SU11248 exhibited dose-dependent efficacy and regressed large established subcutaneous FLT3-ITD tumors when administered at 40 and 20 mg/kg/d in athymic mice.
Daily oral administration of (A) SU11248 at 40 mg/kg/d or (C) a dose response of 20, 5, and 1 mg/kg/d was initiated when MV4;11 tumors reached an average of 400 mm3 volume. (A) Additionally, SU11248 (▪) was administered to mice bearing large tumors (2000 mm3) from the original vehicle-treated control group (●). (B) In mice with fully regressed tumors, dosing of SU11248 at 40 mg/kg/d was ceased and tumor regrowth occurred in some animals. When tumor volume exceeded 1000 mm3, SU11248 administration at 40 mg/kg/d recommenced to evaluate any alteration in sensitivity to the compound (4 mice). Tumor volume was measured on the indicated days, with the mean tumor volume ± SEM indicated for each group, each of which consisted of 10 mice (excluding panel B). (D) Athymic mice bearing established MV4;11 tumor xenografts were given a single oral dose of SU11248 (40 mg/kg) or citrate buffer vehicle; predose animals received no treatment. FLT3 (top panel) or Stat5 (bottom panel) were immunoprecipitated from tumor lysates, and Western blots were probed for phosphotyrosine or phospho-Stat5, respectively. Blots were reprobed for total FLT3 or Stat5. Each lane represents a separate animal. Lane labeled “ctrl” is positive control cell lysate for FLT3 immunoprecipitation.
