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 deoxynucleoside triphosphate synthesis and is considered to be an excellent target of cancer chemotherapy. Trimidox, a newly synthesized compound, inhibits this enzyme and has in vitro and in vivo antitumour activity. As trimidox was able to upregulate the expression of the transferrin receptor in HL-60 human promyelocytic leukaemia cells, we have now investigated the capability of trimidox to interfere with iron metabolism. We show by photometric and polarographic methods that trimidox is able for form an iron complex. However, its cytotoxic action cannot be circumvented by addition of iron-saturated transferrin or iron-ammonium citrate, indicating that the iron complexing capacity is not responsible for the mechanism of action of this compound. When HL-60, K562 or L1210 leukaemia cells were incubated with the trimidox-iron complex itself, we could observe increases of the 50% growth inhibitory capacity of the complex in comparison with trimidox alone. We conclude that trimidox is able to form 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 this new and promising anticancer agent.
Szekeres
T
T
Institut für Medizinische Chemie, Universität Wien, Austria.
Vielnascher
E
E
Novotny
L
L
Vachalkova
A
A
Fritzer
M
M
Findenig
G
G
Göbl
R
R
Elford
H L
HL
Goldenberg
H
H
D001550:Benzamidines / Q000737:chemistry* / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000633:toxicity*; D018922:HL-60 Cells; D006801:Humans; D007501:Iron / Q000494:pharmacology; D007700:Kinetics; D010084:Oxidation-Reduction; D011048:Polarography; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
C074761:3,4,5-trihydroxybenzamidoxime; D001550:Benzamidines; D004791:Enzyme Inhibitors; D007501:Iron; D012264:Ribonucleotide Reductases