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Survivin-directed RNA interference cocktail is a potent suppressor of tumour growth in vivo
  1. H Caldas,
  2. M P Holloway,
  3. B M Hall,
  4. S J Qualman,
  5. R A Altura
  1. Center for Childhood Cancer, Columbus Children’s Research Institute, Columbus, OH, USA
  1. Correspondence to:
 Rachel A Altura
 Columbus Children’s Research Institute, WA5021, 700 Children’s Drive, Columbus, OH 43205, USA; AlturaR{at}ccri.net

Abstract

Background: Survivin is proposed to play a central role in the progression and resistance to therapy of diverse tumour types. High levels of this molecule in tumour cells also correlate with loss of the TP53 tumour suppressor gene, suggesting a molecular connection between TP53 loss and transcriptional induction of Survivin. Patients with TP53 germline mutations, such as those with Li-Fraumeni syndrome, are particularly susceptible to sarcomas, including rhabdomyosarcomas. Our study aimed to identify rhabdomyosarcoma tumours that express Survivin, in order to test novel Survivin-targeted therapies in these tumours.

Methods: Tumour microarray slides composed of 63 primary rhabdomyosarcoma tumours were stained with a polyclonal antibody to Survivin to identify tumours expressing Survivin. Subcutaneous tumours were then established in NOD/SCID mice using RH30red cells, a red fluorescent clone of the RH30 human alveolar rhabdomyosarcoma cell line. Tumours were treated by hydrodynamic injection with a cocktail of Survivin-shRNA-encoding plasmids for a period of 2 weeks.

Results: Over 80% of primary rhabdomyosarcoma tumours expressed Survivin. Treatment of rhabdomyosarcoma xenografts showed greater than 70% reduction in growth when compared with control injected tumours at study completion (average tumour sizes: 1683 v 304 mm3, p<0.05).

Conclusions: Our findings support a role for Survivin in rhabdomyosarcoma biology and provide preliminary evidence for the therapeutic use of Survivin-targeted RNA interference for human tumours that express high levels of this molecule.

  • ARMS, alveolar rhabdomyosarcoma
  • ERMS, embryonal rhabdomyosarcoma
  • FFS, failure-free survival
  • LFS, Li-Fraumeni syndrome
  • RMS, rhabdomyosarcoma
  • RPE cells, retinal pigment epithelial cells
  • apoptosis
  • soft tissue sarcoma
  • Survivin
  • RNAi
  • xenografts

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Footnotes

  • Published Online First 20 May 2005

  • This work was supported in part by the Columbus Children’s Research Institute, and by grants from the Elsa U. Pardee and the Hope Street Kids Foundations

  • Competing interests: none declared

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