The most stringent definition of therapeutic synergy is a therapeutic effect achieved with a program of a combination therapy that exceeds the optimal effect achieved at any tolerated dose of monotherapy connected with the same drugs used in the combination. These results provide additional data for that combination of the Bcl natural compound library 2 inhibitor with L asp or TPT in the treatment of pediatric ALL. To try the generality of our findings, fixed ratio combination cytotoxicity assays were carried out on an additional five xenografts, and all showed synergy or powerful synergy between ABT 737 and T asp or TPT. Rationale for Combining ABT 737, TPT, and L asp in the Treatment of ALL. Since we have shown above that ABT 737 exerts synergistic ex vivo and in vivo antileukemic results when combined with either TPT or L asp, we further explored the rationale to produce this three drug combination. First, we examined the effects of those drugs around the quantities of important apoptosis regulatory proteins in ex vivo cultured Chromoblastomycosis xenograft cells. Consistent with its qualities like a DNAdamaging adviser, a concentration of TPT that is feasible in the plasma of patients with cancer caused a transient increase in p53 expression in EVERY 19 cells within 2 h of exposure but had no important effects on the levels of the anti-apoptotic proteins Mcl 1, Bcl 2, Bcl t, or Bcl XL or pro apoptotic Noxa, Puma, or Bim. In comparison, coverage of ALL 19 cells to L asp caused a rapid and specific down-regulation of Mcl 1 compared with merely a delayed induction of p53 and other Bcl 2 family proteins. This result was confirmed in two additional xenografts after a 4 h exposure to either L asp or TPT. These results suggest that TPT, L asp, and ABT 737 target nonoverlapping aspects of the intrinsic apoptosis pathway, which might lead to cytotoxicity against ALL cells ex vivo and in vivo. On this assumption, we examined the triple drug combination against ATP-competitive ALK inhibitor ALL 19. The combination of TPT, L asp, and ABT 737 was highly synergistic ex vivo, whereas the combination of TPT with L asp was averagely antagonistic. It’s remarkable that the three drug combination detained the in vivo progression of 19 by 50 days longer than expected if the effects of the three drugs were simply additive. In this experiment, L asp and ABT 737 alone were ineffective in delaying the progression of ALL 19, TPT caused a substantial delay, whereas the triple combination resulted in a delay of 85. 5 days. In the triple combination group, only three of eight mice reached a leukemia related function, deaths of the remaining mice were presumed to be age related. It’s remarkable that the in vivo synergistic effect of the triple combination was much greater than either the combination of ABT 737/L asp or ABT 737/TPT. To confirm the generality of the in vivo synergy between TPT, M asp, and ABT 737 one more two chemoresistant xenografts were tested.