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Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2′-deoxycytidine by human cytidine deaminase

  • Original Articles
  • Deamination, Cytidine Deaminase, Cytosine Arabinoside, 5-Aza-2′-Deoxycytidine
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Summary

Deamination of the nucleoside analogues ARA-C and 5-AZA-CdR by CR deaminase results in a loss of antileukemic activity. To prevent the inactivation of these analogues, inhibitors of CR deaminase may prove to be useful agents. In the present study we investigated the effects of the deaminase inhibitors Zebularine, 5-F-Zebularine, and diazepinone riboside on the deamination of CR, ARA-C, and 5-AZA-CdR using highly purified human CR deaminase (EC 3.5.4.5). These inhibitors produced a competitive type of inhibition with each substrate, the potency of which followed the patterns diazepinone riboside>5-F-Zebularine and THU>Zebularine. 5-AZA-CdR was more sensitive than ARA-C to the inhibition produced by these deaminase inhibitors. The inhibition constants for diazepinone riboside lay in the range of 5–15nm, suggesting that this inhibitor could be an excellent candidate for use in combination chemotherapy with either ARA-C or 5-AZA-CdR in patients with leukemia.

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Abbreviations

CdR:

deoxycytidine

CR:

cytidine

ARA-C:

cytosine arabinoside

ARA-U:

uridine arabinoside

5-AZA-CdR:

5-aza-2′-deoxycytidine

5-AZA-UdR:

5-aza-2′-deoxyuridine

THU:

tetrahydrouridine

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Authors and Affiliations

  1. Départment de Pharmacologie, Université de Montréal and Centre de Recherche Pédiatrique, Hôpital Ste-Justine, H3T 1C5, Montréal, Québec, Canada

    Josée Laliberté & Richard L. Momparler

  2. Laboratory of Medicinal Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, 20 892, Bethesda, MD, USA

    Victor E. Marquez

Authors
  1. Josée Laliberté
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  2. Victor E. Marquez
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  3. Richard L. Momparler
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Additional information

This work was supported by CAFIR (Université de Montréal) and Centre de Recherche HSJ. J. L. is supported by a studentship from HSJ and MRC

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Laliberté, J., Marquez, V.E. & Momparler, R.L. Potent inhibitors for the deamination of cytosine arabinoside and 5-aza-2′-deoxycytidine by human cytidine deaminase. Cancer Chemother. Pharmacol. 30, 7–11 (1992). https://doi.org/10.1007/BF00686478

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  • DOI: https://doi.org/10.1007/BF00686478

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