Capacity of deoxycytidine to selectively antagonize cytotoxicity of 5-halogenated analogs of deoxycytidine without loss of antiherpetic activity.

摘要

Enzyme kinetic studies from this laboratory (M. Dobersen and S. Greer, Biochemistry 17:920-928, 1978) suggested that deoxycytidine could antagonize the toxicity of 5-halogenated analogs of deoxycytidine without interfering with their antiviral activity. Antagonism by deoxycytidine of the toxicity of 5-chlorodeoxycytidine without impairing its anti-herpes simplex virus type 2 activity is demonstrated in the present studies. Tetrahydrouridine, an inhibitor of cytidine deaminase, was utilized. The high Km for deoxycytidine (0.6 mM) with respect to the herpes pyrimidine nucleoside kinase as compared with the low Km for 5-chlorodeoxycytidine (1.1 microM) accounts for the absence of antagonism of the antiviral activity. The high Km for 5-chlorodeoxycytidine (56 microM) as compared with the low Km of deoxycytidine (2 microM) with respect to mammalian deoxycytidine kinase accounts, in great part, for the antagonism of toxicity. In addition, antagonism of toxicity by deoxycytidine is the result of factors other than the kinetic parameters of nucleoside kinases, as indicated by its antagonism of the cytotoxicity of 5-chlorodeoxyuridine. This may be attributed to replenishment of low dCTP pools, diminished because of effector inhibition of ribonucleoside diphosphate reductase by Cl-dUTP. Resistance of the herpes-encoded enzymes to effector control may also play a role in the selective antagonism. Cell culture studies with high concentrations of tetrahydrouridine and 2'-deoxytetrahydrouridine suggest that competition by deoxycytidine for deaminases may not play a major role. The fact that deoxycytidine antagonizes the toxicity of chlorodeoxyuridine also argues against competition for the deaminases as a major reason for its effect. Limited studies with a topical herpes simplex virus type 2 infection system indicate heightened efficacy of 5-chlorodeoxycytidine (and tetrahydrouridine) when deoxycytidine is coadministered. The concepts of selective antagonism of a chemotherapeutic agent derived from these studies may be applied to other approaches that extent beyond viral chemotherapy.