Treatment of Imatinib-Sensitive and -Resistant Chronic Myelogenous Leukemia Cells with a Combination of Imatinib and Farnesyltransferase Inhibitors.

Abstract

Farnesyl protein transferase inhibitors (FTIs) represent a new class of anticancer agents. We were interested whether the farnesyltransferase inhibitors L-744,832 and LB42918 alone and in combination with imatinib are active in imatinib-sensitive and -resistant CML cells. LB42918 was more potent with ED50 = 4 ± 1 μM (mean ± S.D., n = 3) in the BCR-ABL+ imatinib-sensitive cell line EM-3 vs. ED50 = 25 ± 2 μM for L-744,832 after 48 hrs of treatment and assessment by MTT assay. The growth of imatinib-sensitive K562 and LAMA84 cells was not measurably inhibited by L-744,832 doses up to 25 μM. Similarly, the growth of K562 was not affected by 25 μM of LB42918. However, for LB42918 in LAMA84 cells an ED50 value of 30 ± 11 μM could be determined. In the imatinib-sensitive cell line EM-3, combination index values (CI) obtained using the method of Chou and Talalay indicated synergistic effects following simultaneous treatment with imatinib and FTI (CI = 0.5 ± 0.2 and 0.7 ± 0.2 at ED75 for imatinib + L-744,832 and imatinib + LB42918 respectively). In the cell imatinib-sensitive and -resistant lines K562 and LAMA84 a trend to lower ED50 values of imatinib was determined when up to 16 μM of L-744,832 or LB42918 were added, indicating potentiation of imatinib activity. Annexin V / propidium showed a strong increase of the apoptotic cell fraction in all imatinib-sensitive and an increase in the imatinib-resistant cells treated for 48 hrs by the combination imatinib + L-744,832 or imatinib + LB42918 as compared to treatment with each drug alone. Growth inhibition of CFU-GM colonies of primary imatinib-sensitive CML cells obtained from 4 patients is stronger after treatment with different concentrations of the combination of both drugs than after monotherapy with either imatinib or L-744,832. On the basis of the observed potentiation effects FTIs may find their place as supplement for CML patients on imatinib treatment.