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Chronic Lymphocytic Leukemia

LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells

Leukemia volume 24, pages 1580–1587 (2010)Cite this article

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Abstract

B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell–cell interactions and soluble cytokines such as tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, caspase activation and DNA fragmentation. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. CLL cells from patients with poor prognostic indicators showed LMP-420 sensitivity equal to that for cells from patients with favorable characteristics. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-κB and immune response pathways in CLL cells. LMP-420 had minimal effects on normal peripheral blood mononuclear cell, B- and T-cell function, and hematopoietic colony formation. Our data suggest that LMP-420 may be a useful treatment for CLL with negligible hematologic toxicities.

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Acknowledgements

This work was supported in part by the National Institutes of Health, the Leukemia and Lymphoma Society, the Veterans Affairs Research Service and institutional awards from Duke University. We thank the patients and healthy volunteers for donating blood for this research. We also thank Derek Cyr for biostatistical consultation and Nelson Chao for critically reading and reviewing the paper.

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Authors and Affiliations

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

    Y M Mowery, M N Kennedy, S V Pizzo & G J Cianciolo

  2. Department of Medicine, Durham VA Medical Center, Durham, NC, USA

    J B Weinberg & K M Bond

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

    J B Weinberg, J O Moore, M C Lanasa, J P Gockerman, L F Diehl & D R Friedman

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  1. Y M Mowery
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Correspondence to D R Friedman.

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Mowery, Y., Weinberg, J., Kennedy, M. et al. LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells. Leukemia 24, 1580–1587 (2010). https://doi.org/10.1038/leu.2010.150

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