Combination Treatment of Imatinib-sensitive and -resistant BCR-ABL-positive CML Cells with Imatinib and Farnesyltransferase Inhibitors

Abstract

Background: Resistance to imatinib monotherapy frequently emerges in advanced stages of chronic myelogenous leukemia (CML), supporting the rationale for combination drug therapy. In the present study, the activities of the farnesyltransferase inhibitors (FTIs) L744,832 and LB42918, as single agents and in combination with imatinib, were investigated in different imatinib-sensitive and -resistant BCR-ABL-positive CML cells. Materials and Methods: Growth inhibition of the cell lines and primary patient cells was assessed by MTT assays and colony-forming cell assays, respectively. Drug interactions were analyzed according to the median-effect method of Chou and Talalay. The determination of apoptotic cell death was performed by annexin V/propidium iodide staining. Results: Combinations of both FTIs with imatinib displayed synergism or sensitization (potentiation) in all the cell lines tested. In primary chronic phase CML cells, additive and synergistic effects were discernible for the combination of imatinib plus L744,832 and imatinib plus LB42918, respectively. Annexin V/propidium iodide staining showed enhancement of imatinib-induced apoptosis with either drug combination, both in imatinib-sensitive and -resistant cells. Conclusion: The results indicated the potential of L744,832 and LB42918 as combination agents for CML patients on imatinib treatment.