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a base found in DNA and RNA and derived from pyrimidine; pairs with guanine (同)C

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/07/21 16:26:41」(JST)

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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]

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]

When used in protocols designated as high dose, cytarabine can cause cerebral and cerebellar dysfunction, ocular toxicity, pulmonary toxicity, severe GI ulceration and peripheral neuropathy (rare).

To prevent the side effects and improve the therapeutic efficiency, various derivatives of these 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.

UpToDate Contents

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English Journal

Midostaurin, bortezomib and MEC in relapsed/refractory acute myeloid leukemia.

Walker AR1, Wang H1, Walsh K1, Bhatnagar B1, Vasu S1, Garzon R1, Canning R1, Geyer S2, Wu YZ1, Devine SM1, Klisovic R1, Blum W1, Marcucci G3.
Leukemia & lymphoma.Leuk Lymphoma.2016 Sep;57(9):2100-8. doi: 10.3109/10428194.2015.1135435. Epub 2016 Jan 19.
Targeting aberrant tyrosine kinase activity may impact clinical outcome in acute myeloid leukemia (AML). We conducted a phase I study of the tyrosine kinase inhibitor midostaurin with bortezomib alone and in combination with chemotherapy in patients with AML. Patients on dose levels 1 and 2 (DL1 &am
PMID 26784138

Gemcitabine induces cell senescence in human pancreatic cancer cell lines.

Song Y1, Baba T2, Mukaida N3.
Biochemical and biophysical research communications.Biochem Biophys Res Commun.2016 Aug 26;477(3):515-9. doi: 10.1016/j.bbrc.2016.06.063. Epub 2016 Jun 14.
Patients with pancreatic ductal adenocarcinoma (PDAC) commonly require chemotherapy because they frequently develop metastatic disease or locally advanced tumors. Gemcitabine, an analogue of cytosine arabinoside, is commonly used for PDAC treatment. We observed that gemcitabine induced senescence ph
PMID 27311854

High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk-oriented consolidation: A critical review of a 10-year, single-center experience in younger, non M3 AML patients.

Guolo F1, Minetto P1, Clavio M1, Miglino M1, Di Grazia C2, Ballerini F1, Pastori G1, Guardo D1, Colombo N1, Kunkl A3, Fugazza G1, Rebesco B4, Sessarego M1, Lemoli RM1, Bacigalupo A2, Gobbi M1.
American journal of hematology.Am J Hematol.2016 Aug;91(8):755-62. doi: 10.1002/ajh.24391. Epub 2016 Jun 15.
About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida)
PMID 27084986

Japanese Journal

白血病における抗がん剤耐性の分子機構 (特集造血器腫瘍診療における注目すべき薬剤耐性とその克服)

宮地勇人,松下弘道,浅井さとみ
血液内科 63(5), 493-497, 2011-11
NAID 40019086636

Cytosine-arabinoside Stimulates the Capablity of Human Marrow Stromal Cells to Support Normal Hematopoiesis

Li HongZhang,Koh Ki-Ryang,Toramoto Takuya,Nakamae Hirohisa,Yamane Takahisa,Ohta Kensuke,Hino Masayuki
Osaka City Medical journal 56(2), 11-20, 2010-12
NAID 110007865051

Related Pictures

★リンクテーブル★

リンク元	「シタラビン」「ara-C」「cytarabine hydrochloride」「シトシンアラビノシド」「arabinofuranosylcytosine」
関連記事	「cytosine」

「シタラビン」

Cytarabine
Systematic (IUPAC) name
	4-amino-1-[(2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one
Clinical data
Trade names	Cytosar-U
AHFS/Drugs.com	Monograph
MedlinePlus	a682222
Pregnancy; category	AU: D; US: D (Evidence of risk); ;
Routes of; administration	Injectable (intravenous injection or infusion, intrathecal, or subcutaneously)
Legal status
Legal status	℞ (Prescription only);
Pharmacokinetic data
Bioavailability	20% oral
Protein binding	13%
Metabolism	Liver
Biological half-life	biphasic: 10 min, 1–3 hr
Excretion	Renal
Identifiers
CAS Number	147-94-4
ATC code	L01BC01 (WHO)
PubChem	CID 6253
IUPHAR/BPS	4827
DrugBank	DB00987
ChemSpider	6017
UNII	04079A1RDZ
KEGG	D00168
ChEBI	CHEBI:28680
ChEMBL	CHEMBL803
Chemical data
Formula	C9H13N3O5
Molar mass	243.217 g/mol
	SMILES O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@@H]2O)CO ;
	InChI 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 ;
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