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Synergistic Interaction between 1-β -D-arabinofuranosylcytosine, Thymidine, and Hydroxyurea against Human B Cells and Leukemic Blasts in vitro
Jerome A. Streifel and Stephen B. Howell
Proceedings of the National Academy of Sciences of the United States of America
Vol. 78, No. 8, [Part 2: Biological Sciences] (Aug., 1981), pp. 5132-5136
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/10498
Page Count: 5
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Isobologram analysis was used to examine the interaction between 1-β -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.
Proceedings of the National Academy of Sciences of the United States of America © 1981 National Academy of Sciences