Imatinib mesylate selectively influences the cellular metabolism of cytarabine in BCR/ABL negative leukemia cell lines and normal CD34+ progenitor cells.
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.
Bornhäuser
M
M
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
Illmer
T
T
Le Coutre
P
P
Pursche
J
J
von Bonin
M
M
Freiberg-Richter
J
J
Schaich
M
M
Platzbecker
U
U
Thiede
C
C
Ottmann
O G
OG
Köhne
Ch
Ch
Braess
J
J
Ehninger
G
G
Schleyer
E
E
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D001549:Benzamides; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D017353:Gene Deletion; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate