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3-Deazauridine enhances the antileukemic action of 5-aza-2′-deoxycytidine and targets drug-resistance due to deficiency in deoxycytidine kinase
Author(s):
Noël J.-M. Raynal
,
Louise F. Momparler
,
Georges E. Rivard
,
Richard L. Momparler
Publication date
Created:
January 2011
Publication date
(Print):
January 2011
Journal:
Leukemia Research
Publisher:
Elsevier BV
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Abstract
New approaches should be sought to treat high-risk acute lymphoblastic leukemia (ALL). Since aberrant DNA methylation plays an important role in leukemogenesis of ALL, it can be targeted by 5-aza-2'-deoxycytidine (5-AZA-CdR), a potent inhibitor of DNA methylation. 5-AZA-CdR is a prodrug that is activated by deoxycytidine kinase (DCK). Leukemic cells lacking DCK are drug-resistant. In a previous phase I study, we reported that 5-AZA-CdR could induce remissions in ALL. However, some patients developed drug-resistance due to deficiency in DCK. These observations aroused our interest in 3-deazauridine (3-DU), a CTP synthetase inhibitor that is effective against leukemic cells deficient in DCK. In this report, we observed that 3-DU enhanced the in vitro antineoplastic action of 5-AZA-CdR on human leukemic cells by increasing its incorporation into DNA. Using an optimized dose-schedule we showed that this combination could cure some mice bearing L1210 leukemia, even in the presence of a subpopulation of drug-resistant (L1210/ARA-C) leukemic cells lacking DCK. 3-DU alone also cured some mice with L1210/ARA-C leukemia. In a pilot study on 3 relapsed patients with advanced ALL, the combination of 5-AZA-CdR and 3-DU produced a marked reduction in leukemic blasts, confirming our preclinical observations. Furthermore, after several treatments with these agents all three patients developed drug-resistance to 5-AZA-CdR as determined by an in vitro drug sensitivity test. In two patients we showed by enzymatic analysis that the drug-resistance was due to deficiency in DCK. Our preclinical and clinical results provide a strong rationale to further investigate the combination of 5-AZA-CdR and 3-DU for the treatment of advanced ALL. Crown Copyright © 2010. Published by Elsevier Ltd. All rights reserved.
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Author and article information
Journal
Title:
Leukemia Research
Abbreviated Title:
Leukemia Research
Publisher:
Elsevier BV
ISSN (Print):
01452126
Publication date Created:
January 2011
Publication date (Print):
January 2011
Volume
: 35
Issue
: 1
Pages
: 110-118
Article
DOI:
10.1016/j.leukres.2010.04.014
SO-VID:
651d93c6-ac10-4469-937d-8b98f511d85f
Copyright ©
© 2011
License:
https://www.elsevier.com/tdm/userlicense/1.0/
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