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Hydroxyurea enhances 3′‐azido‐3′‐deoxythymidine (AZT) cytotoxicity in human chronic myeloid leukemia models *
Author(s) -
Tosi Patrizia,
Visani Giuseppe,
Ottaviani Emanuela,
Tura Sante,
Darnowski James W.
Publication year - 1994
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.1994.tb00098.x
Subject(s) - myeloid leukemia , in vivo , zidovudine , cytotoxicity , ic50 , cell culture , pharmacology , progenitor cell , myeloid , chemistry , dna synthesis , in vitro , leukemia , bone marrow , microbiology and biotechnology , immunology , biology , biochemistry , stem cell , virus , genetics , viral disease
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.