Iron binding capacity of didox (3,4-dihydroxybenzohydroxamic acid) and amidox (3,4-dihydroxybenzamidoxime) new inhibitors of the enzyme ribonucleotide reductase.
Ribonucleotide reductase is the rate limiting enzyme of deoxynucleoside triphosphate synthesis and is considered to be an excellent target of cancer chemotherapy. Didox and amidox are newly synthesized compounds, which inhibit this enzyme and have in vitro and in vivo antitumor activity. We have now investigated the capability of didox and amidox to interfere with the iron metabolism. We show by photometric and polarographic methods, that didox and amidox are capable of forming an iron complex. However, their cytotoxic action cannot be completely circumvented by addition of Fe-ammoniumcitrate, indicating that the iron complexing capacity may not be responsible for the mechanism of action of these compounds. When L1210 leukemia cells were incubated with the didox-iron or amidox-iron complex itself, changes of the 50% growth inhibitory capacity of the complex in comparison with didox or amidox alone could be shown. We conclude, that didox and amidox are capable of forming iron complexes, but in contrast to other agents, the anticancer activity cannot be contributed to this effect alone. Future studies will have to elucidate the molecular mechanism of action of these new and promising anticancer agents.
Fritzer-Szekeres
M
M
Clinical Institute for Medical and Chemical Laboratory Diagnostics, University of Vienna, Waehringerguertel, Austria.
Novotny
L
L
Vachalkova
A
A
Findenig
G
G
Elford
H L
HL
Szekeres
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D058085:Iron Compounds / Q000378:metabolism*; D007939:Leukemia L1210 / Q000188:drug therapy; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy; D051379:Mice; D010084:Oxidation-Reduction; D010091:Oximes / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D011048:Polarography; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D058085:Iron Compounds; D010091:Oximes; C070491:Amidox; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid