SYNERGISTIC GROWTH-INHIBITORY AND DIFFERENTIATING EFFECTS OF TRIMIDOXAND TIAZOFURIN IN HUMAN PROMYELOCYTIC LEUKEMIA HL-60 CELLS

Increased ribonucleotide reductase (RR) activity has been linked with malignant transformation and tumor cell growth, Therefore, this enzyme is considered to be an excellent target for cancer chemotherapy. We h ave examined the effects of a newly patented RR inhibitor, trimidox (3 ,4,5-trihydroxybenzohydroxamidoxime). Trimidox inhibited the growth of human promyelocytic leukemia HL-60 cells with an IC50 of 35 mu mol/L. Incubation of HL-60 cells with 50 mu mol/L trimidox for 24 hours decr eased deoxyguanosine triphosphate (dGTP) and deoxycytidine triphosphat e (dCTP) pools to 24% and 39% of control values, respectively. Incubat ion of HL-60 cells with 20 to 80 mu mol/L trimidox even up to a period of 4 days did not alter the distribution of cells in different phases of cell cycle. Sequential incubation of HL-60 cells with trimidox (25 mu mol/L) for 24 hours and then with 10 mu mol/L tiazofurin (an inhib itor of inosine monophosphate dehydrogenase) for 4 days produced syner gistic growth inhibitory activity, and the cell number decreased to 16 % of untreated controls. When differentiation-linked cell surface mark er expressions were determined in cells treated with trimidox and tiaz ofurin, a significantly increased fluorescence intensity was observed for the CD 11b (2.9-fold), CD 33 (1.9-fold), and HLA-D cell surface an tigens. Expression of the transferrin receptor (CD71) increased 7.3-fo ld in cells treated with both agents, compared with untreated controls . Our results suggest that trimidox in combination with tiazofurin mig ht be useful in the treatment of leukemia. (C) 1994 by The American So ciety of Hematology.