Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Adams, DJ; Levesque, MC; Weinberg, JB; Smith, KL; Flowers, JL; Moore, J; Colvin, OM; Silber, R

Published Date

  • December 2001

Published In

Volume / Issue

  • 15 / 12

Start / End Page

  • 1852 - 1859

PubMed ID

  • 11753605

Pubmed Central ID

  • 11753605

Electronic International Standard Serial Number (EISSN)

  • 1476-5551

International Standard Serial Number (ISSN)

  • 0887-6924

Digital Object Identifier (DOI)

  • 10.1038/sj.leu.2402291

Language

  • eng