Abstract
Over-expression of anti-apoptotic members of the Bcl-2 family, including Bcl-2 and Bcl-XL, have been observed in more that 80% of B-cell Lymphomas. AT-101 has recently been found to be a potent small molecule inhibitor of Bcl-XL and Bcl-2. We investigated the toxicity and antitumor activity of oral AT-101 in SCID beige mice following subcutaneous injection with 1 x 107 RL-DLBCL cells. In the first experiment we explored four daily (25, 50, 75, 100 mg/kg) and three weekly (200, 240, 280 mg/kg) dose levels of AT-101 in cohorts of 5 mice. The 25 mg/kg/day for 4 weeks schedule exhibited the safest profile with some tumor growth delay compared to the control. Higher daily doses of 50, 75 and 100 mg/kg/day were associated with significant weight lost (i.e. > 10% of the initial weight) after 14, 10 and 7 days respectively, with death of all animals in these dose groups by day 23, 21 and 16 respectively. The weekly schedules exhibited later onset toxicity with the 240 mg/kg cohort exhibiting the best reduction in tumor growth compared to control (p=0.063). In a second single agent experiment additional schedules were explored to try to improve the toxicity profile. These schedules included 100, 120, 140 mg/kg on days 1, 4, 8, 11 followed by 1 week; a 35 and 50 mg/kg/day for 2 weeks out of 4; a 100 mg/kg for 3 days/week for 3 weeks out of 4; and a 240 and 280 mg/kg/week for 3 weeks out of 4. Significant weight loss was noted at 5–7 days in the dose groups at 100 mg/kg daily, 120–140 and 280 mg/kg. Overall, tumor volume assessment showed a statistically significant advantage for the 35 mg/kg daily schedule compared to control (p=0.008), with this dose and schedule being the most effective and least toxic. In terms of dose intensity, it’s interesting to note that 35 mg/kg/day for two weeks delivered a total dose of 490 mg/kg. Combination experiments with cyclophosphamide (50 mg/kg) and rituximab (10 mg/mg) i.p. on days 2, 4, 6, 8 demonstrated marked improvement in favor of the triplet combination (see Fig. below). AT-101 (35 mg/kg) was administered p.o. from day 0 to day 9 These data suggest that targeting Bcl-2 and Bcl-XL with AT-101 may help chemosensitize lymphoma to conventional therapies and improve therapeutic outcomes.
Figure
