her investigators suggested that alternate pathways in addition to apoptosis may lead to the inhibition of cell growth mediated by tyrosine kinase inhibitors.41,42 There are several pharmacological mechanisms by which CML cells develop resistance to tyrosine AZD2171 475108-18-0 kinase inhibitors, such as 
surface molecules including MDR 1, which reportedly mediates the efflux of imatinib. Such mechanisms may also lead to the resistance of other tyrosine kinase inhibitors, such as nilotinib.43 45 Specifically, a predominant acquisition of MDR1 dependent resistance is found in the majority of patients with advanced CML and other leukemias, as well as in patients during relapse.
46,47 These pharmacokinetic mechanisms of resistance to tyrosine kinase inhibitors may occur in addition or may induce the well described pharmacodynamic mechanisms involving the BCR ABL gene in patients with CML.48 It should be stressed that our real time RT PCR data show a highly significant reduction of more than 13% in MDR1 gene AZD8055 expression after transfection with BCRABL siRNA in mutated 32Dp210Thr315Ile cells. The combination of BCR ABL siRNA with imatinib or nilotinib resulted in an additional reduction of MDR1 gene expression of 27% or 30%. In addition to impaired drug transport, aberrant activation of signal transduction proteins, including nuclear factor ?B, has been implicated in treatment failure in hematologic malignancies including CML.
49,50 Our study demonstrates that BCR ABL siRNA reliably and effectively induces apoptosis and inhibition of proliferation in factor independent 32Dp210 BCR ABL oligoclonal cell lines, including those resistant to imatinib and particularly those with the T315I mutation. Moreover, additive effects of BCRABL siRNA with tyrosine kinase inhibitors, such as imatinib or nilotinib, result in anti proliferative and enhanced proapoptotic effects in 32Dp210 cells. In addition, the combination of BCR ABL siRNA with imatinib or nilotinib significantly reversed MDR1 dependent multidrug resistance of mutated 32Dp210 cells. Modulation of breakpoint specific siRNA by agents such as tyrosine kinase inhibitors might open the door to new important alternative or complementary approaches for the treatment of BCR ABL expressing hematologic disorders. Chronic myeloid leukemia is a clonal, multistep, multilineage myeloproliferative disorder.
It is initiated and propagated by a rare population of CML stem cells that have acquired a BCR ABL fusion gene. The BCR ABL fusion gene encodes a chimeric oncoprotein that displays constitutively elevated tyrosine kinase activity that drives CML pathogenesis. These features deregulate cellular proliferation and apoptosis control through eff ects on multiple intracellular signaling pathways, including the Ras, phosphatidylinositol 3 kinase, JAK STAT, and NF B pathways. Recently, imatinib mesylate, which is an inhibitor of the BCR ABL tyrosine kinase, has shown promise in treating CML patients. However, early relapses and IM resistant disease have emerged as signifi cant clinical problems in some IM treated CML patients. Relapses are frequently associated with mutations in the BCRABL kinase domain, accounting for 60 90% of relapses. Dasatinib and nilotinib are more recently produce
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