Title:
|
A novel orally available inhibitor of focal adhesion signaling increases
survival in a xenograft model of diffuse large B-cell lymphoma with
central nervous system involvement
|
Author:
|
Bosch, Rosa; Moreno, María José; Diéguez González, Rebeca; Céspedes, María Virtudes; Gallardo, Alberto; Trias, Manuel; Grañena Batista, Alberto; Sierra, Jorge; Casanova, Isolda; Mangues, Ramon
|
Abstract:
|
Central nervous system dissemination is a relatively uncommon but almost always fatal complication in diffuse large B-cell lymphoma patients. Optimal therapy for central nervous involvement in this malignancy has not been established. In this paper, we aimed to evaluate the therapeutic effect of E7123, a celecoxib derivative that inhibits focal adhesion signaling, in a novel xenograft model of diffuse large B-cell lymphoma with central nervous system involvement. Cells obtained after disaggregation of HT subcutaneous tumors (HT-SC cells) were intravenously injected in NOD/SCID mice. These mice received oral vehicle or 75 mg/kg of E7123 daily until they were euthanized for weight loss or signs of sickness. The antitumor effect of E7123 was validated in an independent experiment using a bioluminescent mouse model. Intravenously injected HT-SC cells showed higher take rate and higher central nervous system tropism (associated with increased expression of beta 1-integrin and p130Cas proteins) than HT cells. The oral administration of E7123 significantly increased survival time in 2 independent experiments using mice injected with unmodified or bioluminescent HT-SC cells. We have developed a new xenograft model of diffuse large B-cell lymphoma with central nervous system involvement that can be used in the pre-clinical evaluation of new drugs for this malignancy. E7123 is a new, well-tolerated and orally available therapeutic agent that merits further investigation since it may improve current management of diffuse large B-cell lymphoma patients with central nervous system involvement. |
Subject(s):
|
-Malalties del sistema nerviós central -Limfomes -Central nervous system diseases -Lymphomas |
Rights:
|
(c) Ferrata Storti Foundation, 2013
|
Document type:
|
Article Article - Published version |
Published by:
|
Ferrata Storti Foundation
|
Share:
|
|