Inhibition of herpes simplex virus transformed and nontransformed cells by acycloguanosine: Mechanisms of uptake and toxicity

the toxic effects of acycloguanosine (acGuo), a potent inhibitor of herpes simplex virus (HSV) replication, were analyzed in HSV-transformed and nontransformed cells of different mammalian species. Large inter- and intraspecies variations in acGuo sensitivity were observed. In the transformed cells, the expression of the HSV thymidine kinase (TK) activity increased acGuo sensitivity by at least 10-fold, and this enhanced sensitivity was associated with a 10-fold increase in the uptake and phosphorylation of acGuo to its triphosphate (acGTP). In contrast, in the nontransformed cells, the presence or absence of the cellular TK activity did not have a significant effect on acGuo sensitivity. However, deoxyguanosine (dGuo) reversed the inhibitory effects of aeGuo on nontransformed cells, in association with decreased formation of acGTP. Thus, the major pathway for uptake and phosphorylation of acGuo in nontransformed cells does not involve TK activity, as it does in HSV transformed cells. Instead, it appears that the pathway for acGuo metabolism in nontransformed cells shares a common step with the pathway for dGuo uptake and phosphorylation. This cellular pathway for acGuo metabolism could determine the acGuo sensitivity of viruses other than HSV.