In vivo effect of ABT-737 in mice bearing lymphomas overexpressing Bcl-2, Mcl-1, and Bcl-w. (A) Eμ-myc FLR tumor cells overexpressing Bcl-2, Bcl-w, or Mcl-1 were injected intravenously into C57BL/6 mice, and tumors allowed to develop over 22 to 36 days. When the tumor burden was high (average WBC count > 200 × 109 cells/L), mice were divided into groups (n ≥ 3, except for the Bcl-2 diluent group in iii and iv, where n = 2) matched for both WBC and platelet count, and treated by intraperitoneal injection of (i,ii) 100 mg/kg ABT-737 or vehicle; (iii,iv) 75 mg/kg ABT-737 or vehicle. Peripheral blood was collected 12 hours after treatment, and WBC and platelet numbers were determined. The Bcl-2– and Bcl-w–overexpressing tumors in i and ii were derived from the same pool (10) of Eμ-myc fetal liver cells. The Bcl-2– and Mcl-1–overexpressing tumors in iii and iv were also derived from the same pool (12) of Eμ-myc fetal liver cells. The Bcl-w–overexpressing FLR lymphomas tested in iii and iv were from another pool (11) of Eμ-myc fetal liver cells. Mean and standard deviation is shown. (Bi) Eμ-myc FLR tumor cells overexpressing Bcl-2 or Bcl-w (derived from Eμ-myc fetal liver pool 10) were injected intravenously into C57BL/6 mice, and tumors allowed to develop over time until WBC counts were greater than 50 × 109cells/L. ABT-737 (100 mg/kg) or vehicle was administered intraperitoneally daily, and WBC numbers were counted after 7 days of therapy. **P < .01. (ii) Eμ-myc FLR tumor cells overexpressing Bcl-2 (derived from Eμ-myc fetal liver pool 2) were injected intravenously into C57BL/6 mice, and tumors allowed to develop over 19 days until the mice became leukemic (WBC count > 13 × 106 cells/mL). From days 20 through 37, mice were injected intraperitoneally with ABT-737 (100 mg/kg) or vehicle daily and WBC counts were recorded over 2 weeks after therapy. ***P < .001. (C) Eμ-myc FLR tumor cells overexpressing Bcl-2 (derived from Eμ-myc fetal liver pool 12) were injected intravenously into C57BL/6 mice, and tumors allowed to develop over time until WBC counts were greater than 200 × 109 cells/L. Mice were injected intraperitoneally with the diluent for vorinostat (DMSO; n = 3) and the diluent for ABT-737 (vehicle; n = 3), ABT-737 (25 mg/kg) and DMSO (n = 3), vorinostat (200 mg/kg) and vehicle (n = 3), or vorinostat (200 mg/kg) and ABT-737 (25 mg/kg, n = 4). Peripheral blood was collected 12 hours before and 12 hours after treatment, and WBC and platelet numbers were determined. Mean and SD are shown.
