Monitoring of intracellular 1-beta-D-arabinofuranosylcytosine 5 '-triphosphate in 1-beta-D-arabinofuranosylcytosine therapy at low and conventional doses

1-beta -D-Arabinofuranosylcytosine (ara-C) is used empirically at a low, co nventional, or high dose. Ara-C therapy may be optimal if it is directed by the clinical pharmacokinetics of the intracellular active metabolite of ar a-C, 1-beta -D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP). However, ara-CTP has seldom been monitored during low - and conventional-dose ara-C therapies because detection methods were insufficiently sensitive. Here, w ith the use of our newly established method (Cancer Res., 56, 1800-1804 (19 96)), ara-CTP was monitored in leukemic cells front acute myelogenous leuke mia patients receiving low- or conventional-dose ara-C [subcutaneous ara-C administration (10 mg/m(2)) (3 patients), continuous ara-C infusion (20 or 70 mg/m(2)/24 h) (7 patients), 2-h ara-C infusion (70 mg/m(2)) (4 patients) , and 2-h infusion of N-4-behenoyl-1-beta -D-arabinofuranosylcytosine, a de aminase-resistant ara-C derivative (70 mg/m(2)) (6 patients)]. Ara-CTP coul d he determined at levels under 1 muM. There was a close correlation betwee n the elimination half-life values of the plasma ara-C and the intracellula r ara-CTP, The presence of ara-C in the plasma was important to maintain ar a-CTP, The continuous ara-C and the 2-h N-4-behenoyl-1-beta -D-arabinofuran osylcytosine infusions maintained ara-CTP and the plasma ara-C longer than the subcutaneous ara-C or the 2-h ara-C infusion. They also afforded relati vely higher ara-CTP concentrations, and consequently produced ara-CTP more efficiently than the 2-h ara-C infusion. Different administration methods p roduced different quantities of ara-CTP even at the same dose.