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Horm Metab Res 2003; 35(11/12): 822-827
DOI: 10.1055/s-2004-814153
Original
© Georg Thieme Verlag Stuttgart · New York

Insulin-like Growth Factor Binding Protein-6 and CCI-779, an Ester Analogue of Rapamycin, Additively Inhibit Rhabdomyosarcoma Growth

M.  A.  Gallicchio1 , M.  van Sinderen1 , L.  A.  Bach1
  • 1 Department of Medicine, University of Melbourne, Austin Hospital, Studley Rd, Heidelberg, Victoria, 3084, Australia
Further Information

Publication History

Received 1 September 2003

Accepted after Revision 14 October 2003

Publication Date:
07 January 2004 (online)

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Abstract

Rhabdomyosarcomas secrete high levels of insulin-like growth factor-II, suggesting this autocrine growth factor plays a major role in the unregulated growth of this childhood cancer. Treatment of Rh30 rhabdomyosarcoma cells with insulin-like growth factor binding protein-6 (IGFBP-6; 1000 ng/ml), which binds insulin-like growth factor-II with high affinity, inhibited growth in vitro (p < 0.001). Co-incubation of cells with rapamycin (1.56 ng/ml), an inhibitor of p70 S6 kinase, and IGFBP-6 (200 ng/ml) resulted in a significant reduction in Rh30 cell number compared to rapamycin or IGFBP-6 alone (p < 0.05 for both). Co-treatment of Rh30 cells with CCI-779 (5 and 50 ng/ml), an ester analogue of rapamycin, and IGFBP-6 (200 or 1000 ng/ml) also inhibited growth in vitro relative to CCI-779 alone (p < 0.01 and p < 0.001, respectively). In a nude mouse model, xenografts of Rh30 cells transfected with a recombinant vector encoding IGFBP-6 (phBP6-E3) showed delayed growth relative to vector control xenografts (27 days vs. 19 days to reach an average tumour volume of 0.5 cm3; p < 0.001). Treatment with CCI-779 (10 mg/kg) of mice inoculated with vector control xenografts, also delayed growth (to 31 days; p = 0.0055) relative to untreated mice with vector control xenografts. Co-treatment with CCI-779 (10 mg/kg) reduced phBP6-E3 transfected xenograft growth even further (to 45 days) compared to vector control xenografts (p < 0.001, day 33). CCI-779 thus acts additively with IGFBP-6 to reduce rhabdomyosarcoma growth both in vitro and in vivo.

Key words

Cancer - Xenograft - Insulin-like Growth Factor

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L. Bach

Department of Medicine, University of Melbourne

Austin Hospital · Studley Rd. · Heidelberg · Victoria, 3084 · Australia

Phone: +61(39496)3581

Fax: +61(39457)5485

Email: l.bach@unimelb.edu.au

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