5-アザシチジン

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.

Intact vials should be stored under refrigeration & are stable for a least 4 yr. Although the drug is stable for 3 yr at room temp, refrigeration is recommended because degradation may result at elevated temperatures. The constituted soln hydrolyzes at room temp & should be used within 30 min. ... Azacitidine 0.5 & 2 mg/ml in Ringer's injection, lactated, was stable for up to one month when frozen at -20 °C in polypropylene syringes.

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.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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)

In clinical trials, serum enzyme elevations occurred in up to 16% of patients on azacitidine therapy for cancer or myelodysplasia who had concurrent, underlying liver disease or liver metastases, but rarely in persons without a preexisting hepatic illness. In subsequent studies, liver adverse reactions attributed to azacitidine have rarely been reported, at least when it is given in conventional doses. Nevertheless, monitoring of serum enzyme levels is recommended in treating patients who have concurrent liver disease. Cases of clinically apparent liver injury attributed to azacitidine in patients without underlying liver disease have not been reported in the literature.

Azacitidine (5-azacytidine) is a chemical analogue of the cytosine nucleoside used in DNA and RNA. Azacitidine is thought to induce antineoplastic activity via two mechanisms; inhibition of DNA methyltransferase at low doses, causing hypomethylation of DNA, and direct cytotoxicity in abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA at high doses, resulting in cell death. As azacitidine is a ribonucleoside, it incoporates into RNA to a larger extent than into DNA. The incorporation into RNA leads to the dissembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of protein. Its incorporation into DNA leads to a covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequent cytotoxicity.

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=320-67-2]

Human systemic effects by iv route: nausea, vomiting & diarrhea, reduction in white cell count (leukopenia & agranulocytosis).

Acute Toxicity: Nausea & vomiting; diarrhea; fever; rash; drowsiness. Delayed Toxicity: Bone marrow depression; hepatic damage; muscle pain & weakness; possibly cardiotoxicity. /From table/

A skin irritant.

... Treated human cells, in which separation does not depend upon the quantity of heterochromatin, /was coducted/ with 2x10(-5) and 6x10(-6) M 5-AC for 5 and 8 hr. Compared with the control, 5-AC treatment resulted in an increased frequency of separated centromeres of acrocentric chromosomes in relation to those of non-acrocentric chromosomes. In the control the acrocentric chromosomes are the last to separate; in the treated population there was almost random separation of the two types of chromosomes. This epigenetic alteration might be another factor which results in genesis of aneuploidy.

High dose azacitidine causes renal dysfunction manifested by tubular acidosis, polyuria and increased urinary excretion of electrolytes, glucose and amino acids.

Azacitidine

Group 2A: Probably carcinogenic to humans

Volume 50: (1990) Pharmaceutical Drugs

1990

1989

NB Overall evaluation upgraded to Group 2A with supporting evidence from other relevant data

Drug Induced Liver Injury Rank (DILIrank 2.0)

Azacitidine

Ambiguous-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

An experimental teratogen. Other experimental reproductive effects.

DNA methylation is an epigenetical mechanism that plays crucial roles in cellular differentiation and tissue development in embryogenesis. The aim of the present study was to determine the effects of a demethylating agent, 5-azacytidine, on testicular development during embryonal life in mouse. Ten pregnant mice were administered 5-azacytidine (5-azaC) (ip 2 mg/kg of agent dissolved in 0.1 mg/ml PBS) during 8th (Group 1), 11th (Group 2), 14th (Group 3) and 18th (Group 4) days of pregnancy periods and male siblings of these animals were obtained (experimental groups) whereas the control group animals received no treatment and siblings of this group were also obtained. Testicular tissues from all groups were taken 20 days after birth and examined at the light and electron microscopical levels. All pregnancies were terminated in Group 1 animals, therefore no observations could be done in this group. While Group 2 and 3 siblings showed distinctive kongenital abnormalities such as; anancephaly, growth failure, cleft palate, extremity abnormalities, supernumerary ribs and whirled shaped-tails, no such abnormalities were observed in Group 4 when compared to the control group. Microscopical examination of testicular tissues in groups 2 and 3 demonstrated cellular disintegration of spermatocytes in seminiferous tubules. In addition, cytoplasmic vacuoles and thickening of the basement membrane were also evident in both groups 2 and 3. Apoptotic-like cells were seen especially in group 2 and rarely in group 3. There were no structural alterations in group 4 animals, except a decreased number of spermatocytes in seminiferous tubules when compared to the control group, possibly indicating the completion of embryogenesis in this group. In conclusion, it could be suggested that the demethylating agent 5-azacytidine may trigger an unknown gene reactivation during early embryogenesis possibly affecting the cell and tissue differentiation in developing mammalian embryos.

The cytosine analog 5-azacytidine (5-AzaC) is a demethylating agent that is also known to induce mutagenesis in mammalian cells. In this study, the mutagenic potential of this drug was tested in the G10 and G12 transgenic Chinese hamster cell lines, which have a single bacterial gpt gene integrated into the genome at different sites, with its expression driven by a simian virus 40 (SV40) promoter. We show that the mutation frequencies following a 48-h exposure to different concentrations of 5-AzaC were 10 to 20 times higher than those of any of the other numerous mutagens that have been tested in the G10-G12 system. Moreover, the mutation frequencies were much higher in the G10 cell line than in the G12 cells. Detailed molecular analysis of the 6-thioguanine (6-TG)-resistant variants demonstrated that transgene silencing by de novo DNA methylation and increased chromatin condensation in the SV40 promoter was the major factor responsible for this high level of 6-TG resistance. As would be expected, exposure to 5-AzaC lowered the overall genomic DNA methylation levels, but it unexpectedly caused hypermethylation and increased chromatin condensation of the transgene in both the G10 and G12 cell lines. These results provide the first evidence that 5-AzaC may also induce transgene-specific DNA methylation, a phenomenon that can further be used for the elucidation of the mechanism that controls silencing of foreign DNA.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

Anticancer agent used to treat acute myclogenous leukemia

For treatment of patients with the following French-American-British myelodysplastic syndrome subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation (now classified as acute myelogenous leukemia with multilineage dysplasia), and chronic myelomonocytic leukemia.