The effect of inhibition of cytidine deaminase by tetrahydrouridine on the utilization of deoxycytidine and 5 bromodeoxycytidine for deoxyribonucleic acid synthesis

The effect of cytidine deaminase activity on the utilization of deoxycytidine and 5 bromodeoxycytidine for DNA synthesis in normal and neoplastic mouse tissues was investigated utilizing tetrahydrouridine to inhibit cytidine deaminase in vivo. Tetrahydrouridine increased approximately 3 fold the incorporation of deoxycytidine into the DNA of two transplantable lymphomas, a mammary adenocarcinoma, and bone marrow. The utilization of deoxycytidine for DNA synthesis was also increased by tetrahydrouridine in mouse testes, but not in the spleen or small intestine. The toxicity of 5 fluorodeoxycytidine was similarly increased by inhibition of cytidine deaminase. In contrast to the effect of tetrahydrouridine on deoxycytidine, the incorporation of 5 bromodeoxycytidine into DNA was decreased approx 70% by inhibition of cytidine deaminase with tetrahydrouridine. This suggests that the incorporation of 5 bromodeoxycytidine into DNA proceeds mainly by deamination of the nucleoside to 5 bromodeoxyuridine, followed by phosphorylation to 5 bromodeoxyuridylate, rather than the alternative pathway proceeding by phosphorylation of 5 bromodeoxycytidine to 5 bromodeoxycytidylate, followed by deamination of the nucleotide to 5 bromodeoxyuridylate.