LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells.
Leukemia
; 24(9): 1580-7, 2010 Sep.
Article
em En
| MEDLINE
| ID: mdl-20613784
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Purinas
/
Compostos de Boro
/
Leucemia Linfocítica Crônica de Células B
/
Fator de Necrose Tumoral alfa
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Leukemia
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
Reino Unido