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The combination of imatinib and a farnesyltransferase inhibitor might be effective for reducing the number of BCR/ABL-positive leukemia cells. In this study, we examined the differences in the mechanisms of the growth inhibitory effect of the combination of imatinib and R115777 (Zarnestra™) among BCR/ABL-positive cell lines. Steel and Peckham isobologram analysis indicated that this combination had a strong synergistic inhibitory effect on growth in all imatinib-resistant cell lines and their parental cell lines. Levels of cleaved caspase 3 were increased by the combination treatment in all cell lines. However, both the level of cleaved PARP and the number of annexin-V-positive cells were much less increased in KCL22 and KCL22/SR cells than in K562, KU812, K562/SR and KU812/SR cells. The combination treatment promoted p27KIP1 accumulation and induced a significant increase in the percentage of G0/G1 KCL22 and KCL22/SR cells. In other cell lines, the percentage of G0/G1 cells was not increased but rather decreased. The results indicate that induction of apoptosis and blockage of the cell cycle were major mechanisms of the synergistic inhibitory effect of the combination treatment, but the relative importance of these mechanisms differed among cell types. Additional treatment for overriding the G1 checkpoint may be required to eradicate leukemia cells, in which the combination induces cell cycle arrest.