Azacitidine

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Azacitidine
Azacitidine.svg
Clinical data
Trade names Vidaza, Azadine, Onureg
Other names5-Azacytidine, Azacytidine, Ladakamycin, 4-Amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one, U-18496, CC-486
AHFS/Drugs.com Monograph
MedlinePlus a607068
License data
Pregnancy
category
  • AU:X (High risk) [1]
Routes of
administration 		Subcutaneous, intravenous, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 4 hr. [8]
Identifiers
  • 4-Amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.005.711 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H12N4O5
Molar mass 244.207 g·mol−1
3D model (JSmol)
  • O=C1/N=C(\N=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)CO)N
  • 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 Yes check.svgY
  • Key:NMUSYJAQQFHJEW-KVTDHHQDSA-N Yes check.svgY
   (verify)

Azacitidine, sold under the brand name Vidaza among others, is a medication used for the treatment of myelodysplastic syndrome, myeloid leukemia, [5] [6] and juvenile myelomonocytic leukemia. [4] [9] It is a chemical analog of cytidine, a nucleoside in DNA and RNA.[ medical citation needed ] Azacitidine and its deoxy derivative, decitabine (also known as 5-aza-2′-deoxycytidine) were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer. [10]

Contents

The most common adverse reactions in children with juvenile myelomonocytic leukemia include pyrexia, rash, upper respiratory tract infection, and anemia. [9]

Medical uses

Azacitidine is indicated for the treatment of myelodysplastic syndrome, [4] for which it received approval by the U.S. Food and Drug Administration (FDA) on 19 May 2004. [11] [4] [12] 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. [13]

Azacitidine is also indicated for the treatment of myeloid leukemia [5] [6] [14] and juvenile myelomonocytic leukemia. [4] [9] The combination of azacitidine and venetoclax is also approved for AML. [15]

Mechanism of action

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, [16] 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 [17] and human T-lymphotropic virus. [18]

Inhibition of methylation

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. [19] [20]

Toxicity

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. [4]

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. [4]

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. [4]

Based on animal studies and its mechanism of action, azacitidine can cause severe fetal damage. Sexually active women of reproductive potential should use contraception during 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. [4]

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. [21]

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. [4]

History

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. [9]

Research

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. [22]

Azacitidine induces tumor regression on isocitrate dehydrogenase-1 mutant glioma xenografts in mice. [23]

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. [24]

Azacitidine also has antiviral effects in animal studies as well as its anti-cancer actions, but has not been tested for clinical use. [25] [26]

Related Research Articles

<span class="mw-page-title-main">Ribavirin</span> Antiviral medication

Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, peginterferon alfa-2b or peginterferon alfa-2a. Among the viral hemorrhagic fevers it is sometimes used for Lassa fever, Crimean–Congo hemorrhagic fever, and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken orally or inhaled. Despite widespread usage, since the 2010s it has faced scrutiny for a lack of efficacy in treating viral infections it has historically been prescribed for.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Cytarabine</span> Chemical compound (chemotherapy medication)

Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by injection into a vein, under the skin, or into the cerebrospinal fluid. There is a liposomal formulation for which there is tentative evidence of better outcomes in lymphoma involving the meninges.

<span class="mw-page-title-main">Tipifarnib</span> Chemical compound

Tipifarnib is a farnesyltransferase inhibitor. Farnesyltransferase inhibitors block the activity of the farnesyltransferase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive.

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

<span class="mw-page-title-main">Decitabine</span> Medication for the treatment of conditions where certain blood cells are dysfunctional,

Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog.

Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia that affects children, commonly those aged four and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is two (2) years old. The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.

Demethylating agents are chemical substances that can inhibit methylation, resulting in the expression of the previously hypermethylated silenced genes. Cytidine analogs such as 5-azacytidine (azacitidine) and 5-azadeoxycytidine (decitabine) are the most commonly used demethylating agents. They work by inhibiting DNA methyltransferases. Both compounds have been approved in the treatment of myelodysplastic syndrome (MDS) by Food and Drug Administration (FDA) in United States. Azacitidine and decitabine are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given orphan drug status. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. There are many other demethylating agents that can be used to inhibit the growth of other diseases.

<span class="mw-page-title-main">Sapacitabine</span> Chemical compound

Sapacitabine is a chemotherapeutic drug developed by US biotechnology firm Cyclacel currently undergoing clinical trials against leukemia.

A hypomethylating agent is a drug that inhibits DNA methylation: the modification of DNA nucleotides by addition of a methyl group. Because DNA methylation affects cellular function through successive generations of cells without changing the underlying DNA sequence, treatment with a hypomethylating agent is considered a type of epigenetic therapy.

<span class="mw-page-title-main">Omacetaxine mepesuccinate</span> Chemical compound

Omacetaxine mepesuccinate, formerly named as homoharringtonine or HHT, is a pharmaceutical drug substance that is indicated for treatment of chronic myeloid leukemia (CML).

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

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<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

Lenzilumab is a humanized monoclonal antibody that targets colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-CSF).

Pharmacoepigenetics is an emerging field that studies the underlying epigenetic marking patterns that lead to variation in an individual's response to medical treatment.

<span class="mw-page-title-main">Epigenetic priming</span> Type of modification to a cells epigenome

Epigenetic priming is the modification to a cell's epigenome whereby specific chromatin domains within a cell are converted from a closed state to an open state, usually as the result of an external biological trigger or pathway, allowing for DNA access by transcription factors or other modification mechanisms. The action of epigenetic priming for a certain region of DNA dictates how other gene regulation mechanisms will be able to act on the DNA later in the cell’s life. Epigenetic priming has been chiefly investigated in neuroscience and cancer research, as it has been found to play a key role in memory formation within neurons and tumor-suppressor gene activation in cancer treatment respectively.

<span class="mw-page-title-main">Decitabine/cedazuridine</span> Medication

Decitabine/cedazuridine, sold under the brand name Inqovi among others, is a fixed-dose combination anticancer medication used for the treatment of adults with myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). It is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor.

<span class="mw-page-title-main">Bisantrene</span> Chemical compound

Bisantrene is an anthracenyl bishydrazone with anthracycline-like antineoplastic activity and an antimetabolite. Bisantrene intercalates with and disrupts the configuration of DNA, resulting in DNA single-strand breaks, DNA-protein crosslinking, and inhibition of DNA replication. This agent is similar to doxorubicin in chemotherapeutic activity, but unlike anthracyclines like doxorubicin, it exhibits little cardiotoxicity.

References

  1. ↑ "Azacitidine (Vidaza) Use During Pregnancy". Drugs.com. 5 May 2020. Retrieved 12 August 2020.
  2. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  3. ↑ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada . 3 August 2022. Retrieved 25 March 2024.
  4. 1 2 3 4 5 6 7 8 9 10 "Vidaza- azacitidine injection, powder, lyophilized, for solution". DailyMed. 2 March 2020. Retrieved 27 September 2020.
  5. 1 2 3 "Onureg- azacitidine tablet, film coated". DailyMed. 20 May 2021. Retrieved 24 May 2022.
  6. 1 2 3 "Onureg EPAR". European Medicines Agency. 20 April 2021. Retrieved 6 September 2021.
  7. ↑ "Onureg Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  8. ↑ Vallerand AH, Deglin JH (2009). Davis's drug guide for nurses . Philadelphia: F.A. Davis Company. pp.  204–206. ISBN   978-0-8036-1912-8.
  9. 1 2 3 4 "FDA approves azacitidine". U.S. Food and Drug Administration. 20 May 2022. Retrieved 24 May 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  10. ↑ Cihák A (1974). "Biological effects of 5-azacytidine in eukaryotes". Oncology. 30 (5): 405–22. doi:10.1159/000224981. PMID   4142650.
  11. ↑ "Drug Approval Package: Vidaza (Azacitidine) NDA #050794". U.S. Food and Drug Administration (FDA). 14 July 2004. Retrieved 26 September 2020.
  12. ↑ "Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations". fda.gov. U.S. Food and Drug Administration (FDA). Retrieved 20 May 2016.
  13. ↑ Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R (March 2005). "FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension". The Oncologist. 10 (3): 176–82. doi:10.1634/theoncologist.10-3-176. PMID   15793220. S2CID   11375964.
  14. ↑ Molica M, Mazzone C, Niscola P, Carmosino I, Di Veroli A, De Gregoris C, et al. (October 2022). "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". Cancers. 14 (19): 4897. doi: 10.3390/cancers14194897 . PMC   9564161 . PMID   36230820.
  15. ↑ DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. (August 2020). "Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia". The New England Journal of Medicine. 383 (7): 617–629. doi: 10.1056/NEJMoa2012971 . PMID   32786187. S2CID   221121486.
  16. ↑ Martens UM, ed. (2010). "11 5-Azacytidine/Azacitidine". Small molecules in oncology. Recent Results in Cancer Research. Vol. 184. Heidelberg: Springer. pp. 159–170. doi:10.1007/978-3-642-01222-8. ISBN   978-3-642-01222-8.
  17. ↑ Dapp MJ, Clouser CL, Patterson S, Mansky LM (November 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.
  18. ↑ Diamantopoulos PT, Michael M, Benopoulou O, Bazanis E, Tzeletas G, Meletis J, Vayopoulos G, Viniou NA (January 2012). "Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations". Virology Journal. 9: 1. doi: 10.1186/1743-422X-9-1 . PMC   3305386 . PMID   22214262.
  19. ↑ Stresemann C, Lyko F (July 2008). "Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine". International Journal of Cancer. 123 (1): 8–13. doi: 10.1002/ijc.23607 . PMID   18425818. S2CID   14125490.
  20. ↑ Navada SC, Steinmann J, Lübbert M, Silverman LR (January 2014). "Clinical development of demethylating agents in hematology". The Journal of Clinical Investigation. 124 (1): 40–6. doi:10.1172/JCI69739. PMC   3871232 . PMID   24382388.
  21. ↑ Subbanna S, Nagre NN, Shivakumar M, Basavarajappa BS (December 2016). "A single day of 5-azacytidine exposure during development induces neurodegeneration in neonatal mice and neurobehavioral deficits in adult mice". Physiology & Behavior. 167: 16–27. doi:10.1016/j.physbeh.2016.08.036. PMC   5159185 . PMID   27594097.
  22. ↑ Whitelaw E, Garrick D (2005). "Chapter 7: The Epigenome". In Ruvinsky A, Marshall Graves JA (eds.). Mammalian Genomics . Wallingford, U.K.: CABI Publishing. ISBN   0-85199-910-7.
  23. ↑ Borodovsky A, Salmasi V, Turcan S, Fabius AW, Baia GS, Eberhart CG, et al. (October 2013). "5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft". Oncotarget. 4 (10): 1737–47. doi:10.18632/oncotarget.1408. PMC   3858560 . PMID   24077805.
  24. ↑ Kaur K, Yang J, Eisenberg CA, Eisenberg LM (October 2014). "5-azacytidine promotes the transdifferentiation of cardiac cells to skeletal myocytes". Cellular Reprogramming. 16 (5): 324–30. doi:10.1089/cell.2014.0021. PMID   25090621.
  25. ↑ Wang X, Zou P, Wu F, Lu L, Jiang S (December 2017). "Development of small-molecule viral inhibitors targeting various stages of the life cycle of emerging and re-emerging viruses". Frontiers of Medicine. 11 (4): 449–461. doi: 10.1007/s11684-017-0589-5 . PMC   7089273 . PMID   29170916.
  26. ↑ Ianevski A, Zusinaite E, Kuivanen S, Strand M, Lysvand H, Teppor M, et al. (June 2018). "Novel activities of safe-in-human broad-spectrum antiviral agents". Antiviral Research. 154: 174–182. doi:10.1016/j.antiviral.2018.04.016. hdl: 10138/301108 . PMC   7113852 . PMID   29698664.
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