Effect of XIAP inhibitors and TRAIL on primary childhood ALL cells ex vivo and in a NOD/SCID mouse model in vivo. Primary leukemic blasts from children with ALL before the onset of chemotherapy were left untreated (□) or were treated for 24 hours with 1 μg/mL TRAIL (■) in the presence of 10 nM XIAP inhibitors, control compound, or DMSO. Apoptosis was determined by forwardside scatter analysis and flow cytometry (A) and colony formation was assessed as described in “Methods” (B). (C-F) NOD/SCID mice were inoculated with 107 human leukemic cells. Treatment started on day 3 with 40 mg/kg XIAP inhibitor 2 and/or 50 μg TRAIL/mouse. Drugs were administered intraperitoneally 5 days/week for 4 weeks and mice were killed on day 34. The percentage of human CD45+ cells on day 34 (C), the number of white blood cells on day 34 (D), and spleen weight on day 34 (E) are depicted by box plots; the line inside each box denotes median; boxes, 25th and 75th percentiles; error bars, minimum and maximum; #P < .05; *P < .01; and n.s., not significant. (F) Spleens are depicted at autopsy on day 34.
