Trimidox (3,4,5-trihydroxybenzamidoxime), a newly synthesized analog of
didox (N,3,4-trihydroxybenzamide) reduced the activity of
ribonucleotide reductase (EC 1.17.4.1) in extracts of L1210 cells by 50% (50% growth-inhibitory concentration, IC50) at 5 microM, whereas
hydroxyurea, the only
ribonucleotide reductase inhibitor in clinical use, exhibited an IC50 of 500 microM.
Ribonucleotide reductase activity was also measured in situ by incubating L1210 cells for 24 h with
trimidox at 7.5 microM, a concentration that inhibits cell proliferation by 50% (IC50) or at 100 microM for 2 h; these concentrations resulted in a decrease in
enzyme activity to 22% and 50% of the control value, respectively.
Trimidox and
hydroxyurea were cytotoxic to L1210 cells with IC50 values of 7.5 and 50 microM, respectively. Versus
ribonucleotide reductase,
trimidox and
hydroxyurea yielded IC50 values of 12 and 87 microM, respectively. A dose-dependent increase in life span was observed in mice bearing intraperitoneally transplanted L1210
tumors.
Trimidox treatment (200 mg/kg; q1dx9) significantly increased the life span of mice bearing
L1210 leukemia (by 82% in male mice and 112% in female mice). The anti-
tumor activity appeared more pronounced in female mice than in male mice. Viewed in concert, these findings suggest that
trimidox is a new and potent inhibitor of
ribonucleotide reductase and that it is a promising candidate for the
chemotherapy of
cancer in humans.