8 & 9. pp. 1541- 1544, 2004. Amidox, an Inhibitor of Ribonucleotide Reductase,. Potentiates the Action of Ara-C in HL-60 Human. Promyelocytic Leukemia Cells.
Amidox, an Inhibitor of Ribonucleotide Reductase, Potentiates the Action of Ara-C in HL-60 Human Promyelocytic Leukemia Cells W. Bauer,* Z. Horvath, T. H&htl, Po Saiko, D. Karl, M. Fritzer-Szekeres, and T. Szekeres Clinieal Institute of Medieal and Chemical Laboratorydiagnostics. Univcrsity of Vienna, Vienna, Austria
ABSTRACT Amidox O .4-dihydroxybenzamidoxime), a new polyhydroxy-substituted benzoie acid derivative. is a polen! inhihitor or the enzyme ribonucle.otide reduclase (RR), which cataly~cs thc de novo synthesis of DNA. RR is considered to be an excellent target for cancer chemolherapy. In thc prescnt study we invcstigated the antineopla.~tic effects of Amido)( alone and in combinatioll with Arabinofuranosylcytosine (Ara-C) in HL-60 human promyelocylic leukemiil cells. Jn growlh inhibition experimenls Amidox yieldcd an lC~n of JO ~tM . colony forrnation was inhibite.d at an IC 50 of 20 11M as dClennincd by a soft agar a~say . Exposure of the edls 10 75 and 100 ~tM Arnidox fo!" 24 hours was shown 10 signiticantly deerease intraceUular dCTP, dGTP and dATP pools. whereas dTTP conccntration incrcased. as dcterrnined by HPLC. TIle wmbination of Amidllx with Ara-C yielded Illore thall additive eytotoxie effects both in growth inhihiti()n assays and in soft agar assays. We could show that-after
*Correspondcnce: W. Bauer. Clinical Institute of Mediea! and Chernieal Laboratorydiagnostics. University of Vienna. Vicnna, Austria. 1541 DOI: lO.IOH t/NCN·2UOO27766 Copyright () 2004 by Marcel Dekkcr. Ine.
preincubating the ceHs with 75 and 100 11M Amidox and ~uh ~equent exposurc La AraC- intracellular Ara-CTP levels increased by 576% and 1143%, rcspective1y . In conclusion, Amidox might offer an additional option for the treatment of leuk.emia
