[Studies on intracellular kinetics of ara-C triphosphate in HL-60, human leukemia cells in relation to reasonable administration of ara-C].

To study the pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C), which is one of the main drugs used in chemotherapy for acute leukemia, its intracellular metabolism was investigated using HL-60 cells derived from human acute non-lymphocytic leukemia. The concentration of the drug and its metabolites in the cells were serially determined and the following results were obtained. 1) The uptake of ara-C into HL-60 cell (1 X 10(7)/ml) was very rapid when they were incubated with 2 microM ara-C. The total intracellular ara-C content per 10(9) cells exceeded the ara-C concentration in the extracellular fluid at about 7 minutes after the start of incubation. It reached about 4 times higher than the extracellular concentration after 60 minutes. 2) Conversion of ara-C to the active form, ara-CTP, was also rapid. The intracellular concentration of ara-CTP was about 3 times higher than the ara-C concentration in the extracellular fluid after incubation for 60 minutes. 3) Total accumulation of ara-C in the cells was dependent on the extracellular ara-C concentration up to a concentration of 100 microM. The production of ara-CTP occurred in such a way that, when the extracellular ara-C concentration was lower than 10 microM, more than 90% of the uptake of ara-C was converted to ara-CTP, while at concentrations above 10 microM the efficiency at production (the ratio of total ara-C to ara-CTP production) was decreased. The maximum intracellular ara-CTP concentration was estimated to reach to 45 microM.(ABSTRACT TRUNCATED AT 250 WORDS)