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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.
Mowery, Y M; Weinberg, J B; Kennedy, M N; Bond, K M; Moore, J O; Lanasa, M C; Gockerman, J P; Diehl, L F; Pizzo, S V; Cianciolo, G J; Friedman, D R.
Afiliação
  • Mowery YM; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
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.
Assuntos

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

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