Trimidox, an inhibitor of ribonucleotide reductase, synergistically enhances the inhibition of colony formation by Ara-C in HL-60 human promyelocytic leukemia cells.

Ribonucleotide reductase is the rate-limiting enzyme for the de novo synthesis of deoxynucleoside triphosphates and therefore represents a good target for cancer chemotherapy. Trimidox (3,4,5-trihydroxybenzamidoxime) was identified as a potent inhibitor of this enzyme and was shown to significantly decrease deoxycytidine triphosphate (dCTP) pools in HL-60 leukemia cells. We now investigated the ability of trimidox to increase the antitumor effect of 1-beta-D-arabinofuranosyl cytosine (Ara-C). Ara-C is phosphorylated by deoxycytidine kinase, which is subject to negative allosteric regulation by dCTP. Therefore, a decrease of dCTP may cause increased Ara-C phosphorylation and enhanced incorporation of Ara-C into DNA. Ara-C incorporation indeed increased 1.51- and 1.89-fold after preincubation with 75 and 100 microM trimidox, respectively. This was due to the significantly increased 1-beta-D-arabinofuranosyl cytosine triphosphate pools (1.9- and 2.5-fold) after preincubation with trimidox. We also investigated the effects of a combination of trimidox and Ara-C on the colony formation of HL-60 cells. A synergistic potentiation of the effect of Ara-C could be observed, when trimidox was added. Trimidox, which decreases intracellular deoxynucleoside triphosphate concentrations thus leading to apoptosis, enhanced the induction of apoptosis caused by Ara-C. We conclude, that trimidox is capable of synergistically enhancing the effects of Ara-C and therefore this drug combination might be further tested in animals.