Figure 5.

In vivo antitumor activity of G-749 in xenograft and engrafted mouse model. (A-B) Pharmacodynamic analysis of G-749 in a subcutaneous MV4-11 xenograft model. (A) MV4-11 tumor-bearing mice received a single oral dose of G-749 HCl salt (10 mg/kg). Mice were euthanized at the indicated time point. From homogenized tumor tissues, the levels of p-FLT3 were measured by p-FLT3 ELISA in comparison with the vehicle-treated control group. The data from 3 mice at each point are presented (±SD). (B) The p-STAT5 and p-ERK1/2 in the same tumor tissue as in panel A were determined. (C) When the tumor size reached ∼450-600 mm³ in volume, mice (n = 9) received daily oral administration of vehicle or G-749 HCl salt (3, 10, and 30 mg/kg per day) for 28 days. The group of mice treated with 30 mg/kg per day of G-749 was subsequently monitored for an additional 28 days to examine tumor regrowth. ANOVA with Dunnett’s posttest was performed, ***P < .0001 at day 28. Significant inhibition of tumor growth and tumor regression was observed from 4 days onward (P < .05) (D) in vivo antitumor activity in an engrafted tumor model. The disseminated NOD/SCID mice were intravenously inoculated with Molm-14 cells. From 7 days after inoculation, mice received daily oral administration of G-749 (10 or 20 mg/kg per day) (n = 7) for 28 days. The log-rank test was made to compare survival curves between the vehicle-treated group and the 10 mg/kg per day (χ² = 13.7, df = 1, P = .0002) or 20 mg/kg per day group (χ² = 13.28, df = 1, P = .0003). The gray bars indicate the G-749 dosing period.