Identification

Name
Decitabine
Accession Number
DB01262
Description

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic neoplasms with variable underlying etiology and presentation, including neutropenia and thrombocytopenia. Further mutations leading to increased proliferation of cancerous cells can eventually lead to secondary acute myeloid leukemia, which has a poor prognosis.9,10 Among treatment options, nucleoside analogues such as decitabine and azacitidine integrate into cellular DNA and inhibit the action of DNA methyltransferases, leading to global hypomethylation and related downstream therapeutic benefits.3,4,5,8,11

Decitabine was developed by MGI Pharma/SuperGen Inc. and was approved by the FDA for the treatment of MDS on February 5, 2006. It was first marketed under the name Dacogen®.11 It is also available as an oral combination product together with the cytidine deaminase inhibitor cedazuridine.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 228.2053
Monoisotopic: 228.085854892
Chemical Formula
C8H12N4O4
Synonyms
  • 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-s-triazin-2(1H)-one
  • 5-aza-2'-deoxycytidine
  • 5-azadeoxycytidine
  • DAC
  • Decitabina
  • Decitabine
External IDs
  • NSC-127716

Pharmacology

Indication

Decitabine is indicated for the treatment of patients with myelodysplastic syndromes (MDS) including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), as well as for MDS scored as belonging to the intermediate-1, intermediate-2, or high-risk group in the International Prognostic Scoring System.11

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Decitabine is a prodrug analogue of the natural nucleotide 2’-deoxycytidine, which, upon being phosphorylated intracellularly, is incorporated into DNA and exerts numerous effects on gene expression.3,4,5,8,11 The use of decitabine is associated with neutropenia and thrombocytopenia. In addition, decitabine can cause fetal harm in pregnant women; effective contraception and avoidance of pregnancy are recommended during treatment with decitabine.11

Mechanism of action

Myelodysplastic syndromes (MDS) are a group of hematopoietic neoplasms that manifest in peripheral cytopenias and may eventually progress to secondary acute myeloid leukemia (sAML). Included in the over 45 genes commonly mutated in MDS patients are those involved in DNA methylation and histone modification, and it is well-established that alteration of the epigenetic landscape is a feature of myeloid leukemias.9,10

Decitabine is considered a prodrug, as it requires transport into cells and subsequent phosphorylation by distinct kinases to generate the active molecule 5-aza-2'-deoxycytidine-triphosphate, which is incorporated by DNA polymerase during DNA replication.3,5,6,7,8,11 Once incorporated into DNA, decitabine is recognized as a substrate by DNA methyltransferase enzymes (DNMTs), specifically DNMT1, but due to the presence of an N5 rather than C5 atom, traps the DNMT through the irreversible formation of a covalent bond.6,7 At low concentrations, this mode of action depletes DNMTs and results in global DNA hypomethylation while at high concentrations, it additionally results in double-strand breaks and cell death.4,7,8

The general hypothesis regarding decitabine's therapeutic efficacy is that the global hypomethylation it induces results in the expression of previously silent tumour suppressor genes.1,2,3,4,5,6,7,8,11 However, there are other putative mechanisms also related to this change in DNA methylation, including indirect alteration of transcription through effects on transcription factors, indirectly altering histone modifications and chromatin structure, and activating pathways involved in DNA damage response.3,5,7,8 The overall effect of decitabine is a decrease in neoplastic cell proliferation and an increase in the expression of tumour suppressor genes.

TargetActionsOrganism
ADNA
other/unknown
Humans
ADNA (cytosine-5)-methyltransferase 1
inhibitor
Humans
UDNA (cytosine-5)-methyltransferase 3A
inhibitor
Humans
UDNA (cytosine-5)-methyltransferase 3B
inhibitor
Humans
Absorption

Decitabine administered intravenously at 15 mg/m2 for three hours every eight hours over three days resulted in a Cmax of 73.8 ng/mL (66% coefficient of variation, CV), an AUC0-∞ of 163 ng*h/mL (62% CV), and a cumulative AUC of 1332 ng*h/mL (95% CI of 1010-1730).11

Similarly, decitabine at 20 mg/m2 for one hour once daily over five days resulted in a Cmax of 147 ng/mL (49% CV), an AUC0-∞ of 115 ng*h/mL (43% CV), and a cumulative AUC of 570 ng*h/mL (95% CI of 470-700).11

Volume of distribution

Decitabine as an apparent volume of distribution of 4.59 ± 1.42 L/kg.4

Protein binding

Decitabine exhibits negligible (< 1%) plasma protein binding.5,11

Metabolism

Decitabine is phosphorylated inside cells by the sequential action of deoxycytidine kinase, nucleotide monophosphate kinase, and nucleotide diphosphate kinase, prior to being incorporated into newly synthesized DNA by DNA polymerase.3,6,7,8 Decitabine not incorporated into cellular DNA undergoes deamination by cytidine deaminase followed by additional degradation prior to excretion.3,6,8

Hover over products below to view reaction partners

Route of elimination

Less than 1% of administered decitabine is excreted in the urine.4

Half-life

Decitabine has a half-life of 0.62 hours (49% CV) when administered intravenously at 15 mg/m2 for three hours every eight hours over three days, and a half-life of 0.54 hours (43% CV) at 20 mg/m2 for one hour once daily over five days.11

Clearance

Decitabine has a clearance of 125 L/hr/m2 (53% CV) when administered intravenously at 15 mg/m2 for three hours every eight hours over three days, and a clearance of 210 L/hr/m2 (47% CV) at 20 mg/m2 for one hour once daily over five days.11

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Decitabine has demonstrated mutagenic potential in L5178Y mouse lymphoma cells and an Escherichia coil lac-I transgene within the colonic DNA of mice. Decitabine treatment increased chromosomal rearrangements in fruit fly larvae. In mouse models, decitabine exposure in utero (approximately 7% of the recommended daily dose) resulted in decreased weight and decreased male fertility. Adult male mice administered with between 0.3 and 1% of the recommended daily dose of decitabine three times a week for seven weeks had smaller testes with abnormal histology, decreased sperm count, and decreased fertility.11

There is no known antidote for decitabine overdose. Patients experiencing an overdose are at an increased risk of severe adverse effects such as myelosuppression, including prolonged and severe neutropenia and thrombocytopenia. Symptomatic and supportive measures are recommended.11

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Decitabine is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Decitabine.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Decitabine.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Decitabine.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Decitabine.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Decitabine.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Decitabine.
AlefaceptThe risk or severity of adverse effects can be increased when Alefacept is combined with Decitabine.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Decitabine.
AllopurinolThe risk or severity of adverse effects can be increased when Allopurinol is combined with Decitabine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DacogenInjection, powder, lyophilized, for solution50 mg/20mLIntravenousEisai Limited1996-05-032018-12-31US flag
DacogenInjection, powder, for solution50 mgIntravenousJanssen Cilag International Nv2012-09-20Not applicableEU flag
DacogenPowder50 mgIntravenousOtsuka Pharmaceutical Co., Ltd.Not applicableNot applicableCanada flag
DacogenInjection, powder, lyophilized, for solution50 mg/20mLIntravenousOtsuka America Pharmaceutical, Inc.2006-05-02Not applicableUS flag
Decitabine50 mg/10mLIntravenousSun Pharmaceutical Industries, Inc.2014-01-24Not applicableUS flag
DemylocanPowderIntravenousPendopharm Division Of Pharmascience IncNot applicableNot applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DecitabineInjection, powder, lyophilized, for solution50 mg/10mLIntravenousDr.Reddy's Laboratories Limited2013-07-11Not applicableUS flag
DecitabineInjection, powder, lyophilized, for solution50 mg/20mLIntravenousMylan Institutional LLC2018-10-10Not applicableUS flag
DecitabineInjection, powder, lyophilized, for solution50 mg/20mLIntravenousAmneal Pharmaceuticals LLC2019-12-01Not applicableUS flag
DecitabineInjection50 mg/10mLIntravenousCipla USA Inc.2017-11-16Not applicableUS flag
DecitabineInjection, powder, lyophilized, for solution50 mg/20mLIntravenousNorthstar RxLLC2017-11-20Not applicableUS flag
DecitabineInjection, powder, lyophilized, for solution50 mg/10mLIntravenousMsn Laboratories Private Limited2019-08-28Not applicableUS flag
DecitabineInjection, powder, lyophilized, for solution50 mg/10mLIntravenousNovadoz Pharmaceuticals Llc2019-08-28Not applicableUS flag
DecitabineInjection, powder, lyophilized, for solution50 mg/20mLIntravenousChemi Pharma Llc2019-10-312019-12-05US flag
DecitabineInjection, powder, lyophilized, for solution50 mg/20mLIntravenousAccord Healthcare Inc.2017-03-08Not applicableUS flag
DecitabineInjection, powder, lyophilized, for solution50 mg/10mLIntravenousNorthStar Rx LLC2019-02-18Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
InqoviDecitabine (35 mg) + Cedazuridine (100 mg)TabletOralOtsuka Pharmaceutical Co., Ltd.Not applicableNot applicableCanada flag
InqoviDecitabine (35 mg/1) + Cedazuridine (100 mg/1)Tablet, film coatedOralTaiho Pharmaceutical Co., Ltd.2020-07-07Not applicableUS flag

Categories

ATC Codes
L01BC08 — Decitabine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as triazinones. These are compounds containing a triazine ring which bears a ketone group a carbon atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Triazines
Sub Class
Triazinones
Direct Parent
Triazinones
Alternative Parents
Aminotriazines / 1,3,5-triazines / Tetrahydrofurans / Heteroaromatic compounds / Secondary alcohols / Oxacyclic compounds / Azacyclic compounds / Primary amines / Primary alcohols / Organopnictogen compounds
show 2 more
Substituents
1,3,5-triazine / Alcohol / Amine / Amino-1,3,5-triazine / Aminotriazine / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound
show 11 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
2'-deoxyribonucleoside (CHEBI:50131)

Chemical Identifiers

UNII
776B62CQ27
CAS number
2353-33-5
InChI Key
XAUDJQYHKZQPEU-KVQBGUIXSA-N
InChI
InChI=1S/C8H12N4O4/c9-7-10-3-12(8(15)11-7)6-1-4(14)5(2-13)16-6/h3-6,13-14H,1-2H2,(H2,9,11,15)/t4-,5+,6+/m0/s1
IUPAC Name
4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydro-1,3,5-triazin-2-one
SMILES
NC1=NC(=O)N(C=N1)[[email protected]]1C[[email protected]](O)[[email protected]@H](CO)O1

References

Synthesis Reference

Julian Paul Henschke, Xiaoheng Zhang, Jianbo Yu, Kun Hu, Lijun Mei, "Synthesis of Decitabine." U.S. Patent US20100087637, issued April 08, 2010.

US20100087637
General References
  1. Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. [PubMed:17925555]
  2. Wijermans PW, Ruter B, Baer MR, Slack JL, Saba HI, Lubbert M: Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res. 2008 Apr;32(4):587-91. Epub 2007 Sep 18. [PubMed:17881052]
  3. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. doi: 10.1007/978-3-642-01222-8_10. [PubMed:20072836]
  4. Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. [PubMed:16015501]
  5. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
  6. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
  7. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  8. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  9. Kennedy JA, Ebert BL: Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome. J Clin Oncol. 2017 Mar 20;35(9):968-974. doi: 10.1200/JCO.2016.71.0806. Epub 2017 Feb 13. [PubMed:28297619]
  10. Gill H, Leung AY, Kwong YL: Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy. Int J Mol Sci. 2016 Mar 24;17(4):440. doi: 10.3390/ijms17040440. [PubMed:27023522]
  11. FDA Approved Drug Products: decitabine for injection [Link]
  12. Cayman Chemical: decitabine MSDS [Link]
  13. SignalChem decitabine product sheet [Link]
Human Metabolome Database
HMDB0015391
KEGG Drug
D03665
PubChem Compound
451668
PubChem Substance
46505657
ChemSpider
397844
BindingDB
96274
RxNav
15657
ChEBI
50131
ChEMBL
CHEMBL1201129
ZINC
ZINC000016929327
Therapeutic Targets Database
DAP000641
PharmGKB
PA164749631
Drugs.com
Drugs.com Drug Page
Wikipedia
Decitabine
FDA label
Download (100 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingPreventionAcute Myeloid Leukemia (AML)1
4TerminatedTreatmentMyelodysplastic Syndromes (MDS)1
4Unknown StatusTreatmentDiffuse Large B-Cell Lymphoma (DLBCL)1
4Unknown StatusTreatmentHigher-risk Myelodysplastic Syndrome / Relapsed /Refractory Acute Myeloid Leukemia1
4Unknown StatusTreatmentMyelodysplastic Syndrome1
4Unknown StatusTreatmentT-lymphoblastic Lymphoma1
3Active Not RecruitingTreatmentAcute Myeloid Leukemia (AML)1
3Active Not RecruitingTreatmentAcute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome / Adult Acute Megakaryoblastic Leukemia (M7) / Adult Acute Minimally Differentiated Myeloid Leukemia (M0) / Adult Acute Monoblastic Leukemia (M5a) / Adult Acute Monocytic Leukemia (M5b) / Adult Acute Myeloblastic Leukemia With Maturation (M2) / Adult Acute Myeloblastic Leukemia Without Maturation (M1) / Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Adult Acute Myelomonocytic Leukemia (M4) / Adult Erythroleukemia (M6a) / Adult Pure Erythroid Leukemia (M6b) / Secondary Acute Myeloid Leukemia (Secondary AML, sAML) / Untreated Adult Acute Myeloid Leukemia1
3Active Not RecruitingTreatmentMDS1
3CompletedTreatmentAcute Myeloid Leukemia (AML)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Eisai Inc.
  • MGI Pharma
  • Pharmachemie BV
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous50 mg
Injection, powder, for solutionIntravenous; Parenteral50 MG
Injection, powder, lyophilized, for solution
Injection, powder, lyophilized, for solutionIntravenous50 mg/20mL
Injection, solution, concentrateIntravenous50 mg
Powder
InjectionIntravenous50 mg
Injection, powder, lyophilized, for solutionIntravenous50 mg
InjectionIntravenous50 mg/10mL
Injection, powder, lyophilized, for solutionIntravenous50 mg/1
Injection, powder, lyophilized, for solutionIntravenous50 mg/10mL
PowderIntravenous
Injection, powder, for solution50 mg
TabletOral
Tablet, film coatedOral
PowderIntravenous50 mg
Prices
Unit descriptionCostUnit
Dacogen 50 mg vial1706.4USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8618075No2008-10-162028-10-16US flag
US8268800No2010-08-222030-08-22US flag
US9567363No2008-10-162028-10-16US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

    Learn more

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)193-196SignalChem Product Sheet
water solubility11 mg/mLSignalChem Product Sheet
Predicted Properties
PropertyValueSource
Water Solubility5.5 mg/mLALOGPS
logP-2ALOGPS
logP-2.2ChemAxon
logS-1.6ALOGPS
pKa (Strongest Acidic)13.89ChemAxon
pKa (Strongest Basic)-0.25ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area120.74 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity50.68 m3·mol-1ChemAxon
Polarizability21.15 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9862
Blood Brain Barrier+0.8787
Caco-2 permeable-0.8362
P-glycoprotein substrateNon-substrate0.7192
P-glycoprotein inhibitor INon-inhibitor0.9216
P-glycoprotein inhibitor IINon-inhibitor0.953
Renal organic cation transporterNon-inhibitor0.8791
CYP450 2C9 substrateNon-substrate0.8359
CYP450 2D6 substrateNon-substrate0.8511
CYP450 3A4 substrateNon-substrate0.5356
CYP450 1A2 substrateNon-inhibitor0.9276
CYP450 2C9 inhibitorNon-inhibitor0.9265
CYP450 2D6 inhibitorNon-inhibitor0.9446
CYP450 2C19 inhibitorNon-inhibitor0.9379
CYP450 3A4 inhibitorNon-inhibitor0.9635
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9629
Ames testNon AMES toxic0.588
CarcinogenicityNon-carcinogens0.8109
BiodegradationNot ready biodegradable0.8957
Rat acute toxicity1.9436 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9654
hERG inhibition (predictor II)Non-inhibitor0.8972
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Other/unknown
Curator comments
Decitabine is phosphorylated to form 5-aza-2'-deoxycytidine-triphosphate, which is subsequently integrated into DNA. Once incorporated, decitabine is able to interact with, and inhibit the action of, DNMTs such as DNMT1 and to exert other effects including inducing DNA damage at higher concentrations.
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. Appleton K, Mackay HJ, Judson I, Plumb JA, McCormick C, Strathdee G, Lee C, Barrett S, Reade S, Jadayel D, Tang A, Bellenger K, Mackay L, Setanoians A, Schatzlein A, Twelves C, Kaye SB, Brown R: Phase I and pharmacodynamic trial of the DNA methyltransferase inhibitor decitabine and carboplatin in solid tumors. J Clin Oncol. 2007 Oct 10;25(29):4603-9. [PubMed:17925555]
  2. Atallah E, Kantarjian H, Garcia-Manero G: The role of decitabine in the treatment of myelodysplastic syndromes. Expert Opin Pharmacother. 2007 Jan;8(1):65-73. [PubMed:17163808]
  3. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
  4. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
  5. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  6. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. doi: 10.1007/978-3-642-01222-8_10. [PubMed:20072836]
  7. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  8. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS: A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics. 2016 Jun 21;8:71. doi: 10.1186/s13148-016-0237-y. eCollection 2016. [PubMed:27330573]
  9. FDA Approved Drug Products: decitabine for injection [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
DNMT1 acts to methylate newly synthesized hemimethylated DNA during cellular division and is therefore thought to be the primary target for irreversible covalent modification by decitabine incorporated into DNA.
General Function
Zinc ion binding
Specific Function
Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is ...
Gene Name
DNMT1
Uniprot ID
P26358
Uniprot Name
DNA (cytosine-5)-methyltransferase 1
Molecular Weight
183163.635 Da
References
  1. Ando T, Nishimura M, Oka Y: Decitabine (5-Aza-2'-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. Leukemia. 2000 Nov;14(11):1915-20. [PubMed:11069027]
  2. Karpf AR, Moore BC, Ririe TO, Jones DA: Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2'-deoxycytidine. Mol Pharmacol. 2001 Apr;59(4):751-7. [PubMed:11259619]
  3. Csankovszki G, Nagy A, Jaenisch R: Synergism of Xist RNA, DNA methylation, and histone hypoacetylation in maintaining X chromosome inactivation. J Cell Biol. 2001 May 14;153(4):773-84. [PubMed:11352938]
  4. Takebayashi S, Nakao M, Fujita N, Sado T, Tanaka M, Taguchi H, Okumura K: 5-Aza-2'-deoxycytidine induces histone hyperacetylation of mouse centromeric heterochromatin by a mechanism independent of DNA demethylation. Biochem Biophys Res Commun. 2001 Nov 9;288(4):921-6. [PubMed:11688997]
  5. Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J: Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003 Dec 1;102(12):3865-70. Epub 2003 Aug 7. [PubMed:12907443]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  7. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. doi: 10.1007/978-3-642-01222-8_10. [PubMed:20072836]
  8. Saba HI, Wijermans PW: Decitabine in myelodysplastic syndromes. Semin Hematol. 2005 Jul;42(3 Suppl 2):S23-31. [PubMed:16015501]
  9. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
  10. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
  11. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  12. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  13. Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD: DNA methylation inhibitor 5-Aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol. 2008 Jan;28(2):752-71. Epub 2007 Nov 8. [PubMed:17991895]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
DNMT3A and 3B are primarily responsible for establishing the DNA methylation landscape during development. Some evidence exists to suggest that decitabine may inhibit these enzymes, though it is likely that DNMT1 is the main methylase involved in the mechanism of action of decitabine.
General Function
Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. It modifies DNA in a non-processive manner and also methylates non-CpG sites. May preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. Plays a role in paternal and maternal imprinting. Required for methylation of most imprinted loci in germ cells. Acts as a transcriptional corepressor for ZBTB18. Recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. Can actively repress transcription through the recruitment of HDAC activity.
Specific Function
Chromatin binding
Gene Name
DNMT3A
Uniprot ID
Q9Y6K1
Uniprot Name
DNA (cytosine-5)-methyltransferase 3A
Molecular Weight
101857.595 Da
References
  1. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  2. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  3. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS: A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics. 2016 Jun 21;8:71. doi: 10.1186/s13148-016-0237-y. eCollection 2016. [PubMed:27330573]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
DNMT3A and 3B are primarily responsible for establishing the DNA methylation landscape during development. Some evidence exists to suggest that decitabine may inhibit these enzymes, though it is likely that DNMT1 is the main methylase involved in the mechanism of action of decitabine.
General Function
Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. May preferentially methylates nucleosomal DNA within the nucleosome core region. May function as transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Seems to be involved in gene silencing (By similarity). In association with DNMT1 and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. Functions as a transcriptional corepressor by associating with ZHX1. Required for DUX4 silencing in somatic cells (PubMed:27153398).
Specific Function
Chromatin binding
Gene Name
DNMT3B
Uniprot ID
Q9UBC3
Uniprot Name
DNA (cytosine-5)-methyltransferase 3B
Molecular Weight
95750.18 Da
References
  1. Palii SS, Van Emburgh BO, Sankpal UT, Brown KD, Robertson KD: DNA methylation inhibitor 5-Aza-2'-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B. Mol Cell Biol. 2008 Jan;28(2):752-71. Epub 2007 Nov 8. [PubMed:17991895]
  2. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  3. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  4. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS: A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics. 2016 Jun 21;8:71. doi: 10.1186/s13148-016-0237-y. eCollection 2016. [PubMed:27330573]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Protein homodimerization activity
Specific Function
Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based...
Gene Name
DCK
Uniprot ID
P27707
Uniprot Name
Deoxycytidine kinase
Molecular Weight
30518.315 Da
References
  1. Schwarzenberg J, Radu CG, Benz M, Fueger B, Tran AQ, Phelps ME, Witte ON, Satyamurthy N, Czernin J, Schiepers C: Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway. Eur J Nucl Med Mol Imaging. 2011 Apr;38(4):711-21. doi: 10.1007/s00259-010-1666-z. Epub 2010 Dec 3. [PubMed:21127859]
  2. Arner ES, Eriksson S: Mammalian deoxyribonucleoside kinases. Pharmacol Ther. 1995;67(2):155-86. [PubMed:7494863]
  3. Ueda K, Masuda A, Fukuda M, Tanaka S, Hosokawa M, Iwakawa S: Monophosphorylation by deoxycytidine kinase affects apparent cellular uptake of decitabine in HCT116 colon cancer cells. Drug Metab Pharmacokinet. 2017 Dec;32(6):301-310. doi: 10.1016/j.dmpk.2017.10.001. Epub 2017 Oct 10. [PubMed:29174536]
  4. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. doi: 10.1007/978-3-642-01222-8_10. [PubMed:20072836]
  5. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
  6. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
  7. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  8. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  9. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS: A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics. 2016 Jun 21;8:71. doi: 10.1186/s13148-016-0237-y. eCollection 2016. [PubMed:27330573]
  10. Momparler RL, Derse D: Kinetics of phosphorylation of 5-aza-2'-deoxyycytidine by deoxycytidine kinase. Biochem Pharmacol. 1979 Apr 15;28(8):1443-4. doi: 10.1016/0006-2952(79)90454-4. [PubMed:87202]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
Curator comments
Decitabine is not a direct substrate of UMP-CMP kinase; rather, monophosphorylated decitabine is subsequently converted to a diphosphate through the action of this enzyme. Eventual conversion to a triphosphate is required for integration into cellular DNA and the downstream mechanism of action of decitabine.
General Function
Uridylate kinase activity
Specific Function
Catalyzes the phosphorylation of pyrimidine nucleoside monophosphates at the expense of ATP. Plays an important role in de novo pyrimidine nucleotide biosynthesis. Has preference for UMP and CMP as...
Gene Name
CMPK1
Uniprot ID
P30085
Uniprot Name
UMP-CMP kinase
Molecular Weight
22222.175 Da
References
  1. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  2. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  3. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS: A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics. 2016 Jun 21;8:71. doi: 10.1186/s13148-016-0237-y. eCollection 2016. [PubMed:27330573]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
Curator comments
Decitabine is not a direct substrate of nucleoside diphosphokinase; rather, diphosphorylated decitabine is subsequently converted to a triphosphate through the action of this enzyme. The conversion to this triphosphate form is the final step required for integration into cellular DNA and the downstream mechanism of action of decitabine.
General Function
Ribosomal small subunit binding
Specific Function
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-sit...

Components:
References
  1. Oki Y, Aoki E, Issa JP: Decitabine--bedside to bench. Crit Rev Oncol Hematol. 2007 Feb;61(2):140-52. Epub 2006 Oct 4. [PubMed:17023173]
  2. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  3. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS: A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics. 2016 Jun 21;8:71. doi: 10.1186/s13148-016-0237-y. eCollection 2016. [PubMed:27330573]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Deamination of decitabine by cytidine deaminase and subsequent degradation is thought to be the main pathway of elimination.
General Function
Zinc ion binding
Specific Function
This enzyme scavenges exogenous and endogenous cytidine and 2'-deoxycytidine for UMP synthesis.
Gene Name
CDA
Uniprot ID
P32320
Uniprot Name
Cytidine deaminase
Molecular Weight
16184.545 Da
References
  1. Daskalakis M, Blagitko-Dorfs N, Hackanson B: Decitabine. Recent Results Cancer Res. 2010;184:131-57. doi: 10.1007/978-3-642-01222-8_10. [PubMed:20072836]
  2. Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H: Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer. 2008 Jun;112(11):2341-51. doi: 10.1002/cncr.23463. [PubMed:18398832]
  3. Stresemann C, Lyko F: Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int J Cancer. 2008 Jul 1;123(1):8-13. doi: 10.1002/ijc.23607. [PubMed:18425818]
  4. Seelan RS, Mukhopadhyay P, Pisano MM, Greene RM: Effects of 5-Aza-2'-deoxycytidine (decitabine) on gene expression. Drug Metab Rev. 2018 May;50(2):193-207. doi: 10.1080/03602532.2018.1437446. Epub 2018 Feb 18. [PubMed:29455551]
  5. Diesch J, Zwick A, Garz AK, Palau A, Buschbeck M, Gotze KS: A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers. Clin Epigenetics. 2016 Jun 21;8:71. doi: 10.1186/s13148-016-0237-y. eCollection 2016. [PubMed:27330573]
  6. Chabot GG, Bouchard J, Momparler RL: Kinetics of deamination of 5-aza-2'-deoxycytidine and cytosine arabinoside by human liver cytidine deaminase and its inhibition by 3-deazauridine, thymidine or uracil arabinoside. Biochem Pharmacol. 1983 Apr 1;32(7):1327-8. doi: 10.1016/0006-2952(83)90293-9. [PubMed:6189497]
  7. FDA Approved Drug Products: decitabine for injection [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Pyrimidine- and adenine-specific:sodium symporter activity
Specific Function
Sodium-dependent and pyrimidine-selective. Exhibits the transport characteristics of the nucleoside transport system cit or N2 subtype (N2/cit) (selective for pyrimidine nucleosides and adenosine)....
Gene Name
SLC28A1
Uniprot ID
O00337
Uniprot Name
Sodium/nucleoside cotransporter 1
Molecular Weight
71583.18 Da
References
  1. Rius M, Stresemann C, Keller D, Brom M, Schirrmacher E, Keppler D, Lyko F: Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation. Mol Cancer Ther. 2009 Jan;8(1):225-31. doi: 10.1158/1535-7163.MCT-08-0743. [PubMed:19139132]

Drug created on May 16, 2007 11:38 / Updated on July 16, 2020 10:16

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