Cytarabine: Difference between revisions

{{Short description|Chemical compound (chemotherapy medication)}}

{{Redirect|Alexan|a person|Georg Friedrich Alexan}}

{{Redirect|AR3|the IPCC Third Assessment Report|AR3 (IPCC)}}

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{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 460111587

| width = 200

| alt =

| image2 = Cytarabine ball-and-stick.png

| alt2 =

<!-- Clinical data -->

| pronounce =

| tradename = Cytosar-U, Depocyt, others

| DailyMedID = <!-- DailyMed may use generic or brand name (generic name preferred) -->

| pregnancy_AU = D

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = injectable (intravenous injection or infusion, intrathecal, or subcutaneously)

| class =

| ATC_prefix = L01

| ATC_suffix = BC01

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_US_comment =

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = 20% by mouth

| metabolism = [[Liver]]

| metabolites =

| onset =

| elimination_half-life = biphasic: 10 min, 1–3 hr

| duration_of_action =

| excretion = [[Kidney]]

<!-- Identifiers -->

| CAS_supplemental =

| IUPHAR_ligand = 4827

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| NIAID_ChemDB =

| PDB_ligand = AR3

| synonyms =

<!-- Chemical and physical data -->

| IUPAC_name = 4-amino-1-[(2''R'',3''S'',4''S'',5''R'')-3,4-dihydroxy-5- (hydroxymethyl)oxolan-2-yl] pyrimidin-2-one

| C=9 | H=13 | N=3 | O=5

| SMILES = O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@@H]2O)CO

| density =

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<!-- Definition and medical uses -->

'''Cytarabine''', also known as '''cytosine arabinoside''' ('''ara-C'''), is a [[chemotherapy medication]] used to treat [[acute myeloid leukemia]] (AML), [[acute lymphocytic leukemia]] (ALL), [[chronic myelogenous leukemia]] (CML), and [[non-Hodgkin's lymphoma]].<ref name=AHFS2016/> It is given by [[intravenous|injection into a vein]], [[Subcutaneous injection|under the skin]], or into the [[intrathecal|cerebrospinal fluid]].<ref name=AHFS2016/> There is a [[liposomal]] formulation for which there is tentative evidence of better outcomes in [[lymphomatous meningitis|lymphoma involving the meninges]].<ref name=AHFS2016>{{cite web|title=Cytarabine|url=https://www.drugs.com/monograph/cytarabine.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20160611124414/http://www.drugs.com/monograph/cytarabine.html|archive-date=11 June 2016}}</ref>

<!-- Side effects and mechanism -->

Common side effects include [[bone marrow suppression]], vomiting, diarrhea, [[liver problems]], rash, ulcer formation in the mouth, and bleeding.<ref name=AHFS2016/> Other serious side effects include [[loss of consciousness]], lung disease, and [[allergic reactions]].<ref name=AHFS2016/> Use during [[pregnancy]] may harm the baby.<ref name=AHFS2016/> Cytarabine is in the [[antimetabolite]] and [[Nucleoside analogue|nucleoside analog]] families of medication.<ref name=BNF69>{{cite book|title=British national formulary: BNF 69|date=2015|publisher=British Medical Association|isbn=9780857111562|page=589|edition=69}}</ref> It works by blocking the function of [[DNA polymerase]].<ref name=AHFS2016/>

<!-- Society and culture -->

Cytarabine was patented in 1960 and approved for medical use in 1969.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=511|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA511|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220145216/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA511|archive-date=2016-12-20}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref>

==Medical uses==

Cytarabine is mainly used in the treatment of [[acute myeloid leukaemia]], [[acute lymphocytic leukaemia]] (ALL) and in [[lymphoma]]s,<ref name="pmid18024370">{{cite journal | vauthors = Pigneux A, Perreau V, Jourdan E, Vey N, Dastugue N, Huguet F, Sotto JJ, Salmi LR, Ifrah N, Reiffers J | title = Adding lomustine to idarubicin and cytarabine for induction chemotherapy in older patients with acute myeloid leukemia: the BGMT 95 trial results | journal = Haematologica | volume = 92 | issue = 10 | pages = 1327–1334 | date = October 2007 | pmid = 18024370 | doi = 10.3324/haematol.11068 | doi-access = free }}</ref> where it is the backbone of [[induction chemotherapy]].

Cytarabine also possesses [[Antiviral drug|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.<ref name="pmid15825312">{{cite journal | vauthors = Lauter CB, Bailey EJ, Lerner AM | title = Assessment of cytosine arabinoside as an antiviral agent in humans | journal = Antimicrobial Agents and Chemotherapy | volume = 6 | issue = 5 | pages = 598–602 | date = November 1974 | pmid = 15825312 | pmc = 444699 | doi = 10.1128/aac.6.5.598 }}</ref>

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 [[neuron]]s.{{citation needed|date=February 2013}} Recently, cytarabine was reported to promote robust and persistent neuronal differentiation in NSC-34 motor neuron-like cell line. Cytarabine is permissive, dispensable, and mostly irreversible in priming NSC-34 cells for neurite initiation and regeneration after mechanical dislodgement.<ref>{{cite journal | vauthors = Vitale G, Amadio S, Liguori F, Volonté C | title = Empowering the NSC-34 cell line as a motor neuron model: cytosine arabinoside's action | journal = Neural Regeneration Research | date = September 2024 | pmid = 39314144 | doi = 10.4103/NRR.NRR-D-24-00034 | doi-access = free }}</ref>

==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]].{{citation needed|date=January 2023}}

Toxicity: [[pancreatitis]], [[leukopenia]], thrombocytopenia, [[anemia]], GI disturbances, [[stomatitis]], [[conjunctivitis]], [[pneumonitis]], [[fever]], and [[dermatitis]], [[Chemotherapy-induced acral erythema|palmar-plantar erythrodysesthesia]]. Rarely, [[myelopathy]] has been reported after high dose or frequent [[intrathecal]] Ara-C administration.<ref>{{cite journal | vauthors = Watterson J, Toogood I, Nieder M, Morse M, Frierdich S, Lee Y, Moertel CL, Priest JR | title = Excessive spinal cord toxicity from intensive central nervous system-directed therapies | journal = Cancer | volume = 74 | issue = 11 | pages = 3034–3041 | date = December 1994 | pmid = 7954266 | doi = 10.1002/1097-0142(19941201)74:11<3034::AID-CNCR2820741122>3.0.CO;2-O | doi-access = free }}</ref>

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).{{citation needed|date=January 2023}}

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.<ref>{{cite journal | vauthors = Chhikara BS, Parang K | title = Development of cytarabine prodrugs and delivery systems for leukemia treatment | journal = Expert Opinion on Drug Delivery | volume = 7 | issue = 12 | pages = 1399–1414 | date = December 2010 | pmid = 20964588 | doi = 10.1517/17425247.2010.527330 | s2cid = 2988492 | url = https://digitalcommons.chapman.edu/cgi/viewcontent.cgi?article=1153&context=pharmacy_articles }}</ref>

==Mechanism of action==

Cytosine arabinoside combines a [[cytosine]] base with an [[arabinose]] sugar. It is an [[antimetabolic agent]] with the chemical name of ''1β-arabinofuranosylcytosine''. Certain [[sponge]]s, where similar compounds were originally found, use arabinoside sugars for chemical defense.<ref>{{cite web|url=https://ocean.si.edu/ocean-life/invertebrates/sea-sponges-pharmacies-sea|title=Sea Sponges: Pharmacies of the Sea| vauthors = Hall D |date=November 2019|access-date=25 April 2023|website=Smithsonian Ocean}}</ref> Cytosine arabinoside is similar enough to human deoxycytosine to be incorporated into human DNA, but different enough that it kills the cell. Cytosine arabinoside interferes with the synthesis of DNA. 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 polymerase|DNA]]<ref name="isbn0-7817-7328-8">{{cite book | vauthors = Perry MJ |title=The Chemotherapy source book |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins |location=Philadelphia |year=2008 |pages=80 |isbn=978-0-7817-7328-7 }}</ref> and [[RNA polymerase]]s and [[nucleotide]] reductase enzymes needed for DNA synthesis. Cytarabine is the first of a series of cancer drugs that altered the sugar component of [[nucleosides]]. Other cancer drugs modify the base.<ref>{{cite web | url = http://www.pfeist.net/ALL/arac/ | title = A Tale from the Sea to Ara C | vauthors = Feist P | date = April 2005 | url-status = live | archive-url = https://web.archive.org/web/20070306220251/http://www.pfeist.net/ALL/arac/ | archive-date = 2007-03-06 }}</ref>

Cytarabine is often given by continuous intravenous infusion, which follows a biphasic elimination – initial fast clearance rate followed by a slower rate of the analog.<ref name=" Liliemark 1987">{{cite journal | vauthors = Liliemark JO, Gahrton G, Paul CY, Peterson CO | title = ara-C in plasma and ara-CTP in leukemic cells after subcutaneous injection and continuous intravenous infusion of ara-C in patients with acute nonlymphoblastic leukemia | journal = Seminars in Oncology | volume = 14 | issue = 2 Suppl 1 | pages = 167–171 | date = June 1987 | pmid = 3589691 }}</ref> Cytarabine is transported into the cell primarily by hENT-1.<ref name= "Clarke 2002">{{cite book | vauthors = Clarke ML, Mackey JR, Baldwin SA, Young JD, Cass CE | chapter = The Role of Membrane Transporters in Cellular Resistance to Anticancer Nucleoside Drugs | series = Cancer Treatment and Research | title = Clinically Relevant Resistance in Cancer Chemotherapy | volume = 112 | pages = 27–47 | year = 2002 | pmid = 12481710 | doi = 10.1007/978-1-4615-1173-1_2 | isbn = 978-1-4613-5428-4 }}</ref> It is then monophosphorylated by deoxycytidine kinase and eventually cytarabine-5´-triphosphate, which is the active metabolite being incorporated into DNA during DNA synthesis.{{citation needed|date=January 2023}}

Several mechanisms of resistance have been reported.<ref name=" Shelton 2016">{{cite journal | vauthors = Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF | title = Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs | journal = Chemical Reviews | volume = 116 | issue = 23 | pages = 14379–14455 | date = December 2016 | pmid = 27960273 | pmc = 7717319 | doi = 10.1021/acs.chemrev.6b00209 }}</ref> Cytarabine is rapidly deaminated by cytidine deaminase in the serum into the inactive uracil derivative. Cytarabine-5´-monophosphate is deaminated by deoxycytidylate deaminase, leading to the inactive uridine-5´-monophosphate analog.<ref name= "Drake 1980">{{cite journal | vauthors = Drake JC, Hande KR, Fuller RW, Chabner BA | title = Cytidine and deoxycytidylate deaminase inhibition by uridine analogs | journal = Biochemical Pharmacology | volume = 29 | issue = 5 | pages = 807–811 | date = March 1980 | pmid = 20227960 | doi = 10.1016/0006-2952(80)90561-4 }}</ref> Cytarabine-5´-triphosphate is a substrate for [[SAMHD1]].<ref name=" Hollenbaugh 2017">{{cite journal | vauthors = Hollenbaugh JA, Shelton J, Tao S, Amiralaei S, Liu P, Lu X, Goetze RW, Zhou L, Nettles JH, Schinazi RF, Kim B | title = Substrates and Inhibitors of SAMHD1 | journal = PLOS ONE | volume = 12 | issue = 1 | pages = e0169052 | date = Jan 2017 | pmid = 28046007 | pmc = 5207538 | doi = 10.1371/journal.pone.0169052 | doi-access = free | bibcode = 2017PLoSO..1269052H }}</ref> Furthermore, SAMHD1 has been shown to limit the efficacy of cytarabine efficacy in patients.<ref name=" Schneider 2016">{{cite journal | vauthors = Schneider C, Oellerich T, Baldauf HM, Schwarz SM, Thomas D, Flick R, Bohnenberger H, Kaderali L, Stegmann L, Cremer A, Martin M, Lohmeyer J, Michaelis M, Hornung V, Schliemann C, Berdel WE, Hartmann W, Wardelmann E, Comoglio F, Hansmann ML, Yakunin AF, Geisslinger G, Ströbel P, Ferreirós N, Serve H, Keppler OT, Cinatl J | title = SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia | journal = Nature Medicine | volume = 23 | issue = 2 | pages = 250–255 | date = February 2017 | pmid = 27991919 | doi = 10.1038/nm.4255 | s2cid = 205398095 | url = https://kar.kent.ac.uk/60380/1/Schneider%20et%20al.pdf }}</ref>

When used as an [[Antiviral drug|antiviral]], cytarabine-5´-triphosphate functions by inhibiting viral DNA synthesis.<ref name="isbn0-683-30737-1">{{cite book | vauthors = Lemke TL, Williams DH, Foye WO |title=Foye's principles of medicinal chemistry |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2002 |pages=963 |isbn=0-683-30737-1 }}</ref> Cytarabine is able to inhibit herpesvirus and vaccinia virus replication in cells during tissue culture. However, cytarabine treatment was only effective for herpesvirus infection in a murine model.{{citation needed|date=January 2023}}

In mice, Ara-CTP (cytarabine-5'-triphosphate) blocks memory consolidation, but not short-term memory, of a context fear conditioning event.<ref name = Colón-Cesario2006>{{cite journal | vauthors = Colón-Cesario M, Wang J, Ramos X, García HG, Dávila JJ, Laguna J, Rosado C, Peña de Ortiz S | title = An inhibitor of DNA recombination blocks memory consolidation, but not reconsolidation, in context fear conditioning | journal = The Journal of Neuroscience | volume = 26 | issue = 20 | pages = 5524–33 | date = May 2006 | pmid = 16707804 | pmc = 6675301 | doi = 10.1523/JNEUROSCI.3050-05.2006 }}</ref> The blockage of memory consolidation was proposed to be due to the inhibition by Ara-CTP of the DNA [[non-homologous end joining]] pathway.<ref name = Colón-Cesario2006/> Thus transient DNA breakage followed by non-homologous end joining appear to be necessary steps in the formation of a long-term memory of an event.{{citation needed|date=January 2023}}

==History==

Isolation of arabinose-containing nucleotides from the Caribbean sponge ''Cryptotheca crypta'' (now ''[[Tectitethya crypta]]'') together with the realization that these compounds could act as DNA synthesis chain terminators led to exploration of these novel nucleotides as potential anticancer therapeutics.<ref>{{cite journal | vauthors = Schwartsmann G, Brondani da Rocha A, Berlinck RG, Jimeno J | title = Marine organisms as a source of new anticancer agents | journal = The Lancet. Oncology | volume = 2 | issue = 4 | pages = 221–225 | date = April 2001 | pmid = 11905767 | doi = 10.1016/s1470-2045(00)00292-8 }}</ref> Cytarabine was first synthesized in 1959 by Richard Walwick, Walden Roberts, and Charles Dekker at the [[University of California, Berkeley]].<ref name=Sneader>{{cite book| vauthors = Sneader W | title = Drug discovery: a history| publisher = Wiley| location = New York| year = 2005| page = 258| isbn = 0-471-89979-8}}</ref>

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 brand name Cytosar-U.{{citation needed|date=January 2023}}

==Names==

It is also known as ara-C (arabinofuranosyl cytidine).<ref name="pmid19048119">{{cite journal | vauthors = Ogbomo H, Michaelis M, Klassert D, Doerr HW, Cinatl J | title = Resistance to cytarabine induces the up-regulation of NKG2D ligands and enhances natural killer cell lysis of leukemic cells | journal = Neoplasia | volume = 10 | issue = 12 | pages = 1402–1410 | date = December 2008 | pmid = 19048119 | pmc = 2586691 | doi = 10.1593/neo.08972 }}</ref>

* Cytosar-U

* Tarabine PFS (Pfizer)

* Depocyt (longer-lasting [[liposomal]] formulation)

* AraC

{{Clear}}

== References ==

{{Reflist}}

{{Portal bar|Medicine}}

[[Category:Arabinosides]]

[[Category:Pyrimidine antagonists]]

[[Category:World Health Organization essential medicines]]

[[Category:Cancer treatments]]

[[Category:Wikipedia medicine articles ready to translate]]

[[Category:DNA replication inhibitors]]

[[Category:DNA polymerase inhibitors]]

[[Category:RNA polymerase inhibitors]]

[[Category:Antiviral drugs]]

[[Category:Hydroxymethyl compounds]]