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

Publication ,  Journal Article
Mowery, YM; Weinberg, JB; Kennedy, MN; Bond, KM; Moore, JO; Lanasa, MC; Gockerman, JP; Diehl, LF; Pizzo, SV; Cianciolo, GJ; Friedman, DR
Published in: Leukemia
September 2010

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-kappaB 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.

Duke Scholars

Published In

Leukemia

DOI

EISSN

1476-5551

Publication Date

September 2010

Volume

24

Issue

9

Start / End Page

1580 / 1587

Location

England

Related Subject Headings

  • Vidarabine
  • Tumor Necrosis Factor-alpha
  • Purines
  • Prognosis
  • Male
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Immunology
  • Humans
  • Gene Expression Profiling
  • Flow Cytometry
 

Citation

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Mowery, Y. M., Weinberg, J. B., Kennedy, M. N., Bond, K. M., Moore, J. O., Lanasa, M. C., … Friedman, D. R. (2010). LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells. Leukemia, 24(9), 1580–1587. https://doi.org/10.1038/leu.2010.150
Mowery, Y. M., J. B. Weinberg, M. N. Kennedy, K. M. Bond, J. O. Moore, M. C. Lanasa, J. P. Gockerman, 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, no. 9 (September 2010): 1580–87. https://doi.org/10.1038/leu.2010.150.
Mowery YM, Weinberg JB, Kennedy MN, Bond KM, Moore JO, Lanasa MC, et al. LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells. Leukemia. 2010 Sep;24(9):1580–7.
Mowery, Y. 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, vol. 24, no. 9, Sept. 2010, pp. 1580–87. Pubmed, doi:10.1038/leu.2010.150.
Mowery YM, Weinberg JB, Kennedy MN, Bond KM, Moore JO, Lanasa MC, Gockerman JP, Diehl LF, Pizzo SV, Cianciolo GJ, Friedman DR. LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells. Leukemia. 2010 Sep;24(9):1580–1587.

Published In

Leukemia

DOI

EISSN

1476-5551

Publication Date

September 2010

Volume

24

Issue

9

Start / End Page

1580 / 1587

Location

England

Related Subject Headings

  • Vidarabine
  • Tumor Necrosis Factor-alpha
  • Purines
  • Prognosis
  • Male
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Immunology
  • Humans
  • Gene Expression Profiling
  • Flow Cytometry