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JNCI Journal of the National Cancer Institute 2002 94(22):1673-1679; doi:10.1093/jnci/94.22.1673
© 2002 by Oxford University Press
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Journal of the National Cancer Institute, Vol. 94, No. 22, 1673-1679, November 20, 2002
© 2002 Oxford University Press

ARTICLE

Potential Use of Imatinib in Ewing’s Sarcoma: Evidence for In Vitro and In Vivo Activity

Melinda S. Merchant, Chan-Wook Woo, Crystal L. Mackall, Carol J. Thiele

Affiliation of authors: M. S. Merchant, C.-W. Woo, C. L. Mackall, C. J. Thiele, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Correspondence to: Melinda S. Merchant, M.D., Ph.D., 10 Center Dr., MSC 1298, Bldg. 10/13N240, Bethesda, MD 20892 (e-mail: merchanm{at}mail.nih.gov).

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 µM. Imatinib inhibited SCF-mediated c-kit phosphorylation (IC50 = 0.1–0.5 µM). 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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