Clofarabine

Last updated
Clofarabine
Clofarabine.svg
Clinical data
Trade names Clolar, Evoltra
AHFS/Drugs.com Monograph
MedlinePlus a607012
License data
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only [1]
  • EU:Rx-only [2]
  • In general: ℞ (Prescription only)
Identifiers
  • 5-(6-amino-2-chloro-purin-9-yl) -4-fluoro-2- (hydroxymethyl)oxolan-3-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.159.663 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H11ClFN5O3
Molar mass 303.68 g·mol−1
3D model (JSmol)
  • Clc1nc(c2ncn(c2n1)[C@@H]3O[C@@H]([C@@H](O)[C@@H]3F)CO)N
  • 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 Yes check.svgY
  • Key:WDDPHFBMKLOVOX-AYQXTPAHSA-N Yes check.svgY
   (verify)

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.

Contents

Approval

Clolar was Food and Drug Administration (FDA) approved 28 December 2004. (Under accelerated approval regulations requiring further clinical studies.)

Side effects

Contraindications

Drug interactions

Delivery

Biology

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]

References

  1. "Clolar- clofarabine injection". DailyMed. 31 December 2019. Retrieved 27 September 2020.
  2. "Evoltra EPAR". European Medicines Agency (EMA). 6 March 2009. Retrieved 27 September 2020.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.