ABT-199 potently kills FL5.12-BCL-2 cells (EC50=4 nM), ABT-199 shows much weaker activity against FL5.12-BCL-XL cells (EC50=261 nM). ABT-199 also shows selectivity in cellular mammalian two-hybrid assays, where it disrupts BCL-2-BIM complexes (EC50=3 nM) but is much less effective against BCL-XL-BCL-XS (EC50=2.2 μM) or MCL-1-NOXA complexes.
After a single oral dose of 12.5 mg per kg body weight in xenografts derived from RS4;11 cells (ALL), ABT-199 causes a maximal tumor growth inhibition (TGImax) of 47% (P<0.001) and tumor growth delay (TGD) of 26% (P<0.05)[1]. Treatment of established xenografted (a mouse xenograft model of the T-ALL cell line LOUCY) tumors with 100 mg ABT-199/kg for 4 days resulted in a significant reduction of leukemic burden (P=0.0048).
RS4;11 cells are seeded at 50,000 per well in 96-well plates and treated with compounds diluted in half-log steps starting at 1 μM and ending at 0.00005 μM. All other leukemia and lymphoma cell lines are seeded at 15,000-20,000 cells per well in the appropriate medium and incubated with ABT-199 or Navitoclax for 48 h. Effects on proliferation are determined using Cell TiterGlo reagent. EC50 values are determined by nonlinear regression analysis of the concentration-response data. Mouse FL5.12-BCL-2 and FL5.12-BCL-XL cells are propagated and assessed. Bak-/- Bax-/- double knockout mouse embryonic fibroblasts are seeded into 96-well microtiter plates at 5,000 cells per well in DMEM supplemented with 10% FBS. ABT-199 in the same culture medium is added in half-log dilutions starting at 5 μM. The cells are then incubated at 37°C (5% CO2) for 48 h, and the effects on proliferation are determined using Cell TiterGlo reagent.
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
