In vitro effects of STI 571‐containing drug combinations on the growth of Philadelphia‐positive chronic myelogenous leukemia cells

BACKGROUND Chronic myelogenous leukemia (CML) is characterized by a molecular aberration, a fusion BCR‐ABL gene encoding for aberrant tyrosine kinase activity, which is crucial in the pathogenesis of CML. In vitro, inhibition of BCR‐ABL protein tyrosine kinase activity by a tyrosine kinase inhibitor, Imatinib mesylate (STI571; formerly CGP57148B), successfully suppressed proliferation/survival of the BCR‐ABL positive clones. In clinical studies, hematologic and cytogenetic remissions have been achieved in most patients with chronic phase CML; in accelerated and blastic phases of CML, STI571 appeared less effective. In the current study, the authors tested combinations of STI571 and cytarabine and homoharringtonine (HHT), drugs with documented activity in CML. METHODS The single agents and their combinations were studied for in vitro effect on proliferation of BCR‐ABL positive cell lines KBM5 and KBM7 by 3(4,5‐dimethylthiazol‐2yl)‐2,5 diphenyl‐tetrazolium bromide assay and on primary patient‐derived BCR‐ABL cells by clonogenic assays. The in vitro additive, synergistic, or antagonistic effects of cytarabine and HHT with STI571 were then investigated by computer‐assisted analysis using the CalcuSyn software. RESULTS STI571 consistently suppressed BCR‐ABL positive cell proliferation with a dose‐effect correlation. In the model system used, STI571/cytarabine and STI571/HHT combinations were more effective in inhibiting KBM5 and KBM7 cell growth than each drug as single agent. These results were also verified in primary CML‐derived clonogenic cells in semisolid cultures. CONCLUSIONS In this experimental system, our studies documented additive or synergistic effects with STI571 plus cytarabine or HHT, supporting the future use of STI571 combinations in clinical trials in patients with Philadelphia chromosome‐positive leukemias. Cancer 2002;94:2653–62. © 2002 American Cancer Society. DOI 10.1002/cncr.10543 The authors investigated the in vitro effect of STI571/cytarabine and STI571/homoharringtonine combinations on the growth of two BCR‐ABL positive cell lines and on mononuclear white blood cells derived from patients affected by chronic myelogenous leukemia in chronic phase. Using a software based‐analysis, the authors showed an additive‐synergistic inhibitory effect of these combinations on both cell line proliferation and patient‐derived colony growth, providing support for clinical trials.