi = 10.1634/theoncologist.10-3-176 | s2cid = 11375964 }}

Azacitidine is also indicated for the treatment of myeloid leukemia{{cite journal | vauthors = Molica M, Mazzone C, Niscola P, Carmosino I, Di Veroli A, De Gregoris C, Bonanni F, Perrone S, Cenfra N, Fianchi L, Piccioni AL, Spadea A, Luzi G, Mengarelli A, Cudillo L, Maurillo L, Pagano L, Breccia M, Rigacci L, De Fabritiis P | display-authors = 6 | title = Identification of Predictive Factors for Overall Survival and Response during Hypomethylating Treatment in Very Elderly (≥75 Years) Acute Myeloid Leukemia Patients: A Multicenter Real-Life Experience | journal = Cancers | volume = 14 | issue = 19 | pages = 4897 | date = October 2022 | pmid = 36230820 | pmc = 9564161 | doi = 10.3390/cancers14194897 | doi-access = free }} and juvenile myelomonocytic leukemia. The combination of azacitidine and venetoclax is also approved for AML.{{cite journal | vauthors = DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Döhner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hájek R, Porkka K, Illés Á, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW | display-authors = 6 | title = Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia | journal = The New England Journal of Medicine | volume = 383 | issue = 7 | pages = 617–629 | date = August 2020 | pmid = 32786187 | doi = 10.1056/NEJMoa2012971 | s2cid = 221121486 | doi-access = free }}

Azacitidine is a chemical analogue of the nucleoside cytidine, which is present in DNA and RNA. It is thought to have antineoplastic activity via two mechanisms – at low doses, by inhibiting of DNA methyltransferase, causing hypomethylation of DNA,{{cite book |title=Small molecules in oncology |year=2010 |publisher=Springer |location=Heidelberg |isbn=978-3-642-01222-8 |pages=159–170| veditors = Martens UM |chapter=11 5-Azacytidine/Azacitidine |doi=10.1007/978-3-642-01222-8 |volume=184 |series=Recent Results in Cancer Research }} and at high doses, by its direct cytotoxicity to abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA, resulting in cell death. Azacitidine is a ribonucleoside, so it is incorporated into RNA to a larger extent than into DNA. In contrast, decitabine (5-aza-2'-deoxycytidine) is a deoxyribonucleoside, so it can only incorporate into DNA. Azacitidine's incorporation into RNA leads to the disassembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of proteins. Its incorporation into DNA leads to covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequently leads to cytotoxicity. It has been shown effective against human immunodeficiency virus in vitro{{cite journal | vauthors = Dapp MJ, Clouser CL, Patterson S, Mansky LM | title = 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1 | journal = Journal of Virology | volume = 83 | issue = 22 | pages = 11950–8 | date = November 2009 | pmid = 19726509 | pmc = 2772699 | doi = 10.1128/JVI.01406-09 }} and human T-lymphotropic virus.{{cite journal | vauthors = Diamantopoulos PT, Michael M, Benopoulou O, Bazanis E, Tzeletas G, Meletis J, Vayopoulos G, Viniou NA | title = Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations | journal = Virology Journal | volume = 9 | pages = 1 | date = January 2012 | pmid = 22214262 | pmc = 3305386 | doi = 10.1186/1743-422X-9-1 | doi-access = free }}

After azanucleosides such as azacitidine have been metabolized to 5-aza-2′-deoxycytidine-triphosphate (aka, decitabine-triphosphate), they can be incorporated into DNA and azacytosine can be substituted for cytosine. Azacytosine-guanine dinucleotides are recognized as substrate by the DNA methyltransferases, which catalyze the methylation reaction by a nucleophilic attack. This results in 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 this latter reaction does not occur with azacytosine because its carbon-5 is substituted by nitrogen, leaving the enzyme covalently bound to DNA and blocking its DNA methyltransferase function. 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.{{cite journal | vauthors = Stresemann C, Lyko F | title = Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine | journal = International Journal of Cancer | volume = 123 | issue = 1 | pages = 8–13 | date = July 2008 | pmid = 18425818 | doi = 10.1002/ijc.23607 | s2cid = 14125490 | doi-access = free }}{{cite journal | vauthors = Navada SC, Steinmann J, Lübbert M, Silverman LR | title = Clinical development of demethylating agents in hematology | journal = The Journal of Clinical Investigation | volume = 124 | issue = 1 | pages = 40–6 | date = January 2014 | pmid = 24382388 | pmc = 3871232 | doi = 10.1172/JCI69739 }}

Azacitidine causes anemia (low red blood cell counts), neutropenia (low white blood cell counts), and thrombocytopenia (low platelet counts), and patients should have frequent monitoring of their complete blood counts, at least prior to each dosing cycle. The dose may have to be adjusted based on nadir counts and hematologic response.{{cite web | title=Vidaza- azacitidine injection, powder, lyophilized, for solution | website=DailyMed | date=2 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3495a71a-cc04-4776-851f-f185956f32af | access-date=27 September 2020}}

It can also be hepatotoxic in patients with severe liver impairment, and patients with extensive liver tumors due to metastatic disease have developed progressive hepatic coma and death during azacitidine treatment, especially when their albumin levels are less than 30 g/L. It is contraindicated in patients with advanced malignant hepatic tumors.

Kidney toxicity, ranging from elevated serum creatinine to kidney failure and death, have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for conditions other than myelodysplastic syndrome. Renal tubular acidosis developed in five patients with chronic myelogenous leukemia (an unapproved use) treated with azacitidine and etoposide, and patients with renal impairment may be at increased risk for renal toxicity. Azacitidine and its metabolites are primarily excreted by the kidneys, so patients with chronic kidney disease should be closely monitored for other side effects, since their levels of azacitidine may progressively increase.

Based on animal studies and its mechanism of action, azacitidine can cause severe fetal damage. Sexually active women of reproductive potential should use contraception while receiving azacitidine and for one week after the last dose, and sexually active men with female partners of reproductive potential should use contraception during treatment and for three months following the last dose.

A study undertaken to evaluate the immediate and long-term effects of a single-day exposure to Azacytidine (5-AzaC) on neurobehavioral abnormalities in mice found, that the inhibition of DNA methylation by 5-AzaC treatment causes neurodegeneration and impairs extracellular signal-regulated kinase (ERK1/2) activation and the activity-regulated cytoskeleton-associated (Arc) protein expression in neonatal mice and induces behavioral abnormalities in adult mice, as DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function.{{cite journal | vauthors = Subbanna S, Nagre NN, Shivakumar M, Basavarajappa BS | title = A single day of 5-azacytidine exposure during development induces neurodegeneration in neonatal mice and neurobehavioral deficits in adult mice | journal = Physiology & Behavior | volume = 167 | pages = 16–27 | date = December 2016 | pmid = 27594097 | pmc = 5159185 | doi = 10.1016/j.physbeh.2016.08.036 }}

Azacitidine can also cause nausea, vomiting, fevers, diarrhea, redness at its injection sites, constipation, bruising, petechiae, rigors, weakness, abnormally low potassium levels in the bloodstream, and many other side effects, some of which can be severe or even fatal.

The efficacy of azacitidine to treat juvenile myelomonocytic leukemia was evaluated in AZA-JMML-001 (NCT02447666), an international, multicenter, open-label study to evaluate the pharmacokinetics, pharmacodynamics, safety, and activity of azacitidine prior to hematopoietic stem cell transplantation in 18 pediatric patients with juvenile myelomonocytic leukemia.

Azacitidine can be used in vitro to remove methyl groups from DNA. This may weaken the effects of gene silencing mechanisms that occur prior to methylation. Certain methylations are believed to secure DNA in a silenced state, and therefore demethylation may reduce the stability of silencing signals and confer relative gene activation.{{cite book | vauthors = Whitelaw E, Garrick D | date = 2005| chapter = Chapter 7: The Epigenome | title = Mammalian Genomics | url = https://archive.org/details/mammaliangenomic0000unse | url-access = registration | veditors = Ruvinsky A, Marshall Graves JA | publisher = CABI Publishing | location = Wallingford, U.K. | isbn = 0-85199-910-7 }}

Azacitidine induces tumor regression on isocitrate dehydrogenase-1 mutant glioma xenografts in mice.{{cite journal | vauthors = Borodovsky A, Salmasi V, Turcan S, Fabius AW, Baia GS, Eberhart CG, Weingart JD, Gallia GL, Baylin SB, Chan TA, Riggins GJ | display-authors = 6 | title = 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft | journal = Oncotarget | volume = 4 | issue = 10 | pages = 1737–47 | date = October 2013 | pmid = 24077805 | pmc = 3858560 | doi = 10.18632/oncotarget.1408 }}

In research, 5-azacitidine is commonly used for promoting cardiomyocyte differentiation of adult stem cells. However, it has been suggested that this drug has a compromised efficacy as a cardiac differentiation factor because it promotes the transdifferentiation of cardiac cells to skeletal myocytes.{{cite journal | vauthors = Kaur K, Yang J, Eisenberg CA, Eisenberg LM | title = 5-azacytidine promotes the transdifferentiation of cardiac cells to skeletal myocytes | journal = Cellular Reprogramming | volume = 16 | issue = 5 | pages = 324–30 | date = October 2014 | pmid = 25090621 | doi = 10.1089/cell.2014.0021 | url = https://www.researchgate.net/publication/264462290 }}

Azacitidine also has antiviral effects in animal studies as well as its anti-cancer actions, but has not been tested for clinical use.{{cite journal | vauthors = Wang X, Zou P, Wu F, Lu L, Jiang S | title = Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses | journal = Frontiers of Medicine | volume = 11 | issue = 4 | pages = 449–461 | date = December 2017 | pmid = 29170916 | doi = 10.1007/s11684-017-0589-5 | pmc = 7089273 | doi-access = free }}{{cite journal | vauthors = Ianevski A, Zusinaite E, Kuivanen S, Strand M, Lysvand H, Teppor M, Kakkola L, Paavilainen H, Laajala M, Kallio-Kokko H, Valkonen M, Kantele A, Telling K, Lutsar I, Letjuka P, Metelitsa N, Oksenych V, Bjørås M, Nordbø SA, Dumpis U, Vitkauskiene A, Öhrmalm C, Bondeson K, Bergqvist A, Aittokallio T, Cox RJ, Evander M, Hukkanen V, Marjomaki V, Julkunen I, Vapalahti O, Tenson T, Merits A, Kainov D | display-authors = 6 | title = Novel activities of safe-in-human broad-spectrum antiviral agents | journal = Antiviral Research | volume = 154 | pages = 174–182 | date = June 2018 | pmid = 29698664 | doi = 10.1016/j.antiviral.2018.04.016 | pmc = 7113852 | hdl = 10138/301108 | hdl-access = free }}

{{reflist}}

• {{ClinicalTrialsGov|NCT02447666|Study With Azacitidine in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome (MDS) and Juvenile Myelomonocytic Leukemia (JMML)}}

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