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Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes

Leukemia volume 15, pages 1852–1859 (2001)Cite this article

Abstract

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 IC50for fludarabine was 2.2 μM (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.

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Acknowledgements

This work was supported in part by a grant from Berlex Laboratories, the VA Research Service, the Leukemia and Lymphoma Society of America, and NIH grants AR-39162 and Al-41764. This manuscript is dedicated to the memory of Dr Robert Silber, who initiated the work and inspired the research team. The authors are indebted to Dr Fumihiko Kanzawa for his guidance on application of the three-dimensional drug interaction model.

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  1. R Silber: Deceased

Authors and Affiliations

  1. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    DJ Adams, KL Smith, JL Flowers, J Moore, OM Colvin & R Silber

  2. Veterans Administration Medical Center, Durham, NC, USA

    MC Levesque & JB Weinberg

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Adams, D., Levesque, M., Weinberg, J. et al. Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes. Leukemia 15, 1852–1859 (2001). https://doi.org/10.1038/sj.leu.2402291

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