Hydroxyurea enhances 3′‐azido‐3′‐deoxythymidine (AZT) cytotoxicity in human chronic myeloid leukemia models*

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Abstract
In this report we have evaluated the cytotoxic activity of 3′‐azido‐3′‐deoxythymidine (AZT) used in combination with hydroxyurea (HU), an agent which disrupts de novo thymidylate synthesis. In 2 chronic myeloid leukemia (CML) cell lines, K.562 and RWLeu4, the IC50 of AZT was 8 (μmol/l and 28 μmol/l respectively, after a 5‐day exposure, and the IC50 of HU was 80 μmol/l and 70 μmol/l respectively. In the presence of various concentrations of HU (1 μmol/l‐100 μmol/l) the IC50 of AZT in both cell lines was significantly reduced and subsequent isobologram analysis revealed synergistic activity. Similarly, analysis of [3H]AZT incorporation into the DNA fraction of these cells indicated that exposure to AZT + HU resulted in an increased incorporation of AZT into DNA when compared to incubation in AZT alone. Biochemically, this effect appeared to be related to a decrease in dTTP pools caused by HU. The combination AZT + HU has also been demonstrated to exert a synergistic effect in inhibiting colony growth of bone marrow granulocyte‐macrophage progenitors (CFU‐GM) from patients affected by Ph1+ CML in chronic phase. These results are promising in view of a possible in vivo utilization of this drug combination.