- Cytarabine
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Cytarabine 
Systematic (IUPAC) name 4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one Clinical data AHFS/Drugs.com monograph MedlinePlus a682222 Pregnancy cat. D (USA); D (Aus) Legal status ? Routes Injectable (intravenous injection or infusion, intrathecal, or subcutaneously) Pharmacokinetic data Bioavailability 20% oral Protein binding 13% Metabolism Liver Half-life biphasic: 10 min, 1-3 hr Excretion Renal Identifiers CAS number 147-94-4 
ATC code L01BC01 PubChem CID 6253 DrugBank APRD00499 ChemSpider 6017 UNII 04079A1RDZ KEGG D00168 ChEBI CHEBI:28680 ChEMBL CHEMBL803 Chemical data Formula C9H13N3O5 Mol. mass 243.217 g/mol SMILES eMolecules & PubChem - InChI=1S/C9H13N3O5/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6-,7+,8-/m1/s1
Key:UHDGCWIWMRVCDJ-CCXZUQQUSA-N
(what is this?) (verify)Cytarabine, or cytosine arabinoside, is a chemotherapy agent used mainly in the treatment of cancers of white blood cells such as acute myeloid leukemia (AML) and non-Hodgkin lymphoma.[1] It is also known as Ara-C (Arabinofuranosyl Cytidine).[2] It destroys cancer cells by interfering with DNA synthesis.
It is called cytosine arabinoside because it combines a cytosine base with an arabinose sugar. Cytosine normally combines with a different sugar, deoxyribose, to form deoxycytidine, a component of DNA. Certain sponges, where it was originally found, use arabinoside sugars to form a different compound (not part of DNA). Cytosine arabinoside is similar enough to human cytosine deoxyribose (deoxycytidine) to be incorporated into human DNA, but different enough that it kills the cell. This mechanism is used to kill cancer cells. Cytarabine is the first of a series of cancer drugs that altered the sugar component of nucleosides. Other cancer drugs modify the base.[3]
Contents
History
Cytarabine was first synthesized in 1959 by Richard Walwick, Walden Roberts, and Charles Dekker at the University of California, Berkeley.[4]
It was approved by the United States Food and Drug Administration in June 1969, and was initially marketed in the US by Upjohn under the trade name Cytosar-U.
Pharmacology
Mechanism
Cytosine arabinoside interferes with the synthesis of DNA. It is an antimetabolic agent with the chemical name of 1β-arabinofuranosylcytosine. Its mode of action is due to its rapid conversion into cytosine arabinoside triphosphate, which damages DNA when the cell cycle holds in the S phase (synthesis of DNA). Rapidly dividing cells, which require DNA replication for mitosis, are therefore most affected. Cytosine arabinoside also inhibits both DNA[5] and RNA polymerases and nucleotide reductase enzymes needed for DNA synthesis.
When used as an antiviral, cytarabine functions by inhibiting deoxycytidine use.[6]
Cytarabine is rapidly deaminated in the body into the inactive uracil derivative and therefore is often given by continuous intravenous infusion.
Pharmacokinetics
Orally, less than 20% of a dose of cytarabine is absorbed from the gastrointestinal tract and is ineffective by this route. Subcutaneously or intramuscularly, tritium-labelled cytarabine produces peak plasma concentrations of radioactivity within 20 to 60 minutes which are considerably lower than those attained after intravenous administration. Continuous intravenous infusions produce relatively constant plasma levels in 8 to 24 hours.
Intravenous doses of cytarabine exhibit a biphasic elimination, with an initial distribution half-life of about ten minutes during which time a major portion of the drug is metabolised in the liver to the inactive metabolite uracil arabinoside. The secondary elimination half-life is longer, approximately one to three hours. Metabolism also occurs in the kidneys, gastrointestinal mucosa, granulocytes and other tissues.
Cytarabine is mainly excreted via the kidney with 70 to 80% of a dose administered by any route appearing in the urine within 24 hours; approximately 90% as the metabolite and 10% as unchanged drug.
Clinical uses
Cytarabine is mainly used in the treatment of acute myeloid leukaemia, acute lymphocytic leukaemia (ALL) and in lymphomas,[7] where it is the backbone of induction chemotherapy.
Cytarabine also possesses antiviral activity, and it has been used for the treatment of generalised herpesvirus infection. However, cytarabine is not very selective in this setting and causes bone marrow suppression and other severe side effects, so it is used mainly for the chemotherapy of hematologic cancers.
Cytarabine is also used in the study of the nervous system to control the proliferation of glial cells in cultures, the amount of glial cells having an important impact on neurons.
Side effects
One of the unique toxicities of cytarabine is cerebellar toxicity when given in high doses.
Possible infection resulting from granulocytopenia and other impaired body defences, and hemorrhage secondary to thrombocytopenia
Toxicity: Leukopenia, Thrombocytopenia, anemia, GI disturbances, stomatitis, conjunctivitis, pneumonitis, fever, and dermatitis, Palmar-Plantar Erythrodysesthesia.
Rarely, myelopathy has been reported after high dose or frequent intrathecal Ara-C administration.[8]
Brand names
- Cytosar-U
- Tarabine PFS (Pfizer)
- Depocyt (longer-lasting liposomal formulation)
- AraC
References
- ^ Wang WS, Tzeng CH, Chiou TJ, et al. (June 1997). "High-dose cytarabine and mitoxantrone as salvage therapy for refractory non-Hodgkin's lymphoma" ([dead link]). Jpn. J. Clin. Oncol. 27 (3): 154–7. doi:10.1093/jjco/27.3.154. PMID 9255269. http://jjco.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9255269.
- ^ Ogbomo H, Michaelis M, Klassert D, Doerr HW, Cinatl J (December 2008). "Resistance to cytarabine induces the up-regulation of NKG2D ligands and enhances natural killer cell lysis of leukemic cells". Neoplasia 10 (12): 1402–10. PMC 2586691. PMID 19048119. http://www.neoplasia.com/abstract.php?msid=1944.
- ^ Feist, Patty (April 2005). "A Tale from the Sea to Ara C". http://www.pfeist.net/ALL/arac/.
- ^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 258. ISBN 0-471-89979-8.
- ^ Perry, Michael J. (2008). The Chemotherapy source book. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 80. ISBN 0-7817-7328-8.
- ^ Lemke, Thomas L.; Williams, David H.; Foye, William O. (2002). Foye's principles of medicinal chemistry. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 963. ISBN 0-683-30737-1.
- ^ Pigneux A, Perreau V, Jourdan E, et al. (October 2007). "Adding lomustine to idarubicin and cytarabine for induction chemotherapy in older patients with acute myeloid leukemia: the BGMT 95 trial results". Haematologica 92 (10): 1327–34. doi:10.3324/haematol.11068. PMID 18024370. http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=18024370.
- ^ Watterson J, Toogood I, Nieder M, et al. (December 1994). "Excessive spinal cord toxicity from intensive central nervous system-directed therapies". Cancer 74 (11): 3034–41. doi:10.1002/1097-0142(19941201)74:11<3034::AID-CNCR2820741122>3.0.CO;2-O. PMID 7954266.
External links
- MedlinePlus page on cytarabine
- ADAP drugs page on cytarabine
- BC Cancer network page on cytarabine
- Chembank entry
- Sea to Ara C An essay on the history of cytarabine.
DNA virus antivirals (primarily J05, also S01AD and D06BB) Baltimore I DNA-synthesis
inhibitorTK activatedguanine (Aciclovir#/Valacyclovir, Ganciclovir/Valganciclovir, Penciclovir/Famciclovir)
adenine (Vidarabine)Not TK activatedOtherImiquimod/Resiquimod • PodophyllotoxinHepatitis B (VII) Nucleoside analogues/NARTIs: Entecavir • Lamivudine • Telbivudine • Clevudine
Nucleotide analogues/NtRTIs: Adefovir • TenofovirMultiple/general Nucleic acid inhibitorsMultiple/unknownErbB2/PI3K PathwayNOV-205§ • NOV-002†Categories:- Antineoplastic antimetabolites
- Nucleosides
- Pyrimidones
- InChI=1S/C9H13N3O5/c10-5-1-2-12(9(16)11-5)8-7(15)6(14)4(3-13)17-8/h1-2,4,6-8,13-15H,3H2,(H2,10,11,16)/t4-,6-,7+,8-/m1/s1
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