Synergistic interaction between 1-beta-D-arabinofuranosylcytosine, thymidine, and hydroxyurea against human B cells and leukemic blasts in vitro.
Isobologram analysis was used to examine the interaction between 1-beta-D-arabinofuranosylcytosine (Ara-C), thymidine (dThd), and hydroxyurea. All three 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 six cases studied, whereas dThd decreased the Ara-C nucleotide pool. These results indicate that in SB cells dThd and hydroxyurea work by different mechanisms to augment the Ara-C nucleotide pool and that hydroxyurea may be more effective than dThd as a modulator of Ara-C activity in patients with acute leukemia.
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects*; D002478:Cells, Cultured; D003561:Cytarabine / Q000008:administration & dosage*; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D013936:Thymidine / Q000008:administration & dosage*
D004273:DNA, Neoplasm; D003561:Cytarabine; D013936:Thymidine; D006918:Hydroxyurea