STI-571 (
Imatinib/
Glivec) has been shown to have synergism with various chemotherapeutic agents including
cytosine arabinoside (
Ara-C) in BCR/ABL positive
leukemia cells. The antiproliferative and proapopotic effects of
STI-571 in these experiments are mainly explained by its ability to specifically block the
fusion-protein BCR/ABL which has a constitutively active
tyrosine kinase activity. We investigated the effects of
STI-571 in combination with
Ara-C on BCR/ABL negative
leukemia cell lines and CD34+ hematopoietic progenitor cells in-vitro. Raji, HL-60, K562, Kasumi and KG1a
leukemia cells and CD34+ cells from healthy donors were incubated with 5-20 microg/ml
Ara-C for 5 h alone or in combination with 10 microg/ml
STI-571. Intracellular levels of
Ara-CTP measured by HPLC were increased 1.5-3 fold in
leukemia cells with most promiment effects in HL-60, Kasumi and Raji cells. In HL-60 cells a linear correlation between the concentration of
STI-571 (1-10 microg/ml) and the subsequent levels of
Ara-CTP was observed. A linear increase of
Ara-CTP could be induced by increasing the incubation time with
STI-571 from 2-6 h with a ceiling effect after 8 h. In contrast coincubation of mononuclear cells or purified CD34+ cells with
STI-571 at therapeutic concentrations lead to decreased intracellular levels of
Ara-CTP. The synergism between
Ara-C and
STI-571 was even more pronounced in Raji and HL-60 cells when 300 ng/ml
G-CSF were added at the beginning of the culture period. Intracellular measurements of
STI-571 revealed no decreased or increased levels of the compound when increasing
Ara-C concentrations were used. Our findings indicate that
STI-571 can have significant impact on
nucleoside metabolism in malignant and non-malignant hematopoietic cells. Further investigations will have to show whether theses effects can lead to increased cytotoxicity in primary blasts of patients with acute
leukemia.