Combination treatment of imatinib-sensitive and -resistant BCR-ABL-positive CML cells with imatinib and farnesyltransferase inhibitors.
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.


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.


CONCLUSIONS
The results indicated the potential of L744,832 and LB42918 as combination agents for CML patients on imatinib treatment.
Radujkovic
Aleksandar
A
Research Program Innovative Cancer Diagnostics and Therapy, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Topaly
Julian
J
Fruehauf
Stefan
S
Zeller
W Jens
WJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D004791:Enzyme Inhibitors; C096898:L 744832; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D008715:Methionine; D051231:Farnesyltranstransferase; D016044:Fusion Proteins, bcr-abl