Selective inhibition of ribonucleotide reductase by the monofunctional alkylating agent 5(1-aziridinyl)-2,4-dinitrobenzamide (CB 1954)

The monofunctional alkylating agent 5-(1-aziridinyl)-2,4-dinitrobenzamide (CB 1954) is a potent and selective inhibitor of the growth of the Walker carcinoma (ld₅₀ 0.002 $\text{μg}\text{ml}$). Growth inhibition by CB 1954 is accompanied by a rapid inhibition of DNA synthesis with little effect on RNA and protein biosynthesis. Interference with the biosynthesis of DNA by CB 1954 has been shown to be due to inhibition of ribonucleoside diphosphate reductase. The order of effectiveness of inhibition of the enzyme by CB 1954 in four cell lines parallels the tumour growth inhibitory activity. Furthermore, analogues of CB 1954 with methyl substitution on the amide group were less effective inhibitors of the growth of the Walker carcinoma and also less potent inhibitors of ribonucleotide reductase. Treatment of Walker cells with CB 1954 caused a rapid inhibition of enzyme activity and a corresponding fall in the levels of deoxyribonucleoside triphosphates which corresponded with the effect of the drug on DNA synthesis. A human bladder carcinoma has been shown to be particularly susceptible to growth inhibition by CB 1954. Measurement of the effect of CB 1954 on ribonucleotide reductase from biopsy specimens of human tumours could provide a basis for patient selection for therapy by this agent.