By targeting several kinases simultaneously which makes them non specific

Therefore, it has been widely accepted that continuous and complete target inhibition is a prerequisite for clinical efficacy of TKI treatment. Recently, this paradigm has been challenged by data BMS-582949 (hydrochloride) customer reviews obtained in a clinical trial using the second generation BCR-ABL inhibitor dasatinib. Dasatinib demonstrated similar clinical activity but less side effects for once daily dosing with 100 mg as compared to twice daily dosing with 70 mg. Interestingly, the once daily dosing schedule apparently resulted in transient inhibition of BCR-ABL kinase activity only, as rephosphorylation of the BCR-ABL downstream adaptor protein CRKL was observed 8 h post dasatinib-dosing. In addition, in vitro and ex vivo studies suggested that high-dose pulse-exposure to TKI irreversibly commits BCR-ABL positive cells to apoptosis. This effect was evident upon pulse treatment for only 20 min �C4 h. It was proposed that depth, rather than duration of kinase inhibition, is the critical Haldol D4′ determinant for TKI efficacy. However, the molecular mechanism for apoptosis induction after HD-TKI pulse-exposure has remained elusive. In our present work, we demonstrate that dramatic intracellular drug retention mediates apoptotic cell death upon HD-TKI pulseexposure. In line with this, over-expression of ABC transporters prevented cell death upon HD-TKI pulse-exposure. These findings will be useful to rethink our current framework of pharmacokinetic requirements of TKIs for CML and other diseases. In addition, these studies refine the molecular concept of TKI-induced apoptosis. Induction of apoptosis upon HD-TKI pulse-exposure has been demonstrated by several groups. Based upon these findings, a concept of irreversible commitment to apoptosis upon HD-TKI pulse-exposure was proposed. However, the mechanism of induction of apoptosis upon HD-TKI pulse-exposure remained elusive at the molecular level. This prompted us to investigate the molecular mechanisms of cell death induced by HD-TKI pulse-exposure in more detail. It appeared unlikely that short-term potent kinase inhibition could initiate an irreversible cell death program without altering onset and kinetics of apoptosis. Indeed, the data presented here provide evidence that HD-TKI pulseexposure does not irreversibl