Selective Bcl-2 inhibition to treat chronic lymphocytic leukemia and non-Hodgkin lymphoma.
Clin Adv Hematol Oncol
; 12(4): 224-9, 2014 Apr.
Article
en En
| MEDLINE
| ID: mdl-25003352
ABSTRACT
ABT-199, a second-generation BH3 mimetic, is an orally bioavailable, small molecule inhibitor that selectively targets B-cell lymphoma/leukemia 2 (Bcl-2). Bcl-2 is a key protein that inhibits the intrinsic mitochondrial pathway of apoptosis. First-generation BH3 mimetics such as navitoclax (ABT-263) had a broad range of inhibitory activity against Bcl-2 family members, including Bcl-2, Bcl-XL, and Bcl-w. This drug demonstrated antitumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL); however, on-target Bcl-XL inhibition led to dose-dependent thrombocytopenia and posed a barrier to maximizing the activity of this agent. Through an elegant reengineering of navitoclax, ABT-199 was developed as a Bcl-2-selective small molecule inhibitor. In preclinical studies, ABT-199 was shown to have greater than 100-fold selectivity for Bcl-2 over Bcl-XL. This selectivity has been consistent with the early results of the ongoing phase 1 clinical trial of ABT-199 in which the drug has demonstrated high rates of activity in relapsed/refractory CLL and NHL without dose-dependent thrombocytopenia. On-target tumor lysis syndrome (TLS) has been observed in a subset of patients treated with ABT-199, but changes in initial dosing and stepwise dose escalation have now been implemented to mitigate this risk. Ongoing correlative studies are being performed to help identify patients with the highest chance of response and the greatest risk for TLS.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sulfonamidas
/
Linfoma no Hodgkin
/
Leucemia Linfocítica Crónica de Células B
/
Compuestos Bicíclicos Heterocíclicos con Puentes
/
Proteínas Proto-Oncogénicas c-bcl-2
/
Antineoplásicos
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Clin Adv Hematol Oncol
Asunto de la revista:
HEMATOLOGIA
/
NEOPLASIAS
Año:
2014
Tipo del documento:
Article