Cytotoxic and cell kinetic effects of 3,4,5-trihydroxybenzohydroxamic acid (VF 122) in hepatoma 3924A cells.

: 3, 4, 5-Trihydroxybenzohydroxamic acid (VF 122), an inhibitor of ribonucleotide reductase, killed rat hepatoma 3924A cells in tissue cultured after 7 days of incubation. A concentration of 15 microM caused 50% inhibition of colony-forming ability (IC50). Under the same conditions, hydroxyurea, also an inhibitor of ribonucleotide reductase, had an IC50 of 52 microM. Treatment for 1 hr with VF 122 of exponentially growing culture resulted in a biphasic exponential dose-response curve (Do = 0.5 mM, IC50 = 0.75 mM, and Do = 1.8 mM, IP = 0.8 mM). In plateau-phase cells, a threshold exponential curve was obtained (Do = 2.2 mM, Dq = 1.7 mM, and IC50 = 2.7 mM). Exponentially growing hepatoma 3924A cells were more sensitive to VF 122 than were plateau-phase cultures. In contrast, hydroxyurea killed only exponentially growing 3924A hepatoma cells, exhibiting an exponential plateau dose-response curve without achieving achieving an IC50 value at concentrations from 1 to 200 mM. In synchronized cultures, VF 122 (1 MM for 1 hr) was toxic for cells in mid and late G1 phase, in early and mid S phase, and, to a lesser degree, in G2 phase, Hydroxyurea (10 mM for 1 hr) killed cells only in S phase. Proliferating and resting hepatoma 3924A cells recovered from sublethal and potentially lethal damage induced by VF 122.