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Clin Cancer Res. 2006 Nov 15;12(22):6781-90.

Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma.

Author information

1
Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, V.T. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20057-1482, USA.

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.

EXPERIMENTAL DESIGN:

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.

PMID:
17121899
DOI:
10.1158/1078-0432.CCR-06-0609
[Indexed for MEDLINE]
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