BIOCHEMICAL AND ANTITUMOR-ACTIVITY OF TRIMIDOX, A NEW INHIBITOR OF RIBONUCLEOTIDE REDUCTASE

Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog o f didox (N,3,4-trihydroxy-benzamide) reduced the activity of ribonucle otide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% g rowth-inhibitory concentration, IC50) at 5 mu M, whereas hydroxyurea, the only ribonucleotide reductase inhibitor in clinical use, exhibited an IC50 of 500 mu M Ribonucleotide reductase activity was also measur ed in situ by incubating L1210 cells for 24 h with trimidox at 7.5 mu M, a concentration that inhibits cell proliferation by 50% (IC50) or a t 100 mu M for 2 h; these concentrations resulted in a decrease in enz yme activity to 22% and 50% of the control value, respectively. Trimid ox and hydroxyurea were cytotoxic to L1210 cells with IC50 values of 7 .5 and 50 mu M, respectively. Versus ribonucleotide reductase, trimido x and hydroxyurea yielded IC50 values of 12 and 87 mu M, respectively. A dose-dependent increase in life span was observed in mice bearing i ntraperitoneally transplanted L1210 tumors. Trimidox treatment (200 mg /kg; q1dx9) significantly increased the life span of mice bearing L121 0 leukemia (by 82% in male mice and 112% in female mice). The antitumo r activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that trimidox is a new and p otent inhibitor of ribonucleotide reductase and that it is a promising candidate for the chemotherapy of cancer in humans.