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]

Related Research Articles

<span class="mw-page-title-main">Deoxycytidine</span> Chemical compound

Deoxycytidine is a deoxyribonucleoside, a component of deoxyribonucleic acid. It is similar to the ribonucleoside cytidine, but with one hydroxyl group removed from the C2' position.

A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.

<span class="mw-page-title-main">Cytarabine</span> Chemical compound (chemotherapy medication)

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. It is given by injection into a vein, under the skin, or into the cerebrospinal fluid. There is a liposomal formulation for which there is tentative evidence of better outcomes in lymphoma involving the meninges.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Gemcitabine</span> Chemical compound

Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by intravenous infusion. It acts against neoplastic growth, and it inhibits the replication of Orthohepevirus A, the causative agent of Hepatitis E, through upregulation of interferon signaling.

<span class="mw-page-title-main">Vidarabine</span>

Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

<span class="mw-page-title-main">Azacitidine</span>

Azacitidine, sold under the brand name Vidaza among others, is used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates.

<span class="mw-page-title-main">Cladribine</span>

Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia and B-cell chronic lymphocytic leukemia.

<span class="mw-page-title-main">Fludarabine</span> Chemical compound

Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate, sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatment of leukemia and lymphoma. These include chronic lymphocytic leukemia, non-Hodgkin's lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia. It is given by injection into a vein or by mouth.

<span class="mw-page-title-main">Busulfan</span>

Busulfan is a chemotherapy drug in use since 1959. It is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.

<span class="mw-page-title-main">Purine nucleoside phosphorylase</span> Enzyme

Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

<span class="mw-page-title-main">Deoxyadenosine triphosphate</span> Chemical compound

Deoxyadenosine triphosphate (dATP) is a nucleotide used in cells for DNA synthesis, as a substrate of DNA polymerase. It is classified as a purine nucleoside triphosphate, with its chemical structure consisting of a deoxyribose sugar molecule bound to an adenine and to three phosphate groups. It differs from the energy-transferring molecule adenosine triphosphate (ATP) by a single hydroxyl group, resulting in a deoxyribose instead of a ribose. Two phosphate groups can be hydrolyzed to yield deoxyadenosine monophosphate, which can then be used to synthesize DNA.

<span class="mw-page-title-main">Deoxycytidine kinase</span> Protein-coding gene in the species Homo sapiens

Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.

<span class="mw-page-title-main">Treosulfan</span> Medication given to people before they have a bone marrow transplant

Treosulfan, sold under the brand name Trecondi, is a medication given to people before they have a bone marrow transplant from a donor known as allogeneic hematopoietic stem cell transplantation. It is used as a 'conditioning' treatment to clear the bone marrow and make room for the transplanted bone marrow cells, which can then produce healthy blood cells. It is used together with another medicine called fludarabine in adults and children from one month of age with blood cancers as well as in adults with other severe disorders requiring a bone marrow transplant.

<span class="mw-page-title-main">UCK2</span>

Uridine-cytidine kinase 2 (UCK2) is an enzyme that in humans is encoded by the UCK2 gene.

Purine analogues are antimetabolites that mimic the structure of metabolic purines.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

<span class="mw-page-title-main">Deoxyinosine monophosphate</span> Chemical compound

Deoxyinosine monophosphate (dIMP) is a nucleoside monophosphate and a derivative of inosinic acid. It can be formed by the deamination of the purine base in deoxyadenosine monophosphate (dAMP). The enzyme deoxyribonucleoside triphosphate pyrophosphohydrolase, encoded by YJR069C in S. cerevisiae and containing (d)ITPase and (d)XTPase activities, hydrolyses dITP, resulting in the release of pyrophosphate and dIMP.

References

  1. "Clolar- clofarabine injection". DailyMed. 31 December 2019. Retrieved 27 September 2020.
  2. "Evoltra EPAR". European Medicines Agency (EMA). 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.