GSI treatment prolongs survival in a mouse T-ALL model. (A) Effective plasma compound levels in MRK-003–treated mice. Compound serum levels were analyzed 1 to 5 days after continuous dosing of MRK-003 treatment. Effective and stable compound levels (1-10 μM) were detected in the serum of treated mice after 12 hours at each drug concentration tested. (B) Plasma compound levels decrease during 4-day rest period. Mice were treated for 3 consecutive days with 150 mg/kg MRK-003. After the first treatment, serum was analyzed for compound levels every 24 hours for the duration of the dosing regimen. (C) Intermittent GSI dosing minimizes “on-target” gastrointestinal toxicity. To define a GSI dosing regimen with limited/no associated toxicity, mice were administered vehicle (V) or 150 mg/kg MRK-003 by oral gavage everyday (R1) or for 3 days followed by a 4-day rest period (R2). Mice were monitored daily for loss of body weight and for evidence of diarrhea. (D) Extended survival in MRK-003–treated leukemic mice. Near-end-stage diseased Tal1/Ink4a/Arf^+/− mice were treated with 150 mg/kg MRK-003 (n = 16 mice) or 0.5% methylcellulose (n = 14 mice) orally for 3 days and rested for 4 days until mice were deemed moribund. Median survival for T-ALL mice treated with vehicle is 3 days, and 18 days for GSI treated mice (P < .005).