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Cytarabine (Ara-C)

Cytarabine (right) is a cytadine analog. Note (arrow) cytarbine's arabinose sugar replacing ribose in cytadine1

cytosine

cytosine arabinoside (cytarabine, AraC)

Cytarabine

Cell-Cycle Phases as Drug Targets in Cancer Treatment (in this case, used in management of acute lymphoblastic leukemia2

Figure slightly modified from rPui C-H and Jeha S (2)

 

Cytarabine (Ara-C) Metabolism3

  • Step 1 above highlights the nucleoside transporter (hENT1) responsible for facilitation of cytarabine entry into the cell.

  • The next step involves phosphorylation to a monophosphate form, Ara-CMP, catalyzed by deoxycytosine kinase (dCK). An additional two phosphorylation steps are catalyzed by (a) (deoxy) cytidylate kinase (UMP-CMPK) and (b) nucleoside diphosphate kinases (NDKs).

  • These two phosphorylation steps result in the formation of araCTP, the active anticancer form.

  • Apoptosis occurs upon araCTP incorporation into DNA during DNA synthesis.

  • Note that araCTP formation can be inhibited by pyrimidine nucleotidase 1 which attenuates the effect of deoxycytidine kinase.

    • Other enzymes can promote conversion of ara-C to other species, an effect that reduces AraCTP concentrations thereby potentially limiting its apoptosis-promoting action.

    • For example, cytidine deaminase and deoxycytidylate deaminase are described as inactivating enzymes since they promote Ara-C conversion to Ara-U in the first instance and Ara-CMP, the monophosphate form, to Ara-UMP (uridine monophosphate) in the second case.3

 

 

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References 

  1. Rose HS, Rando RR Pharmacology of Nucleotide Synthesis in Principles of Pharmacology:  The Pathophysiologic Basis of Drug Therapy, Golan DE, Tashjian, JR. AH, Armstrong EJ, Galanter JM, Armstrong AW, Arnaout RA, Rose HS, Lippincott Williams & Wilkins, Philadelphia, pp. 505-516, 2005.
  2. Pui C-H, Jeha S New Therapeutic Strategies for the Treatment of Acute Lymphoblastic Leukaemia Nature Review: Drug Discovery, 6, February 2007, 149-165.
  3. Stam RW, Hubeek I, den Boer ML, Buijs-Gladdines JGCAM, Creutzig U, Kaspers GJL, Pieters R MLL Gene rearrangements have no direct impact on ARA-C sensitivity in infant acute lymphoblastic leukemia and childhood M4/M5 acute myeloid leukemia. Leukemia (2006) 20, 179-182, published on line November 2005.
  4. Chu E, Sartorelli AC Cancer Chemotherapy in Basic and Clinical Pharmacology,  Chapter 55, 10th Edition, (Katzung BG, editor), McGraw-Hill, Lange Series, p.890, 2007.

 

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