Cytosine Arabinoside

Metabolism, Mechanisms of Resistance, and Clinical Pharmacology
  • Isabelle Hubeek
  • Gert-Jan L. Kaspers
  • Gert J. Ossenkoppele
  • Godefridus J. Peters
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The deoxynucleoside analog cytarabine (ara-C) remains one of the most effective drugs used in the treatment of acute leukemia as well as other hematopoietic malignancies. The activity of ara-C depends on the conversion to its cytotoxic triphosphate derivative, ara-CTP. This process is influenced by multiple factors, including transport, phosphorylation, deamination, and levels of competing metabolites, deoxycytidine triphosphate in particular. Furthermore, the efficacy of ara-C is determined by the ability of ara-CTP to interfere with deoxyribonucleic acid (DNA) polymerases in the extent of incorporation into the DNA, leading to chain termination. Finally, several factors in the apoptotic pathway also determine sensitivity to ara-C. Ara-C has been given intravenously over a wide range of doses. The standard or conventional dose varies from 100 to 200 mg/m2 daily and is given by intermittent injection or by continuous infusion over 5–10 d. The presence of drug refractoriness and relapsing leukemia together with insights into the mechanisms of ara-C resistance led to the development of high-dose (1–3 g/m2) ara-C treatment. A number of different strategies have been developed to increase the efficacy of ara-C. First, biochemical modulation of ara-C-mediated cyto-toxicity, in which ara-C is combined with compounds that enhance its metabolism or interfere with its catabolism, has been successful. Second, ara-C has been encapsulated into multivesicular liposomes, and several ara-C prodrugs containing lipophilic side chains in the base or in the sugar moiety have been designed to increase cellular uptake of ara-C and delay its deamination and clearance. Greater understanding of the metabolism and mechanisms of action of ara-C could contribute to the development of novel therapeutic strategies capable of overcoming ara-C resistance and is essential to improve therapeutic efficacy.

Key Words

Acute myeloid leukemia biochemical modulation cytara-bine cytosine arabinoside deoxycytidine kinase high-dose ara-C FLAG fludarabine. 


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Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Isabelle Hubeek
    • 1
  • Gert-Jan L. Kaspers
    • 2
  • Gert J. Ossenkoppele
    • 3
  • Godefridus J. Peters
    • 4
  1. 1.Department of Pediatric Hematology/OncologyVU University Medical CenterAmsterdamThe Netherlands
  2. 2.Department of Pediatric HematologyVU University Medical CenterAmsterdamThe Netherlands
  3. 3.Department of HematologyVU University Medical CenterAmsterdamThe Netherlands
  4. 4.Department of Medical OncologyVU University Medical CenterAmsterdamThe Netherlands

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