The cytotoxic effect of
cytosine arabinoside (
ara-C) depends on the capacity of cells to form and retain intracellularly the phosphorylated metabolite
cytosine arabinoside triphosphate (
ara-CTP). In this study accumulation and cellular retention of
ara-CTP have been measured in vitro in the bone marrow cells of 69 patients with acute
leukemia. Cells were incubated with 3H-ara-C and the amount of
ara-CTP formed was determined after separation of the
nucleotides by thin-layer chromatography. Phosphorylation of
ara-C to
ara-CTP appeared to be a saturable process. The Km-equivalents varied between 1.1 and 16.2 microM
ara-C. Maximal
ara-CTP formation ranged from 12 to 125 pmol
ara-CTP/10(6) cells in 30 min. The phosphorylation activity did not correlate with the percentage of S-phase cells. The intracellular half-life time of
ara-CTP measured in vitro ranged from 53 to 210 min. Phosphorylation of
ara-C was comparable in patients with
acute myeloid leukemia (n = 51) and in patients with
acute lymphoblastic leukemia (n = 18).
Ara-CTP elimination appeared slower in lymphoblasts than in myeloblasts. The average intracellular
ara-CTP level in relapsed patients (n = 34) appeared higher than in previously untreated patients (n = 52). The less favourable outcome of second
remission induction therapy with conventional doses of
ara-C compared to the first
remission induction treatment is not explained by an alteration in the intracellular metabolism of
ara-C.