Cytarabine

Cytarabine is a chemotherapy drug used to treat acute myeloid leukaemia, acting by inhibiting DNA synthesis with an IC50 of 16 nM.

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Cell Cycle/DNA Damage >> Nucleoside Antimetabolite/Analog

Research Areas >> Cancer

IC50: 16 nM (DNA synthesis)

Cytarabine is phosphorylated into a triphosphate form (Ara-CTP) involving deoxycytidine kinase (dCK), which competes with dCTP for incorporation into DNA, and then blocks DNA synthesis by inhibiting the function of DNA and RNA polymerases. Cytarabine displays a higher growth inhibitory activity towards wild-type CCRF-CEM cells compared to other acute myelogenous leukemia (AML) cells with IC50 of 16 nM[1]. Cytarabine apparently induces apoptosis of rat sympathetic neurons at 10 μM, of which 100 μM shows the highest toxicity and kills over 80% of the neurons by 84 hours, involving the release of mitochondrial cytochrome-c and the activation of caspase-3, and the toxicity can be attenuated by p53 knockdown and delayed by bax deletion[2].

Cytarabine (250 mg/kg) also causes placental growth retardation and increases placental trophoblastic cells apoptosis in the placental labyrinth zone of the pregnant Slc:Wistar rats, which increases from 3 hour after the treatment and peaks at 6 hour before returning to control levels at 48 hour, with remarkably enhanced p53 protein, p53 trancriptional target genes such as p21, cyclinG1 and fas and caspase-3 activity[3]. Cytarabine is highly effective against acute leukaemias, which causes the Cytarabine teristic G1/S blockage and synchronization, and increases the survival time for leukaemic Brown Norway rats in a weak dose-related fashion indicating that the use of higher dosages of Cytarabine does not contribute to its antileukaemic effectiveness in man[4].

Stock solution of Cytarabine is prepared in absolute ethanol, and serial dilutions of Cytarabine are prepared. CCRF-CEM cells are suspended in RPMI medium supplemented with 10% FBS, 0.1% gentamicin, and 1% sodium pyruvate. The cells are suspended in their respective media to give 10 mL volumes of cell suspension at a final density of 3-6×104 cells/mL. Appropriate volumes of Cytarabine solution are transferred to the cell suspensions, and incubation is continued for 72 hours. The cells are spun down and resuspended in fresh Cytarabine -free medium, and final cell counts are determined. The data are analyzed by sigmoidal curve fitting of the cell count versus Cytarabine concentration, and the results are expressed as the IC50 (Cytarabine concentration that inhibits cell growth to 50% of the control value).

Pregnant rats are injected intraperitoneally (i.p.) with 250 mg/kg of Cytarabine on Day 13 of gestation (GD13). Under the conditions of this experiment, congenital anomalies and growth retardation are detected at a high rate in perinatal fetuses, although the incidence of fetal death is not markedly increased. At 1, 3, 6, 9, 12, 24, and 48 h after the treatment, six dams each are killed by heart puncture under ether anesthesia, and the placentas are collected. As controls, six pregnant rats are injected i.p. with an equivalent volume of PBS on GD13 and killed at the same time point as Cytarabine-treated groups. Of the six dams obtained at each time point, three are used for histopathological analyses and three for reverse transcription-polymerase chain reaction (RT-PCR) analysis.

[1]. Tobias, S.C. and R.F. Borch, Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug. Mol Pharm, 2004. 1(2): p. 112-6.

[2]. Besirli, C.G., et al. Cytosine arabinoside rapidly activates Bax-dependent apoptosis and a delayed Bax-independent death pathway in sympathetic neurons. Cell Death Differ, 2003. 10(9): p. 1045-58.

[3]. Yamauchi, H., et al., Involvement of p53 in 1-beta-D-arabinofuranosylcytosine-induced trophoblastic cell apoptosis and impaired proliferation in rat placenta. Biol Reprod, 2004. 70(6): p. 1762-7.

[4]. Richel, D.J., et al., Comparison of the antileukaemic activity of 5 aza-2-deoxycytidine and arabinofuranosyl-cytosine in rats with myelocytic leukaemia. Br J Cancer, 1988. 58(6): p. 730-3.

Azacitidine (5-Azacytidine) | Broxuridine | Forodesine (hydrochloride) | Floxuridine | Raltitrexed | Trifluorothymidine | Vidarabine | Tipiracil hydrochloride | Clofarabine | Doxifluridine | Nelarabine | 8-Azaguanine | RX-3117 | Tegafur | LY2334737

MOLECULAR FORMULA :

C9-H13-N3-O5

MOLECULAR WEIGHT :

243.25

WISWESSER LINE NOTATION :

T6NVNJ DZ A- BT5OTJ CQ DQ E1Q

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

Standard Draize test

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Human

TYPE OF TEST :

Standard Draize test

ROUTE OF EXPOSURE :

Administration into the eye

SPECIES OBSERVED :

Human

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

60 mg/kg/90W-I

TOXIC EFFECTS :

Sense Organs and Special Senses (Ear) - change in acuity Behavioral - ataxia Blood - changes in spleen

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

6480 ug/kg/12D-I

TOXIC EFFECTS :

Blood - other changes

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human - child

DOSE/DURATION :

33200 ug/kg/240D-I

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - convulsions or effect on seizure threshold Nutritional and Gross Metabolic - body temperature increase

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human

DOSE/DURATION :

17241 mg/kg/6D-I

TOXIC EFFECTS :

Skin and Appendages - dermatitis, allergic (after systemic exposure)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human - woman

DOSE/DURATION :

720 mg/kg/3D-I

TOXIC EFFECTS :

Brain and Coverings - other degenerative changes

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

649 mg/kg/4D-I

TOXIC EFFECTS :

Peripheral Nerve and Sensation - fasciculations

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

1536 mg/kg/43W-I

TOXIC EFFECTS :

Peripheral Nerve and Sensation - fasciculations Behavioral - ataxia

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Human - man

DOSE/DURATION :

23500 ug/kg/7D-C

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - visual field changes Sense Organs and Special Senses (Eye) - lacrimation Sense Organs and Special Senses (Eye) - conjunctive irritation

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>5 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>5 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>5 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>5 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

3150 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

3779 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>10 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>7 gm/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Administration onto the skin

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

875 mg/kg/5W-I

TOXIC EFFECTS :

Endocrine - changes in spleen weight Blood - changes in erythrocyte (RBC) count Blood - changes in leukocyte (WBC) count

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

300 mg/kg/5D-I

TOXIC EFFECTS :

Blood - changes in bone marrow (not otherwise specified) Blood - changes in leukocyte (WBC) count Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

280 mg/kg/7D-I

TOXIC EFFECTS :

Gastrointestinal - other changes Blood - changes in erythrocyte (RBC) count Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Primate - monkey

DOSE/DURATION :

280 mg/kg/7D-I

TOXIC EFFECTS :

Behavioral - food intake (animal) Gastrointestinal - hypermotility, diarrhea Blood - changes in erythrocyte (RBC) count

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

2500 mg/kg/7W-I

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Blood - lymphoma, including Hodgkin's disease Skin and Appendages - tumors

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

4836 mg/kg/26W-I

TOXIC EFFECTS :

Tumorigenic - equivocal tumorigenic agent by RTECS criteria Lungs, Thorax, or Respiration - tumors Blood - lymphoma, including Hodgkin's disease

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

100 mg/kg

SEX/DURATION :

female 11 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - other effects to embryo

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

20 mg/kg

SEX/DURATION :

female 11 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetal death Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

50 mg/kg

SEX/DURATION :

female 12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

30 mg/kg

SEX/DURATION :

female 12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

7500 ug/kg

SEX/DURATION :

female 10 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Subcutaneous

DOSE :

75 mg/kg

SEX/DURATION :

female 18-20 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - stillbirth Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

90 mg/kg

SEX/DURATION :

female 9-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

360 mg/kg

SEX/DURATION :

female 9-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - live birth index (measured after birth) Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

180 mg/kg

SEX/DURATION :

female 9-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetal death

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Unreported

DOSE :

50 mg/kg

SEX/DURATION :

female 12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

5 mg/kg

SEX/DURATION :

female 10 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - cytological changes (including somatic cell genetic material)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

60 mg/kg

SEX/DURATION :

female 13-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - litter size (e.g. # fetuses per litter; measured before birth) Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

5 mg/kg

SEX/DURATION :

female 11 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

25 mg/kg

SEX/DURATION :

female 10 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

33 mg/kg

SEX/DURATION :

male 1 day(s) pre-mating

TOXIC EFFECTS :

Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

60 mg/kg

SEX/DURATION :

female 13-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - Central Nervous System

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

50 mg/kg

SEX/DURATION :

female 12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - live birth index (measured after birth) Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intraperitoneal

DOSE :

80 mg/kg

SEX/DURATION :

female 6-15 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

45 mg/kg

SEX/DURATION :

female 7-12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetal death Reproductive - Effects on Newborn - live birth index (measured after birth)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

18 mg/kg

SEX/DURATION :

female 7-12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4)

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

9 mg/kg

SEX/DURATION :

female 7-12 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Parenteral

DOSE :

60 mg/kg

SEX/DURATION :

female 13-14 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

TYPE OF TEST :

Specific locus test

TYPE OF TEST :

Specific locus test

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

Unscheduled DNA synthesis

TYPE OF TEST :

DNA inhibition

TYPE OF TEST :

DNA inhibition

TYPE OF TEST :

DNA inhibition

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Cytogenetic analysis

TYPE OF TEST :

Sister chromatid exchange

TYPE OF TEST :

Dominant lethal test

TYPE OF TEST :

Sperm Morphology

TYPE OF TEST :

DNA inhibition

MUTATION DATA

TYPE OF TEST :

Cytogenetic analysis

TEST SYSTEM :

Mammal - species unspecified Fibroblast

DOSE/DURATION :

15 umol/L

REFERENCE :

MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 178,73,1987 *** REVIEWS *** TOXICOLOGY REVIEW 32XPAD "Teratology," Berry, C.L., and D.E. Poswillo, eds., New York, Springer, 1975 Volume(issue)/page/year: -,49,1975 TOXICOLOGY REVIEW ARVPAX Annual Review of Pharmacology. (Palo Alto, CA) V.1-15, 1961-75. For publisher information, see ARPTDI. Volume(issue)/page/year: 5,447,1965 TOXICOLOGY REVIEW CRTXB2 CRC Critical Reviews in Toxicology. (CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- Volume(issue)/page/year: 2,159,1973 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X3689 No. of Facilities: 450 (estimated) No. of Industries: 1 No. of Occupations: 7 No. of Employees: 18673 (estimated) No. of Female Employees: 12859 (estimated)