Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma.
Clin Cancer Res
; 12(22): 6781-90, 2006 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-17121899
ABSTRACT
PURPOSE:
To show the efficacy of targeting EWS/FLI-1 expression with a combination of specific antisense oligonucleotides and rapamycin for the control of Ewing's sarcoma (EWS) cell proliferation in vitro and the treatment of mouse tumor xenografts in vivo. EXPERIMENTALDESIGN:
EWS cells were simultaneously exposed to EWS/FLI-1-specific antisense oligonucleotides and rapamycin for various time periods. After treatment, the following end points were monitored and evaluated expression levels of the EWS/FLI-1 protein, cell proliferation, cell cycle distribution, apoptotic cell death, caspase activation, and tumor growth in EWS xenografts implanted in nude mice.RESULTS:
Simultaneous exposure of EWS cells in culture to an EWS/FLI-1-targeted suppression therapy using specific antisense oligonucleotides and rapamycin resulted in the activation of a caspase-dependent apoptotic process that involved the restoration of the transforming growth factor-beta-induced proapoptotic pathway. In vivo, individual administration of either antisense oligonucleotides or rapamycin significantly delayed tumor development, and the combined treatment with antisense oligonucleotides and rapamycin caused a considerably stronger inhibition of tumor growth.CONCLUSIONS:
Concurrent administration of EWS/FLI-1 antisense oligonucleotides and rapamycin efficiently induced the apoptotic death of EWS cells in culture through a process involving transforming growth factor-beta. In vivo experiments conclusively showed that the combined treatment with antisense oligonucleotides and rapamycin caused a significant inhibition of tumor growth in mice. These results provide proof of principle for further exploration of the potential of this combined therapeutic modality as a novel strategy for the treatment of tumors of the Ewing's sarcoma family.
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Base de dados:
MEDLINE
Assunto principal:
Sarcoma de Ewing
/
Fatores de Transcrição
/
Neoplasias Ósseas
/
Proteínas de Fusão Oncogênica
/
Oligonucleotídeos Antissenso
/
Marcação de Genes
Tipo de estudo:
Evaluation_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article