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  • Title: Potential use of imatinib in Ewing's Sarcoma: evidence for in vitro and in vivo activity.
    Author: Merchant MS, Woo CW, Mackall CL, Thiele CJ.
    Journal: J Natl Cancer Inst; 2002 Nov 20; 94(22):1673-9. PubMed ID: 12441322.
    Abstract:
    BACKGROUND: Ewing's sarcoma cells express c-kit, a receptor tyrosine kinase, and its ligand, stem cell factor (SCF), creating a potential autocrine loop that may promote tumor survival. We thus examined whether the specific tyrosine kinase inhibitor imatinib mesylate (hereafter imatinib; formerly STI571) could inhibit the proliferation of Ewing's sarcoma cells in vitro and in vivo. METHODS: The effect of imatinib on c-kit expression and phosphorylation in Ewing's sarcoma cells was examined by immunoblotting. The effect of imatinib on cell growth and apoptosis was examined with an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay and with a morphologic test and Annexin V staining, respectively. The effect of imatinib oral therapy (every 12 hours for 5-7 days) on primary tumor growth was assessed in Ewing's sarcoma xenografts in SCID/bg mice (5 or 10 mice per group). RESULTS: All Ewing's sarcoma cell lines tested were sensitive to imatinib-mediated apoptosis with a concentration inhibiting growth by 50% (IC50) of 10-12 micro M. Imatinib inhibited SCF-mediated c-kit phosphorylation (IC50 = 0.1-0.5 microM). In the xenograft model, imatinib treatment resulted in the regression or control of primary Ewing's sarcomas. After 6 days of treatment, the mean lower extremity volume including xenograft tumor was 3744 mm3 (95% confidence interval [CI] = 3050 to 4437 mm3), 1442 mm3 (95% CI = 931 to 1758 mm3), and 346 mm3 (95% CI = 131 to 622 mm3) in mice treated with carrier alone or with imatinib at 50 mg/kg or at 100 mg/kg, respectively. CONCLUSIONS: Imatinib interferes with growth of all Ewing's sarcoma cell lines tested in vitro and in vivo. Targeted inhibition of tyrosine kinase-dependent autocrine loops, therefore, may be a viable therapeutic strategy for Ewing's sarcoma.
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