Figure 7
Figure 7. SINEs prolong survival in a mouse model of CLL. (A) KPT-185 and KPT-251 induce similar dose-dependent cytotoxicity of murine TCL1 leukemia cells as measured by MTS assay (N = 14). (B) Overall survival (OS) curve for TCL1-SCID mice treated with 75 mg/kg KPT-251 (N = 10), 34 mg/kg fludarabine (n = 12), or vehicle control (N = 10). Treatment was initiated 14 days after engraftment. Median OS: 130.5 days (KPT-251), 72 days (vehicle), and 71.5 days (fludarabine). (C) Progression-free survival (PFS) curve, with progression defined as increase in circulating CLL (CD19+/TCL1+) cells to > 20 000/μL. Median PFS = 111, 44, and 51 days for KPT-251, vehicle and fludarabine, respectively. (D) Body-weight changes for experiment shown in panel B (KPT-251 and fludarabine-treated mice). (E) Peripheral blood count (PBL) in KPT-251, fludarabine, and vehicle control-treated TCL1-SCID mice. Count was determined by hematoxylin and eosin-stained peripheral blood smear at day 56 (week 8) after initiation of treatment. (F) Overall survival curve for TCL1-SCID mice treated with 75 mg/kg KPT-251 (N = 10) or vehicle control (N = 10). Treatment was initiated 70 days after engraftment. Median survival = 122 days, and 99 days for KPT-251 and vehicle, respectively. (G) PBL counts from TCL1-SCID mice treated 70 days after engraftment with 75 mg/kg KPT-251 or vehicle control (N = 10). Count was determined by hematoxylin and eosin-stained peripheral blood smear. Graph shows last count available for each animal. (H) PBL in TCL1-SCID mice before and 1, 3, or 5 days after administration of a single dose of KPT-251 or vehicle control. Count was determined by hematoxylin and eosin-stained peripheral blood smear. (I) Confocal fluorescence microscopy for p53, FoxO3a, and IκB in tumor cells isolated from mice treated with a single dose of KPT-251 or vehicle control for 72 hours. Results shown are representative of 3 experiments. Z stacks were collected (0.4 μm per slice) and images were chosen from the middle of nuclei. Side views (across bottom and side of figures) are also shown to depict the nuclear localization of p53, FoxO3a, and IκB in the cells.

SINEs prolong survival in a mouse model of CLL. (A) KPT-185 and KPT-251 induce similar dose-dependent cytotoxicity of murine TCL1 leukemia cells as measured by MTS assay (N = 14). (B) Overall survival (OS) curve for TCL1-SCID mice treated with 75 mg/kg KPT-251 (N = 10), 34 mg/kg fludarabine (n = 12), or vehicle control (N = 10). Treatment was initiated 14 days after engraftment. Median OS: 130.5 days (KPT-251), 72 days (vehicle), and 71.5 days (fludarabine). (C) Progression-free survival (PFS) curve, with progression defined as increase in circulating CLL (CD19+/TCL1+) cells to > 20 000/μL. Median PFS = 111, 44, and 51 days for KPT-251, vehicle and fludarabine, respectively. (D) Body-weight changes for experiment shown in panel B (KPT-251 and fludarabine-treated mice). (E) Peripheral blood count (PBL) in KPT-251, fludarabine, and vehicle control-treated TCL1-SCID mice. Count was determined by hematoxylin and eosin-stained peripheral blood smear at day 56 (week 8) after initiation of treatment. (F) Overall survival curve for TCL1-SCID mice treated with 75 mg/kg KPT-251 (N = 10) or vehicle control (N = 10). Treatment was initiated 70 days after engraftment. Median survival = 122 days, and 99 days for KPT-251 and vehicle, respectively. (G) PBL counts from TCL1-SCID mice treated 70 days after engraftment with 75 mg/kg KPT-251 or vehicle control (N = 10). Count was determined by hematoxylin and eosin-stained peripheral blood smear. Graph shows last count available for each animal. (H) PBL in TCL1-SCID mice before and 1, 3, or 5 days after administration of a single dose of KPT-251 or vehicle control. Count was determined by hematoxylin and eosin-stained peripheral blood smear. (I) Confocal fluorescence microscopy for p53, FoxO3a, and IκB in tumor cells isolated from mice treated with a single dose of KPT-251 or vehicle control for 72 hours. Results shown are representative of 3 experiments. Z stacks were collected (0.4 μm per slice) and images were chosen from the middle of nuclei. Side views (across bottom and side of figures) are also shown to depict the nuclear localization of p53, FoxO3a, and IκB in the cells.

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