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.
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 β1-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.
authors.affiliation: Grup d’Oncogènesi i Antitumorals, lnstitut d’Investigacions Biomèdiques Sant Pau, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bosch
authors.forename: María José
authors.initials: MJ
authors.lastname: Moreno
authors.forename: Rebeca
authors.initials: R
authors.lastname: Dieguez-Gonzalez
authors.forename: María Virtudes
authors.initials: MV
authors.lastname: Céspedes
authors.forename: Alberto
authors.initials: A
authors.lastname: Gallardo
authors.forename: Manuel
authors.initials: M
authors.lastname: Trias
authors.forename: Albert
authors.initials: A
authors.lastname: Grañena
authors.forename: Jorge
authors.initials: J
authors.lastname: Sierra
authors.forename: Isolda
authors.initials: I
authors.lastname: Casanova
authors.forename: Ramon
authors.initials: R
authors.lastname: Mangues
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D022001:Focal Adhesions / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011720:Pyrazoles / Q000008:administration & dosage*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides / Q000008:administration & dosage*; D015996:Survival Rate / Q000639:trends; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D000096926:Benzenesulfonamides
chemical_list: D011720:Pyrazoles; D013449:Sulfonamides; C529090:4-(5-(2,5-dimethylphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides