Amidox, an inhibitor of ribonucleotide reductase, potentiates the action of Ara-C in HL-60 human promyelocytic leukemia cells.
Amidox (3,4-dihydroxybenzamidoxime), a new polyhydroxy-substituted benzoic acid derivative, is a potent inhibitor of the enzyme ribonucleotide reductase (RR), which catalyses the de novo synthesis of DNA. RR is considered to be an excellent target for cancer chemotherapy. In the present study we investigated the antineoplastic effects of Amidox alone and in combination with Arabinofuranosylcytosine (Ara-C) in HL-60 human promyelocytic leukemia cells. In growth inhibition experiments Amidox yielded an IC50 of 30 microM, colony formation was inhibited at an IC50 of 20 microM as determined by a soft agar assay. Exposure of the cells to 75 and 100 microM Amidox for 24 hours was shown to significantly decrease intracellular dCTP, dGTP and dATP pools, whereas dTTP concentration increased, as determined by HPLC. The combination of Amidox with Ara-C yielded more than additive cytotoxic effects both in growth inhibition assays and in soft agar assays. We could show that--after preincubating the cells with 75 and 100 microM Amidox and subsequent exposure to Ara-C--intracellular Ara-CTP levels increased by 576% and 1143%, respectively. In conclusion, Amidox might offer an additional option for the treatment of leukemia and thus be further investigated in vitro and in vivo.
Bauer
W
W
Clinical Institute of Medical and Chemical Laboratorydiagnostics, University of Vienna, Vienna, Austria.
Horvath
Z
Z
Höchtl
T
T
Saiko
P
P
Karl
D
D
Fritzer-Szekeres
M
M
Szekeres
T
T
D000362:Agar / Q000737:chemistry; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000008:administration & dosage* / Q000737:chemistry; D003845:Deoxycytosine Nucleotides / Q000737:chemistry; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D010091:Oximes / Q000008:administration & dosage* / Q000737:chemistry; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D003845:Deoxycytosine Nucleotides; D004791:Enzyme Inhibitors; D010091:Oximes; D003561:Cytarabine; C024107:2'-deoxycytidine 5'-triphosphate; D000362:Agar; C070491:Amidox; D012264:Ribonucleotide Reductases