Hydroxyurea enhances 3'-azido-3'-deoxythymidine (AZT) cytotoxicity in human chronic myeloid leukemia models.
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, K562 and RWLeu4, the IC50 of AZT was 8 mumol/l and 28 mumol/l respectively, after a 5-day exposure, and the IC50 of HU was 80 mumol/l and 70 mumol/l respectively. In the presence of various concentrations of HU (1 mumol/l-100 mumol/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.
Tosi
P
P
Istituto di Ematologia, L. e A. Seragnoli, Bologna, Italy.
Visani
G
G
Ottaviani
E
E
Tura
S
S
Darnowski
J W
JW
D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000494:pharmacology*
D015215:Zidovudine; D006918:Hydroxyurea