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Cytarabine (Ara-C)

  • Cytarabine is a cytidine (pyrimidine) analog which can be used for treatment of acute myelocytic leukemia. Side effects and toxicities include myelosuppression and gastrointestinal effects. Pyrimidine and purine analogues, when incorporated into DNA and RNA, inhibit the activity of DNA polymerase, and as a result, causes cell death.1 Furthermore, cytarabine is an S-phase-specific agent which upon conversion to the active form (below) is a competitive inhibitor of DNA polymerase-α as well as DNA polymerase-β.  Upon incorporation into DNA, the cytidine analog interferes with chain elongation and promotes abnormal fragment ligation of newly synthesized DNA.4 The cytotoxicity of ara-C depends in part on the relationship between two enzymes; on one hand, the activity of deoxycytidine kinase promotes the necessary phosphorylation for cytotoxic activity, but on the other hand the activity of cytidine deaminase is inactivating-so the enzyme activity ratio of these two catalysts is important.4

  • Cytarabine (ara-C) is metabolized to araCTP  which then competes with CTP (cytidine triphosphate) for DNA polymerase. If araCTP ends up being incorporated into DNA, chain termination occurs as does cell death. Synergistic effects involving cyclophosphamide and cytarabine occur most likely because of reduced DNA repair secondary to cytarabine-mediated inhibition of DNA polymerase activity. As noted earlier, cytarabine is useful in management of acute myelogenous leukemia (acute myelocytic leukemia, AML). Pharmacotherapeutic efficacy of cytarabine in this clinical application may be enhanced by combination with an anthracycline drug.1

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

 

 

  • The designation of cytarabine as S-phase specific has a pharmacotherapeutic consequence, namely that the drug must be given with strict attention to scheduling.  The options are either by continuous infusion or every 8-12 hours for 5-7 days.  Cytarabine is used for hematologic malignancies, particularly acute myelogenous leukemia and non-Hodgkin's lymphoma; furthermore, cytarabine is not helpful in management of solid tumors.4 

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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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