Document Detail

Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes.
MedLine Citation:
PMID:  11753605     Owner:  NLM     Status:  MEDLINE    
Fludarabine is active but not curative in the treatment of chronic lymphocytic leukemia (B-CLL). Nitric oxide (NO) supplied from exogenous, NO-donating pro-drugs can also induce apoptosis and death of acute leukemia cells. This study investigated combinations of fludarabine with NO-donating pro-drugs for their cytotoxicity against freshly isolated B-CLL lymphocytes following a 72 h exposure in vitro. The median IC(50)for fludarabine was 2.2 microM (n = 85). The nitric oxide donors DETA-NO, PAPA-NO, and MAHMA-NO were also cytotoxic, and their effects were inversely related to rates of NO release. Neither DETA-NO depleted of NO nor DETA itself was effective, indicating that NO was required for cytotoxicity. Drug interactions were evaluated by a modified combination index method. Synergy was observed in combinations of fludarabine or nelarabine (506U78) with DETA-NO in 52% and 88% of samples, respectively. Interestingly, the combination of fludarabine and DETA-NO was more cytotoxic in B-CLL cells less sensitive to fludarabine. DETA-NO did not enhance the activity of other DNA anti-metabolites, topoisomerase I and II inhibitors, or alkylating agents. Finally, the anti-leukemic activity of fludarabine alone or in combination with DETA-NO was found to correlate with inhibition of cellular RNA synthesis. These results indicate that NO donors could enhance fludarabine therapy for B-CLL.
D J Adams; M C Levesque; J B Weinberg; K L Smith; J L Flowers; J Moore; O M Colvin; R Silber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Leukemia     Volume:  15     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2001 Dec 
Date Detail:
Created Date:  2001-12-25     Completed Date:  2002-01-22     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  1852-9     Citation Subset:  IM    
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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MeSH Terms
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Synergism
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*,  pathology
Middle Aged
Nitric Oxide / pharmacology*
Triazenes / pharmacology
Vidarabine / analogs & derivatives*,  pharmacology*
Grant Support
Reg. No./Substance:
0/1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; 0/Triazenes; 10102-43-9/Nitric Oxide; 5536-17-4/Vidarabine; P2K93U8740/fludarabine

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