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J Cancer Res Clin Oncol ; 145(6): 1495-1507, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028540

RESUMO

PURPOSE: Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported. METHODS: Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures. RESULTS: We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity. CONCLUSIONS: Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Animais , Aprepitanto/administração & dosagem , Aprepitanto/farmacologia , Auranofina/administração & dosagem , Auranofina/farmacologia , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Captopril/administração & dosagem , Captopril/farmacologia , Celecoxib/administração & dosagem , Celecoxib/farmacologia , Dissulfiram/administração & dosagem , Dissulfiram/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Camundongos , Camundongos SCID , Minociclina/administração & dosagem , Minociclina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/farmacologia , Reprodutibilidade dos Testes , Sertralina/administração & dosagem , Sertralina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Temozolomida/administração & dosagem , Temozolomida/farmacologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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