Synergistic interaction between 1-beta-D-arabinofuranosylcytosine, thymidine, and hydroxyurea against human B cells and leukemic blasts in vitro.

Publisher Website
Google Scholar
Abstract
Isobologram analysis was used to examine the interaction between 1-.beta.-D-arabinofuranosylcytosine (Ara-C), thymidine (dThd) and hydroxyurea. All 3 pairs of drugs, as well as the triple combination, were synergistic against a human B cell line in vitro across a broad range of concentrations. Synergy was associated with an increase in the Ara-C nucleotide pool and Ara-C triphosphate concentration. dThd increased, and hydroxyurea decreased, the incorporation of Ara-C into trichloroacetic acid-insoluble macromolecules per unit time. Hydroxyurea was more effective than dThd at equimolar concentrations in increasing the acid-soluble Ara-C pool. Maximal stimulation of Ara-C triphosphate formation by dThd occurred at 1 mM and was associated with reduction of the deoxycytidine triphosphate pool to 31% of control. At the same concentration, hydroxyurea increased Ara-C triphosphate formation to a greater extent but increased deoxycytidine triphosphate to 116% of control. When tested at clinically achievable concentrations on blasts from patients with acute leukemia, hydroxyurea increased the Ara-C nucleotide pool in all 6 cases studied, whereas dThd decreased the Ara-C nucleotide pool. In SB cells [human B cells transformed by Epstein-Barr virus] dThd and hydroxyurea apparently work by different mechanisms to augment the Ara-C nucleotide pool. Hydroxyurea may be more effective than dThd as a modulator of Ara-C activity in patients with acute leukemia.