Iron binding capacity of didox (3,4 dihydroxybenzohydroxamic acid) and amidox (3,4 dihydroxybenzamidoxime) two 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 circumvented by addition of Fe-ammoniumcitrate, indicating the iron complexing capacity not to 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, only slight 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 an iron complex, but in contrast to other agents, the anticancer activity cannot be contributed to this effect alone. Further studies will have to elucidate the molecular mechanism of action of these new and promising anticancer agents.
Fritzer-Szekeres
M
M
Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Vienna, Austria.
Novotny
L
L
Vachalkova
A
A
Göbl
R
R
Elford
H L
HL
Szekeres
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000633:toxicity; D007501:Iron / Q000737:chemistry* / Q000494:pharmacology; D007939:Leukemia L1210; D051379:Mice; D010091:Oximes / Q000737:chemistry* / Q000633:toxicity; D011048:Polarography; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D010091:Oximes; C070491:Amidox; D007501:Iron; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid