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On the interaction between cytosine arabinoside and etoposide in vivo and in vitro
Author(s) -
Liliemark Jan,
Knochenhauer Eva,
Gruber Astrid,
Pettersson Birgitta,
Björkholm Magnus,
Peterson Curt
Publication year - 1993
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.1993.tb00069.x
Subject(s) - etoposide , cytarabine , in vivo , in vitro , leukemia , myelocytic leukemia , chemistry , cytosine , pharmacology , medicine , chemotherapy , biology , biochemistry , dna , microbiology and biotechnology
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/m 2 as a 2‐h infusion every 12 h and, during 1 h before the second ara‐C infusion, 100 or 200 mg/m 2 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.