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Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma.
Clin Cancer Res. 2006 Nov 15; 12(22):6781-90.CC

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.

Authors+Show Affiliations

Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, V.T. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia 20057-1482, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Evaluation Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17121899

Citation

Mateo-Lozano, Silvia, et al. "Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 12, no. 22, 2006, pp. 6781-90.
Mateo-Lozano S, Gokhale PC, Soldatenkov VA, et al. Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma. Clin Cancer Res. 2006;12(22):6781-90.
Mateo-Lozano, S., Gokhale, P. C., Soldatenkov, V. A., Dritschilo, A., Tirado, O. M., & Notario, V. (2006). Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 12(22), 6781-90.
Mateo-Lozano S, et al. Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma. Clin Cancer Res. 2006 Nov 15;12(22):6781-90. PubMed PMID: 17121899.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined transcriptional and translational targeting of EWS/FLI-1 in Ewing's sarcoma. AU - Mateo-Lozano,Silvia, AU - Gokhale,Prafulla C, AU - Soldatenkov,Viatcheslav A, AU - Dritschilo,Anatoly, AU - Tirado,Oscar M, AU - Notario,Vicente, PY - 2006/11/24/pubmed PY - 2007/2/7/medline PY - 2006/11/24/entrez SP - 6781 EP - 90 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 12 IS - 22 N2 - 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. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/17121899/Combined_transcriptional_and_translational_targeting_of_EWS/FLI_1_in_Ewing's_sarcoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17121899 DB - PRIME DP - Unbound Medicine ER -