関: ara-C、cytarabine、cytarabine hydrochloride、cytosine arabinoside

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/04/14 00:45:12」(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]

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 U.S. by Upjohn under the trade name Cytosar-U.

Pharmacology

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^[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.

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. Therefore, ara-C is not a useful antiviral agent in humans because of its toxic profile^[8] 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.^[9]

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.^[10]

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".
^ 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. 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.
^ 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. 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.

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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1. 再発性または難治性の急性骨髄性白血病の治療 treatment of relapsed or refractory acute myeloid leukemia

English Journal

A prospective, multicenter phase II study of continuous infusion of FLAG for patients older than 60 yr with resistant acute myeloid leukemia: a comparison with intensive younger patients' trial.

Kim H1, Lee JH2, Joo YD3, Bae SH4, Lee JH2, Kim DY2, Lee WS5, Ryoo HM4, Jo JC1, Choi Y1, Lee KH2; CoOperative Study Group A for Hematology (COSAH).
European journal of haematology.Eur J Haematol.2016 Feb;96(2):188-97. doi: 10.1111/ejh.12568. Epub 2015 May 6.
Relapsed or refractory acute myeloid leukemia (R/R AML) in elderly (≥60 yr old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24-hr CI without idarubicin (C-FLAG), which was compared with the results of C-FLAG with idarubicin (CI-FLAG2) in younger
PMID 25891993

Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan.

Taga T1, Watanabe T2, Tomizawa D3, Kudo K4, Terui K5, Moritake H6, Kinoshita A7, Md SI8, Md HN9, Md HT10, Md AS11, Taki T12, Toki T5, Ito E5, Goto H13, Koh K14, Saito AM15, Horibe K16, Nakahata T17, Tawa A18, Adachi S19.
Pediatric blood & cancer.Pediatr Blood Cancer.2016 Feb;63(2):248-54. doi: 10.1002/pbc.25789. Epub 2015 Oct 20.
BACKGROUND: On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study.PROCEDURE: All patients received induction chemotherapy that consis
PMID 26481183

A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee).

Nelken B1, Cave H2, Leverger G3, Galambrun C4, Plat G5, Schmitt C6, Thomas C7, Vérité C8, Brethon B9, Gandemer V10, Bertrand Y11, Baruchel A12, Rohrlich P13.
Pediatric blood & cancer.Pediatr Blood Cancer.2016 Feb;63(2):270-5. doi: 10.1002/pbc.25751. Epub 2015 Sep 16.
BACKGROUND: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and compl
PMID 26376115

Japanese Journal

Acquired resistance of leukemic cells to AraC is associated with the upregulation of aldehyde dehydrogenase 1 family member A2.

Kawasoe Misaki,Yamamoto Yasuko,Okawa Katsuya,Funato Tadao,Takeda Mayu,Hara Takeshi,Tsurumi Hisashi,Moriwaki Hisataka,Arioka Yuko,Takemura Masao,Matsunami Hidetoshi,Markey Sanford P,Saito Kuniaki
Experimental hematology 41(7), 597-603.e2, 2013-07
… To study the drug resistance mechanisms, protein expression profiles of 1-β-D-arabinofuranosylcytosine (AraC)-sensitive K562 (K562S) cells and AraC-resistant K562 (K562AC) cells were compared using two-dimensional fluorescence difference gel electrophoresis. …
NAID 120005302084

Development of a sensitive and selective LC/MS/MS method for the simultaneous determination of intracellular 1-beta-D-arabinofuranosylcytosine triphosphate (araCTP), cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP) in a human follicular lymphoma cell line

CRAUSTE Celine,LEFEBVRE Isabelle,HOVANEISSIAN Michael,PUY Jean Yves,ROY Beatrice,PEYROTTES Suzanne,COHEN Sabine,GUITTON Jerome,DUMONTET Charles,PERIGAUD Christian
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 877(14), 1417-1425, 2009-05-15
NAID 10028017352

Resistance to Ara-C Up-Regulates the Activation of NF-κB, Telomerase Activity and Fas Expression in NALM-6 Cells(Pharmacology)

Kanno Syu-ichi,Hiura Takako,Shouji Ai [他],OSANAI Yuu,UJIBE Mayuko,ISHIKAWA Masaaki
Biological & pharmaceutical bulletin 30(11), 2069-2074, 2007-11-01
… Cytosine arabinoside (1-β-D-arabinofuranosylcytosine ; …
NAID 110006473484

Related Pictures

★リンクテーブル★

リンク元	「ara-C」「cytarabine hydrochloride」「アラビノフラノシルシトシン」

「ara-C」

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 cat.	D (AU) D (US)
Legal status	℞ Prescription only
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	DB00987
ChemSpider	6017
UNII	04079A1RDZ
KEGG	D00168
ChEBI	CHEBI:28680
ChEMBL	CHEMBL803
Chemical data
Formula	C9H13N3O5
Mol. 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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