5-Aza-2'-deoxycytidine

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).
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).

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.
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.

Description

Decitabine, 5-aza-2’-deoxycytidine, has been launched for the treatment of myelodysplastic syndromes (MDS). MDS are a set of hematologic disorders affecting the bone marrow that result in ineffective formation and development of blood cells. Furthermore, patients with MDS have a high risk of progressing to acute myeloid leukemia (AML). Traditional treatments include blood transfusions, hematopoietic growth factors, and prophylactic antibiotics, but these measures merely improve the quality of life with questionable effects on disease modification. While stem-cell transplantation is an aggressive, potentially curative approach, the advanced age or the other complicating health issues of most patients preclude them from considering this option. Recent advances in the underlying etiology of MDS, however, have led to the development of a new class of compounds known as ‘‘demethylating agents’’. Decitabine follows the successful introduction of the first DNA methyltransferase inhibitor azacitidine.

Chemical properties

white crystalline powder

Originator

Pharmachemie (Netherlands)

The Uses of 5-Aza-2'-deoxycytidine

Decitabine is a potent inhibitor of DNA methylation with IC50 of 438 nM and 4.38 nM in HL-60 and KG1a cells, respectively

The Uses of 5-Aza-2'-deoxycytidine

5-Aza-2′-deoxycytidine has been used as a demethylating agent in breast cancer cell line, chromatin, DNA and promoter region of p16 gene.

The Uses of 5-Aza-2'-deoxycytidine

Used as cancer treatment, in particular to inhibit the growth of pancreatic endocrine tumor cell lines.

Definition

ChEBI: 5-aza-2'-deoxycytidine is a 2'-deoxyribonucleoside.

Background

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. 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.
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?. It is also available as an oral combination product together with the cytidine deaminase inhibitor cedazuridine.

What are the applications of Application

5-Aza-2′-Deoxycytidine is a DNMT inhibitor shown to alter gene expression.

Indications

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.

brand name

Dacogen (Millot Laboratories, France).

General Description

Fine white crystalline powder. Used as a drug.

Air & Water Reactions

Probably light and air sensitive. Water soluble. Decomposes in aqueous solution at a rate that depends on pH: at pH 7 the drug is more stable than at pH 9, but is less stable than at pH 6. At pH 7 and 99°F, approximately 7% conversion occurs in 1 hour .

Reactivity Profile

5-Aza-2'-deoxycytidine is an aminoalcohol. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

Fire Hazard

Flash point data for 5-Aza-2'-deoxycytidine are not available. 5-Aza-2'-deoxycytidine is probably combustible.

Biological Activity

Cytosine analog that once incorporated into DNA acts as a suicide substrate for DNA methyltransferase. Inhibits DNA methyltransferase and results in DNA hypomethylation and activation of silent genes. Chemotherapeutic agent; suppresses growth of human tumor cell lines. Demethylates differentiation-related genes; reverses embryonic stem cell differentiation.

Biochem/physiol Actions

Primary TargetDNA methyltransferase inhibitor

Pharmacokinetics

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. 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.

Clinical Use

Antineoplastic antimetabolite agent:
Treatment of acute myeloid leukaemia

Safety Profile

Poison by intravenous route.Human mutation data reported. When heated todecomposition it emits toxic fumes of NOx.

Synthesis

Silylated 5-aza-cytosine (28) was condensed with 9- fluorenylmethoxycarbonyl (Fmoc) protected 2-deoxy-1-chlororibose (27) with tin chloride (IV) in dichloroethane (Scheme 4). The coupled product 29 was de-protected with excess triethylamine in dry pyridine to give decitabine (IV) in 36% yield after separation from its corresponding |áisomer.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

Metabolism

The exact route of metabolism and elimination is unknown but thought to be through deamination by cytidine deaminase in the liver, kidney, intestinal epithelium and blood to form inactive metabolites.

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. Decitabine not incorporated into cellular DNA undergoes deamination by cytidine deaminase followed by additional degradation prior to excretion.

storage

+4°C

References

1) Bender et al. (1998), Inhibition of DNA methylation by 5-aza-2′-deoxycytidine suppresses the growth of human tumor cell lines; Cancer Res., 58 95 2) El-Serafi et al. (2011), Epigenetic modifiers influence lineage commitment of human bone marrow stromal cells: Differential effects of 5-aza-deoxycytidine and trichostatin A; Differentiation, 81 35