Relationship between plasma Ara-C and intracellular Ara-CTP pools under conditions of continuous infusion and high-dose Ara-C treatment.

Abstract

Plasma level Ara-C and Ara-U in vivo and intracellular Ara-CTP pools in vivo and in vitro were measured using high-performance liquid chromatography and radioimmunoassay. Plasma Ara-C during High Dose therapy was found in two phases; one, a peak at t1/2 of approximately 5-8 minutes, the other approaching that of Continuous Infusion with a t1/2 of about 6 to 8 hours. There appears to be no relationship between peak levels of plasma Ara-C and intracellular Ara-CTP formed during High Dose therapy. Intracellular Ara-CTP pools were found to be higher in peripheral blood than in bone marrow during High Dose treatment and were also higher in bone marrow of patients treated with High Dose rather than conventional dose Ara-C. In vitro experiments with various concentrations of Ara-C on patient cells prior to treatment suggest that patients may benefit from High Dose therapy when an increase in intracellular Ara-CTP occurred with higher extracellular concentrations of Ara-C. In patients with metabolically sensitive cells containing the necessary enzymes to activate Ara-C to Ara-CTP, where resistance is due to limited drug transport, High Dose therapy may prove beneficial. Conversely, in patients with no increase in Ara-CTP pools in vitro due to a depletion of activating enzymes, High Dose treatment may not be warranted. Therefore, it may be possible to determine patients most likely to benefit from High Dose chemotherapy by measuring pre-treatment in vitro intracellular Ara-CTP.