The in vitro and in vivo metabolic activation of the important antiviral agent ganciclovir is being examined. Currently, ganciclovir is under study as an antitumor agent for both animal and human tumors which have been transduced with the herpes simplex gene. The elevated levels of thymidine kinase encoded for by this gene can be used to enhance the phosphorylation of ganciclovir. This leads to a localized antitumor effect caused by the ability of ganciclovir triphosphate to inhibit DNA polymerase. To date, however, the major use of the drug remains treatment of cytomegalovirus infection. While ganciclovir must undergo phosphorylation to exert its activity, the route for metabolism in cytomegalovirus-infected cells (which unlike herpes-infected cells, do not elaborate a virus-encoded kinase) has not been clearly established. We have found that ganciclovir can undergo initial phosphorylation in uninfected mammalian cells by the same 5'-nucleotidase which phosphorylates the dideoxynucleosides 2',3'-dideoxyguanosine and 2',3'- dideoxyinosine. The significance of this pathway in the activation of ganciclovir in infected cells is currently under study.
