期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1981
卷号：78
期号：8
页码：5132-5136
DOI：10.1073/pnas.78.8.5132
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
