Pathway activation in large B-cell non-Hodgkin lymphoma cell lines by doxorubicin reveals prognostic markers of in vivo response.
Leuk Lymphoma
; 49(11): 2170-80, 2008 Nov.
Article
em En
| MEDLINE
| ID: mdl-19021061
ABSTRACT
The principal curative agent in the front-line treatment of patients with diffuse large B-cell lymphoma (DLBCL) is the anthracycline, doxorubicin. To define pathways that may have a functional role in the response of DLBCL in vivo to doxorubicin-based therapies, seven DLBCL cell lines were treated with doxorubicin and the cellular response evaluated. Expression profiling of responses revealed changes in levels of genes consistent with discrete pathway activation that were confirmed functionally. The two most sensitive cell lines (Ly3 and Ly10) displayed activation of the TP53 pathway but not in the remaining five (Ly1, Ly2, Ly4, Ly7 and Ly8), where TP53 mutations were identified. In this latter group, a G2/M delay was invoked. NF-kappaB pathway activation was evident in Ly1 which with Ly4 displayed the most chemoresistant response. Treatment of Ly1 after doxorubicin with the proteasomic inhibitor, bortezomib, additively increased the cytotoxic effect of doxorubicin. Chemoresistance of Ly4 was associated with loss of chromosome 2 (0-9 Mbp) that in vivo was highly correlated with adverse outcome. Thus, the response of DLBCL in vivo and in vitro is defined by several distinct molecular and genetic pathways which is, perhaps, not surprising given the heterogeneous clinical, morphologic and genetic nature of DLBCL.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doxorrubicina
/
Regulação Neoplásica da Expressão Gênica
/
Linfoma Difuso de Grandes Células B
/
Biologia de Sistemas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Leuk Lymphoma
Assunto da revista:
HEMATOLOGIA
/
NEOPLASIAS
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos