Cytarabine
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| Systematic (IUPAC) name |
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4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one
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| Clinical data |
| Trade names |
Cytosar-U |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a682222 |
Pregnancy
category |
- AU: D
- US: D (Evidence of risk)
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| Legal status |
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Routes of
administration |
Injectable (intravenous injection or infusion, intrathecal, or subcutaneously) |
| Pharmacokinetic data |
| Bioavailability |
20% oral |
| Protein binding |
13% |
| Metabolism |
Liver |
| Biological half-life |
biphasic: 10 min, 1-3 hr |
| Excretion |
Renal |
| Identifiers |
| CAS Registry Number |
147-94-4 Y |
| ATC code |
L01BC01 |
| PubChem |
CID: 6253 |
| IUPHAR/BPS |
4827 |
| DrugBank |
DB00987 Y |
| ChemSpider |
6017 Y |
| UNII |
04079A1RDZ Y |
| KEGG |
D00168 Y |
| ChEBI |
CHEBI:28680 Y |
| ChEMBL |
CHEMBL803 Y |
| Chemical data |
| Formula |
C9H13N3O5 |
| Molecular mass |
243.217 g/mol |
SMILES
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O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@@H]2O)CO
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InChI
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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 Y
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Key:UHDGCWIWMRVCDJ-CCXZUQQUSA-N Y
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| Y (what is this?) (verify) |
Cytarabine or cytosine arabinoside (Cytosar-U or Depocyt) 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 kills 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]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[4]
Contents
- 1 Medical uses
- 2 Side effects
- 3 Mechanism of action
- 4 History
- 5 Brand names
- 6 References
- 7 External links
Medical uses
Cytarabine is mainly used in the treatment of acute myeloid leukaemia, acute lymphocytic leukaemia (ALL) and in lymphomas,[5] 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. Therefore, ara-C is not a useful antiviral agent in humans because of its toxic profile[6] and actually 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.[citation needed]
Side effects
One of the unique toxicities of cytarabine is cerebellar toxicity when given in high doses, which may lead to ataxia. Cytarabine may cause granulocytopenia and other impaired body defenses, which may lead to infection, and thrombocytopenia, which may lead to hemorrhage.
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.[7]
To prevent the side effects and improve the therapeutic efficiency, various derivatives of this drugs (including amino acid, peptide, fatty acid and phosphates) have been evaluated, as well as different delivery systems.[8]
Mechanism of action
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[9] and RNA polymerases and nucleotide reductase enzymes needed for DNA synthesis.
When used as an antiviral, cytarabine functions by inhibiting deoxycytidine use.[10]
Cytarabine is rapidly deaminated in the body into the inactive uracil derivative and therefore is often given by continuous intravenous infusion.
History
Cytarabine was first synthesized in 1959 by Richard Walwick, Walden Roberts, and Charles Dekker at the University of California, Berkeley.[11]
It was approved by the United States Food and Drug Administration in June 1969, and was initially marketed in the U.S. by Upjohn under the trade name Cytosar-U.
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". Jpn. J. Clin. Oncol. 27 (3): 154–7. doi:10.1093/jjco/27.3.154. PMID 9255269. [dead link]
- ^ 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.
- ^ Feist, Patty (April 2005). "A Tale from the Sea to Ara C".
- ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ 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.
- ^ Lauter, CB.; Bailey, EJ.; Lerner, AM. (Nov 1974). "Assessment of cytosine arabinoside as an antiviral agent in humans.". Antimicrob Agents Chemother 6 (5): 598–602. doi:10.1128/aac.6.5.598. PMID 15825312.
- ^ 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.
- ^ Chhikara BS, Parang K (2010). "Development of cytarabine prodrugs and delivery systems for leukemia treatment". Expert Opinion on Drug Delivery 7 (12): 1399–1414. doi:10.1517/17425247.2010.527330.
- ^ Perry, Michael J. (2008). The Chemotherapy source book. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 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. p. 963. ISBN 0-683-30737-1.
- ^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 258. ISBN 0-471-89979-8.
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.
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DNA virus antivirals (primarily J05, also S01AD and D06BB)
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| Baltimore I |
| Herpesvirus |
DNA-synthesis
inhibitor |
| TK activated |
| Purine analogue |
- guanine (Aciclovir#/Valaciclovir
- Ganciclovir/Valganciclovir
- Penciclovir/Famciclovir)
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| Pyrimidine analogue |
- uridine (Idoxuridine
- Trifluridine
- Edoxudine)
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| Not TK activated |
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|
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| Other |
- Docosanol
- early protein (Fomivirsen)
- Tromantadine
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|
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| HPV/MC |
- Imiquimod/Resiquimod
- Podophyllotoxin
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| Vaccinia |
|
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| Poxviridae |
|
|
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| Hepatitis B (VII) |
- Nucleoside analogues/NARTIs: Entecavir
- Lamivudine
- Telbivudine
- Clevudine
- Nucleotide analogues/NtRTIs: Adefovir
- Tenofovir
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| Multiple/general |
| Nucleic acid inhibitors |
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| Interferon |
- Interferon alfa 2b
- Peginterferon alfa-2a
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| Multiple/unknown |
- Ribavirin#/Taribavirin†
- Moroxydine
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- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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Index of viral disease
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| Description |
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| Disease |
- Systemic
- Cutaneous
- Zoster
- Human papillomavirus
- Zoonotic
- Symptoms and signs
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| Treatment |
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