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Inhibition of fludarabine metabolism by arabinosylcytosine during therapy

  • Original Articles
  • Fludarabine, Arabinosylcytosine, Deoxycytidine Kinase
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Summary

The active 5′-triphosphate of arabinosyl-2-fluoroadenine (F-ara-ATP) increases the anabolism of arabinosylcytosine (ara-C), whereas ara-C 5′-triphosphate inhibits the phosphorylation of arabinosyl-2-fluoroadenine (F-ara-A) in human leukemia cells in vitro. These interactions have a potential impact on drug scheduling. Clinical trials of relapsed leukemia in which fludarabine (F-ara-A 5′-monophosphate) and ara-C were given in sequence provided the opportunity to evaluate the effects of ara-C infusion on two sequelae: the pharmacokinetics of F-ara-A in plasma and that of F-ara-ATP in leukemia cells. First, F-ara-A pharmacokinetics were altered by ara-C infusion. This was visualized as a transient increase in F-ara-A plasma levels during the ara-C infusion that was given 4 h after fludarabine. The perturbation in F-ara-A plasma levels was dependent on the dose of ara-C. Second, peak F-ara-ATP concentrations were lower in leukemia cells of patients who received ara-C in addition to fludarabine as compared with those who received fludarabine alone. The terminal half-life of F-ara-A in plasma and the half-life of intracellular F-ara-ATP were reduced after the ara-C infusion in a concentration-dependent manner. Studies using purified deoxycytidine kinase support the conclusion that the increase in plasma levels of F-ara-A is in part the result of an effective competition by ara-C for phosphorylation by this enzyme, leading to a perturbation of the pharmacokinetics of intracellular F-ara-ATP.

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Abbreviations

ara-C:

9-β-d-arabinofuranosylcytosine

ara-CTP:

9-β-d-arabinofuranosylcytosine 5′-triphosphate

AUC:

area under the concentration-time curve

AUCp :

inerease in the AUC caused by perturbation

CLL:

chronic lymphocytic leukemia

dCyd kinase:

deoxycytidine kinase

F-ara-A:

9-β-d-arabinofuranosyl-2-fluoroadenine 5

fludarabine:

F-ara-AMP, 9-β-d-arabinofuranosyl-2-fluoroadenine 5′-monophosphate

F-ara-ATP:

9-β-d-arabinofuranosyl-2-fluoroadenine 5′-triphosphate

t 1/2 :

half-life of elimination

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Authors and Affiliations

  1. Department of Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 52, 77030, Houston, TX, USA

    Annette Kemena, Varsha Gandhi, Michael Keating & William Plunkett

  2. The University of Michigan Medical Center, 48109, Ann Arbor, MI, USA

    Donna S. Shewach

Authors
  1. Annette Kemena
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  2. Varsha Gandhi
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  3. Donna S. Shewach
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  4. Michael Keating
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  5. William Plunkett
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Additional information

This work was supported in part by grants CA32839, CA46452, CA53311, and CA57629 from the National Cancer Institute, Department of Health and Human Services, by the German Research Association (DFG), and by a contract from Berlex Laboratories, Inc.

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Kemena, A., Gandhi, V., Shewach, D.S. et al. Inhibition of fludarabine metabolism by arabinosylcytosine during therapy. Cancer Chemother. Pharmacol. 31, 193–199 (1992). https://doi.org/10.1007/BF00685547

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  • DOI: https://doi.org/10.1007/BF00685547

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