On the interaction between cytosine arabinoside and etoposide in vivo and in vitro |
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Authors: | Jan Liliemark,Eva Knochenhauer,Astrid Gruber,Birgitta Pettersson,Magnus Bj rkholm,Curt Peterson |
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Affiliation: | Jan Liliemark,Eva Knochenhauer,Astrid Gruber,Birgitta Pettersson,Magnus Björkholm,Curt Peterson |
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Abstract: | ![]() Abstract: Cytosine arabinoside (ara-C) and etoposide are often used in combination in the treatment of acute myelocytic leukemia (AML). The intracellular phosphorylation of ara-C to its 5′-triphosphate (ara-CTP) is a prerequisite for its cytotoxic effects. It has been shown in vitro that etoposide can impair the formation of ara-CTP in leukemia cells. The present study was undertaken in order to elucidate whether this interaction may be of clinical importance. Leukemia cells were isolated from 3 patients with acute myelocytic leukemia and incubated in medium (RPMI-1640) with or without 10% fetal calf serum or in human plasma. When the cells were incubated in RPMI-1640 with ara-C (10 μmol/l) and etoposide during 2 h, the formation of ara-CTP was decreased to 71 ± 18 (mean ± S.D.) and 30 ± 15% of control at 1 and 10 μg/ml etoposide, respectively. When the cells were incubated in human plasma, the formation of ara-CTP was not influenced by the presence of etoposide (101 ± 6 and 103 ± 20% at 1 and 10 μg/ml etoposide). When incubated in RPMI supplemented with 10% fetal calf serum, the corresponding figures were 81 ± 8 and 70 ± 20%. Six patients with AML were therefore treated with ara-C 0.5 or 1.0 g/m2 as a 2-h infusion every 12 h and, during 1 h before the second ara-C infusion, 100 or 200 mg/m2 etoposide was administered. The median change in the AUC of cellular ara-CTP between the first and second ara-C dose was 0% (-37 to +21%). The corresponding median change in rate of accumulation of ara-CTP in leukemia cells was 12% (-26 to +110%). The concentration of etoposide in plasma during the ara-C infusion was 18.7 ± 5.1 μg/ml while the non-protein bound etoposide was 0.73 ± 0.34 μg/ml. Thus, despite exposure to higher etoposide concentrations in vivo than in vitro, no impairment of ara-CTP formation was seen in the patients. This corresponds to the results obtained when leukemic cells were incubated in plasma. It is concluded that the inhibition of ara-CTP formation by etoposide seen in vitro is offset by the high protein binding of etoposide in plasma (96%) and that etoposide does not impair the formation of ara-CTP in leukemia cells in vivo during treatment with standard-dose etoposide. |
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Keywords: | cytosine arabinoside cytosine arabinoside 5′ -triphosphate etoposide leukemia interaction protein binding |
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