Amidox (3,4-dihydroxybenzamidoxime), a new polyhydroxy-substituted
benzoic acid derivative, is a potent inhibitor of the
enzyme ribonucleotide reductase (RR), which catalyses the de novo synthesis of
DNA. RR is considered to be an excellent target for
cancer chemotherapy. In the present study we investigated the
antineoplastic effects of
Amidox alone and in combination with
Arabinofuranosylcytosine (
Ara-C) in HL-60 human promyelocytic
leukemia cells. In growth inhibition experiments
Amidox yielded an IC50 of 30 microM, colony formation was inhibited at an IC50 of 20 microM as determined by a soft
agar assay. Exposure of the cells to 75 and 100 microM
Amidox for 24 hours was shown to significantly decrease intracellular
dCTP,
dGTP and dATP pools, whereas
dTTP concentration increased, as determined by HPLC. The combination of
Amidox with
Ara-C yielded more than additive cytotoxic effects both in growth inhibition assays and in soft
agar assays. We could show that--after preincubating the cells with 75 and 100 microM
Amidox and subsequent exposure to
Ara-C--intracellular
Ara-CTP levels increased by 576% and 1143%, respectively. In conclusion,
Amidox might offer an additional option for the treatment of
leukemia and thus be further investigated in vitro and in vivo.