title: The thymidylate synthase inhibitor ZD1694 potently inhibits murine and human cytomegalovirus replication in quiescent fibroblasts.
abstract: Tomudex (ZD1694) is a quinazoline-based folate analog and a powerful inhibitor of cellular thymidylate synthase and is approved in Europe for use in oncology. Here the first evidence of its activity against murine and human cytomegalovirus (MCMV and HCMV) is reported. ZD1694 irreversibly inhibited the replication and DNA synthesis of both viruses in quiescent fibroblasts. The corresponding 50% effective concentrations were 0.006 and 0.002 microM respectively, whereas the 50% cytotoxic concentration was >10 microM for both murine and human quiescent fibroblasts. A similar antiviral effect was observed against two ganciclovir-resistant HCMV strains isolated from AIDS patients. Taken as a whole these results demonstrate that cellular thymidylate synthase plays an essential role in viral replication and that ZD1694 merits further investigation as anticytomegaloviral agent.
authors.affiliation: Department of Public Health and Microbiology, University of Torino, Torino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Lembo
authors.forename: G
authors.initials: G
authors.lastname: Gribaudo
authors.forename: L
authors.initials: L
authors.lastname: Riera
authors.forename: A
authors.initials: A
authors.lastname: Mondo
authors.forename: R
authors.initials: R
authors.lastname: Cavallo
authors.forename: A
authors.initials: A
authors.lastname: Angeretti
authors.forename: S
authors.initials: S
authors.lastname: Landolfo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D004279:DNA, Viral / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000821:virology*; D015774:Ganciclovir / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D018146:Muromegalovirus / Q000187:drug effects* / Q000235:genetics; D016133:Polymerase Chain Reaction; D011799:Quinazolines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; C068874:raltitrexed; D015774:Ganciclovir