5-Aza-2′-deoxycytidine

228.21

228.21

219-089-4

776B62CQ27

DTXSID7030432

C981

L01BC08|L - Antineoplastic and immunomodulating agents

29349990

121

-1.2

White to Off-white Powder

1.9±0.1 g/cm3

198-199 °C (decomp)

485.8°C at 760 mmHg

247.6±31.5 °C

1.780

acetic acid/water (1:1): 50 mg/mL

−20°C

1.78E-11mmHg at 25°C

Intravenous-mouse LD50: 22 mg/kg; Intraperitoneal-mouse LD50: 190 mg/kg

Flammable; burning produces toxic nitrogen oxide fumes

D22 +68.5° (30 min)+57.8° (6 hr) (c = 0.5 in water)

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 (NTP, 1992).

Alcohols and Polyols

5-AZA-2'-DEOXYCYTIDINE is an organic compound with both amine and alcohol substituents. 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.

NONH for all modes of transport

3

22-36/37/38-68-61

26-36-36/37

XZ3012000

Xn,Xi,T

Ventilated, low temperature and dry; stored separately from food materials in warehouse

Stable. May be light or air sensitive. Incompatible with strong oxidizing agents.

P201-P261-P281-P305 + P351 + P338-P308 + P313

H302-H315-H319-H335-H341-H360

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Danger|H302 (93.33%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P261, P264, P270, P271, P280, P281, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 45 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should protect this chemical from exposure to light. Keep the container tightly closed under an inert atmosphere, and store it in a freezer. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992)

highly toxic

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.

In early clinical trials using high doses of decitabine, serum enzyme elevations occurred in up to 16% of patients with underlying liver disease or liver metastases, but rarely in persons without hepatic illness. In subsequent studies, serum ALT elevations were reported in 5% to 15% of treated patients, but all were self-limited and no clinically apparent liver injury was reported. Recent studies have reported elevations in serum bilirubin levels in 7% to 12% of treated patients, but the elevations resolved rapidly and were not associated with other clinical or laboratory evidence of liver injury. Monitoring of serum enzyme levels during treatment is recommended only in patients with concurrent liver disease.

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

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.|FDA Label|Treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukaemia (AML), according to the World Health Organization (WHO) classification, who are not candidates for standard induction chemotherapy.|Treatment of acute myeloid leukaemia|Drug: Decitabine

Decitabine is a cytosine analogue and an intravenously administered antineoplastic agent used in the therapy of myelodysplastic syndromes. Decitabine is associated with a low rate of transient serum enzyme elevations during therapy, but has not been implicated in causing clinically apparent liver injury with jaundice.

Antineoplastic Agents

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.

Antimetabolites that are useful in cancer chemotherapy. (See all compounds classified as Antimetabolites, Antineoplastic.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

Decitabine administered intravenously at 15 mg/m² for three hours every eight hours over three days resulted in a C_max of 73.8 ng/mL (66% coefficient of variation, CV), an AUC_0-∞ 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 C_max of 147 ng/mL (49% CV), an AUC_0-∞ of 115 ng\*h/mL (43% CV), and a cumulative AUC of 570 ng\*h/mL (95% CI of 470-700).|Less than 1% of administered decitabine is excreted in the urine.|Decitabine as an apparent volume of distribution of 4.59 ± 1.42 L/kg.|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.

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.

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.

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. 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. 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. 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. 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. 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. The overall effect of decitabine is a decrease in neoplastic cell proliferation and an increase in the expression of tumour suppressor genes.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. IMMEDIATELY call a physician and be prepared to transport the victim to a hospital even if no symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Generally, the induction of vomiting is NOT recommended outside of a physician's care due to the risk of aspirating the chemical into the victim's lungs. However, if the victim is conscious and not convulsing and if medical help is not readily available, consider the risk of inducing vomiting because of the high toxicity of the chemical ingested. Ipecac syrup or salt water may be used in such an emergency. IMMEDIATELY transport the victim to a hospital. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

2' Deoxy 5 azacytidine

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