IRON-BINDING-CAPACITY OF TRIMIDOX (3,4,5-TRIHYDROXYBENZAMIDOXIME), A NEW INHIBITOR OF THE ENZYME RIBONUCLEOTIDE REDUCTASE

Ribonucleotide reductase is the rate limiting enzyme of deoxynucleosid e triphosphate synthesis and is considered to be an excellent target o f cancer chemotherapy Trimidox, a newly synthesized compound, inhibits this enzyme and has in vitro and in vivo antitumour activity. As trim idox was able to upregulate the expression of the transferrin receptor in HL-60 human promyelocytic leukaemia cells, we have now investigate d the capability of trimidox to interfere with iron metabolism. We sho w by photometric and polarographic methods that trimidox is able to fo rm an iron complex. However, its cytotoxic action cannot be circumvent ed by addition of iron-saturated transferrin or iron-ammonium citrate, indicating that the iron complexing capacity is not responsible for t he mechanism of action of this compound. When HL-60, K562 or L1210 leu kaemia cells were incubated with the trimidox-iron complex itself, we could observe increases of the 50% growth inhibitory capacity of the c omplex in comparison with trimidox alone. We conclude that trimidox is able to form an iron complex, but in contrast to other agents, the an ticancer activity cannot be contributed to this effect alone. Further studies will have to elucidate the molecular mechanism of action of th is new and promising anticancer agent.