STI571 (CGP 57148B) inhibits c-abl, bcr-abl, PDGFR and c-kit tyrosine kinaies in vitro with high degree of specificity. Inhibition of bcr-abl was documented in cell syptems and proven to be the basis for successful therapeutic exploration of STI571 in bèr-abl positive diseases. However, the significance of c-kit inhibition is unclear. Recently, inhibition of SCF-induced c-kit phosphorylation was reported in a growth factor-dependent ce[l line M07 and was associated with growth inhibition. This suggested a possibility of therapeutic exploration of STI571 in c-kit positive malignancies. Because about 70% of AML leases are c-kit positive, we were interested in evaluating in vitro effects of STI571 on c-kit positive cell lines and primary c-kit-positive AML-derived blast cells. At concentrations 5-10 micromolar, the drug moderately inhibited proliferation of AML cell line and mbst of patient blasts. The inhibition, however, was not related to the percentage of c-kit expression as detected by flow cytometry. Western blot analysis with c-kit antibody showed a distinct band of 145 KD in all cases. Interestingly, there was no correlation between the intensity of the c-kit band on Western blots and percentage of c-kit positive blast calls as detected by flow cytometry. AML cells were also cultured for 30 minutes in me[dium supplemented with 15% PCS and 5% of PHA-LCM, in presence or absence of S1JI571, before being processed for Western blotting and evaluation of c-kit phosphorylation. Exposure to STI571 did not influence the level of expression of c-kit as determined by densitometry of Western blots. In primary AML cells as well as AML cell (ines, phosphorylation of c-kit was barely detectable even in presence of PHA-LCN-4. No significant changes in phosphorylation were detected after exposure to STI571. Studies of interaction between Ara-C and STI571 in the growth inhibition of AML cells showed no impact of STI571 on Ara-C toxicity. In conclusion, STI571 was mildly effective in reducing cell growth only at high concentrations, without a definite inhibition of SCF independent c-kit phosphorylation. STI571 neither inhibited nor potentiated the antiproliferative activity of Ara-C.