Clofarabine is a purinenucleosideantimetabolite marketed in the United States and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory acute lymphoblastic leukaemia (ALL) in children after at least two other types of treatment have failed. Some investigations of effectiveness in cases of acute myeloid leukaemia (AML) and juvenile myelomonocytic leukaemia (JMML) have been carried out. Ongoing trials are assessing its efficacy for managing other cancers.
Clolar was Food and Drug Administration (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.)
Side effectsedit
Tumor lysis syndrome (TLS). Clofarabine quickly kills leukaemia cells in the blood. The body may react to this. Signs include hyperkalemia, hyperuricemia, and hyperphosphatemia. TLS is very serious and can lead to death if it is not treated right away.
Systemic inflammatory response syndrome (SIRS): symptoms include fast breathing, fast heartbeat, low blood pressure, and fluid in the lungs.
Bone marrow problems (suppression). Clofarabine can stop the bone marrow from making enough red blood cells, white blood cells, and platelets. Serious side effects that can happen because of bone marrow suppression include severe infection (sepsis), bleeding, and anemia.
Effects on pregnancy and breastfeeding. Girls and women should not become pregnant or breastfeed during treatment which may harm the baby.
Dehydration and low blood pressure. Clofarabine can cause vomiting and diarrhea which may lead to low body fluid (dehydration). Signs and symptoms of dehydration include dizziness, lightheadedness, fainting spells, or decreased urination.
Other side effects. The most common side effects are stomach problems (including vomiting, diarrhea, and nausea), and effects on blood cells (including low red blood cells count, low white blood cell count, low platelet count, fever, and infection). Clofarabine can also cause tachycardia and can affect the liver and kidneys.
Dosage is a 2-hour infusion (52 mg/m2) every day for five days. The cycle is repeated every 2 to 6 weeks.
Regular blood tests to monitor his or her blood cells, kidney function, and liver function.
Biologyedit
Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with ara-A and fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine.[3] A chlorine substitution at the 2-position of the adenine base avoids production of a 2-fluoroadenine analog, a precursor to the toxic 2-fluoro-adenosine-5´-triphosphate and prevents deamination of the base as compared to ara-A.[4]
Clofarabine can be administered intravenously or given orally. Clofarabine enters cells via hENT1, hENT2, and hCNT2, where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine-5´-monophosphate. The rate-limiting step in clofarabine metabolism is clofarabine-5´-diphosphosphate. Clofarabine-5´-triphosphate is the active-metabolite, and it inhibits ribonucleotide reductase, resulting in a decrease cellular dNTP concentrations, which promotes greater incorporation of clofarabine-5´-triphosphate during DNA synthesis. Embedded clofarabine-5´-monophosphate in the DNA promotes polymerase arrest at the replication fork, triggering DNA repair mechanisms that without repair lead to DNA strand breaks in vitro and cytochrome c-mediated apoptosis in vitro. Studies using cell lines have shown that clofarabine-5´-triphosphate can also be incorporated into RNA.[5]
Mechanisms of resistance and turnover have been reported. Clofarabine-resistance arises from decreased deoxycytidine kinase activity in vitro.[6] ABC transporter ABCG2 promotes export of clofarabine-5´-monophosphate and thus limits the cytotoxic effects of this analog in vivo.[7] Biochemically, clofarabine-5’-triphosphate was shown to be substrate for SAMHD1, thus potentially limiting the amount of active compound in cells.[8]
Referencesedit
^"Clolar- clofarabine injection". DailyMed. 31 December 2019. Retrieved 27 September 2020.
^Parker WB, Allan PW, Hassan AE, Secrist JA 3rd, Sorscher EJ, Waud WR (Jan 2003). "Antitumor activity of 2-fluoror-2'deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase". Cancer Gene Ther. 10 (1): 23–29. doi:10.1038/sj.cgt.7700520. PMID 12489025. S2CID 35923404.
^Bonate PL, Arthaud L, Cantrell WR Jr, Stephenson K, Secrist JA 3rd, Weitman S (Feb 2014). "Discovery and development of clofarabine: a nucleoside analogue for treating cancer". Nat Rev Drug Discov. 5 (10): 855–63. doi:10.1038/nrd2055. PMID 17016426. S2CID 21361350.
^Shelton J, Lu X, Hollenbaugh JA, Cho JH, Amblard F, Schinazi RF (Dec 2016). "Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs". Chem Rev. 116 (23): 14379–14455. doi:10.1021/acs.chemrev.6b00209. PMC7717319. PMID 27960273.
^Lotfi K, Månsson E, Spasokoukotskaja T, Pettersson B, Liliemark J, Peterson C, Eriksson S, Albertioni F (1999). "Biochemical pharmacology and resistance to 2-chloro-2'-arabino-fluoro-2'deoxyadenosine, a novel analogue of cladribine in human leukemic cells". Clin Cancer Res. 5 (9): 2438–44. PMID 10499616.
^Nagai S, Takenaka K, Nachagari D, Rose C, Domoney K, Sun D, Sparreboom A, Schuetz JD (Mar 2011). "Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity". Cancer Res. 75 (1): 1781–91. doi:10.1158/0008-5472.CAN-10-1919. PMC3531552. PMID 21245102.
^Arnold LH, Kunzelmann S, Webb MR, Taylor IA (Jan 2015). "A continuous enzyme-coupled assay for triphosphohydrolase activity of HIV-1 restriction factor SAMHD1". Antimicrob Agents Chemother. 59 (1): 186–92. doi:10.1128/AAC.03903-14. PMC4291348. PMID 25331707.
External linksedit
"Clofarabine". Drug Information Portal. U.S. National Library of Medicine.
clofarabine, purine, nucleoside, antimetabolite, marketed, united, states, canada, clolar, europe, australia, zealand, product, marketed, under, name, evoltra, approved, treating, relapsed, refractory, acute, lymphoblastic, leukaemia, children, after, least, o. Clofarabine is a purine nucleoside antimetabolite marketed in the United States and Canada as Clolar In Europe and Australia New Zealand the product is marketed under the name Evoltra It is FDA approved for treating relapsed or refractory acute lymphoblastic leukaemia ALL in children after at least two other types of treatment have failed Some investigations of effectiveness in cases of acute myeloid leukaemia AML and juvenile myelomonocytic leukaemia JMML have been carried out Ongoing trials are assessing its efficacy for managing other cancers ClofarabineClinical dataTrade namesClolar EvoltraAHFS Drugs comMonographMedlinePlusa607012License dataEU EMA by INN US DailyMed ClofarabineRoutes ofadministrationIntravenousATC codeL01BB06 WHO Legal statusLegal statusAU S4 Prescription only US only 1 EU Rx only 2 In general Prescription only IdentifiersIUPAC name 5 6 amino 2 chloro purin 9 yl 4 fluoro 2 hydroxymethyl oxolan 3 olCAS Number123318 82 1 YPubChem CID119182IUPHAR BPS6802DrugBankDB00631 YChemSpider106472 YUNII762RDY0Y2HKEGGD03546 YChEBICHEBI 681569 YChEMBLChEMBL1750 YCompTox Dashboard EPA DTXSID5046437ECHA InfoCard100 159 663Chemical and physical dataFormulaC 10H 11Cl F N 5O 3Molar mass303 68 g mol 13D model JSmol Interactive imageSMILES Clc1nc c2ncn c2n1 C H 3O C H C H O C H 3F CO NInChI InChI 1S C10H11ClFN5O3 c11 10 15 7 13 5 8 16 10 17 2 14 5 9 4 12 6 19 3 1 18 20 9 h2 4 6 9 18 19H 1H2 H2 13 15 16 t3 4 6 9 m1 s1 YKey WDDPHFBMKLOVOX AYQXTPAHSA N Y verify Contents 1 Approval 2 Side effects 3 Contraindications 4 Drug interactions 5 Delivery 6 Biology 7 References 8 External linksApproval editClolar was Food and Drug Administration FDA approved 28 December 2004 Under accelerated approval regulations requiring further clinical studies Side effects editTumor lysis syndrome TLS Clofarabine quickly kills leukaemia cells in the blood The body may react to this Signs include hyperkalemia hyperuricemia and hyperphosphatemia TLS is very serious and can lead to death if it is not treated right away Systemic inflammatory response syndrome SIRS symptoms include fast breathing fast heartbeat low blood pressure and fluid in the lungs Bone marrow problems suppression Clofarabine can stop the bone marrow from making enough red blood cells white blood cells and platelets Serious side effects that can happen because of bone marrow suppression include severe infection sepsis bleeding and anemia Effects on pregnancy and breastfeeding Girls and women should not become pregnant or breastfeed during treatment which may harm the baby Dehydration and low blood pressure Clofarabine can cause vomiting and diarrhea which may lead to low body fluid dehydration Signs and symptoms of dehydration include dizziness lightheadedness fainting spells or decreased urination Other side effects The most common side effects are stomach problems including vomiting diarrhea and nausea and effects on blood cells including low red blood cells count low white blood cell count low platelet count fever and infection Clofarabine can also cause tachycardia and can affect the liver and kidneys Contraindications editpregnancy or planned pregnancy breast feeding liver problems kidney problemsDrug interactions editnephrotoxic drugs hepatotoxic drugsDelivery editBy intravenous infusion Dosage is a 2 hour infusion 52 mg m2 every day for five days The cycle is repeated every 2 to 6 weeks Regular blood tests to monitor his or her blood cells kidney function and liver function Biology editClofarabine is a second generation purine nucleoside analog designed to overcome biological limitations observed with ara A and fludarabine A 2 S fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine 3 A chlorine substitution at the 2 position of the adenine base avoids production of a 2 fluoroadenine analog a precursor to the toxic 2 fluoro adenosine 5 triphosphate and prevents deamination of the base as compared to ara A 4 Clofarabine can be administered intravenously or given orally Clofarabine enters cells via hENT1 hENT2 and hCNT2 where upon it is phosphorylated by deoxycytidine kinase to generate clofarabine 5 monophosphate The rate limiting step in clofarabine metabolism is clofarabine 5 diphosphosphate Clofarabine 5 triphosphate is the active metabolite and it inhibits ribonucleotide reductase resulting in a decrease cellular dNTP concentrations which promotes greater incorporation of clofarabine 5 triphosphate during DNA synthesis Embedded clofarabine 5 monophosphate in the DNA promotes polymerase arrest at the replication fork triggering DNA repair mechanisms that without repair lead to DNA strand breaks in vitro and cytochrome c mediated apoptosis in vitro Studies using cell lines have shown that clofarabine 5 triphosphate can also be incorporated into RNA 5 Mechanisms of resistance and turnover have been reported Clofarabine resistance arises from decreased deoxycytidine kinase activity in vitro 6 ABC transporter ABCG2 promotes export of clofarabine 5 monophosphate and thus limits the cytotoxic effects of this analog in vivo 7 Biochemically clofarabine 5 triphosphate was shown to be substrate for SAMHD1 thus potentially limiting the amount of active compound in cells 8 References edit Clolar clofarabine injection DailyMed 31 December 2019 Retrieved 27 September 2020 Evoltra EPAR European Medicines Agency EMA Retrieved 27 September 2020 Parker WB Allan PW Hassan AE Secrist JA 3rd Sorscher EJ Waud WR Jan 2003 Antitumor activity of 2 fluoror 2 deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase Cancer Gene Ther 10 1 23 29 doi 10 1038 sj cgt 7700520 PMID 12489025 S2CID 35923404 Bonate PL Arthaud L Cantrell WR Jr Stephenson K Secrist JA 3rd Weitman S Feb 2014 Discovery and development of clofarabine a nucleoside analogue for treating cancer Nat Rev Drug Discov 5 10 855 63 doi 10 1038 nrd2055 PMID 17016426 S2CID 21361350 Shelton J Lu X Hollenbaugh JA Cho JH Amblard F Schinazi RF Dec 2016 Metabolism Biochemical Actions and Chemical Synthesis of Anticancer Nucleosides Nucleotides and Base Analogs Chem Rev 116 23 14379 14455 doi 10 1021 acs chemrev 6b00209 PMC 7717319 PMID 27960273 Lotfi K Mansson E Spasokoukotskaja T Pettersson B Liliemark J Peterson C Eriksson S Albertioni F 1999 Biochemical pharmacology and resistance to 2 chloro 2 arabino fluoro 2 deoxyadenosine a novel analogue of cladribine in human leukemic cells Clin Cancer Res 5 9 2438 44 PMID 10499616 Nagai S Takenaka K Nachagari D Rose C Domoney K Sun D Sparreboom A Schuetz JD Mar 2011 Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity Cancer Res 75 1 1781 91 doi 10 1158 0008 5472 CAN 10 1919 PMC 3531552 PMID 21245102 Arnold LH Kunzelmann S Webb MR Taylor IA Jan 2015 A continuous enzyme coupled assay for triphosphohydrolase activity of HIV 1 restriction factor SAMHD1 Antimicrob Agents Chemother 59 1 186 92 doi 10 1128 AAC 03903 14 PMC 4291348 PMID 25331707 External links edit Clofarabine Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Clofarabine amp oldid 1176994256, wikipedia, wiki, book, books, library,
