title: Superior cytostatic activity of the ganciclovir elaidic acid ester due to the prolonged intracellular retention of ganciclovir anabolites in herpes simplex virus type 1 thymidine kinase gene-transfected tumor cells.
abstract: Ganciclovir (GCV) and its lipophilic elaidic acid ester prodrug E-GCV were evaluated for their antiherpetic, cytostatic and metabolic properties, E-GCV proved exquisitely inhibitory to the replication of herpes simplex virus type 1 (HSV-1) and HSV-2 in cell cultures (50% effective concentration (EC50): 0.002 microM). It was five- to 10-fold more effective than its parent drug GCV. E-GCV was at least 2000-fold more cytostatic to HSV-1 or HSV-2 thymidine kinase (tk) gene-transfected mammary carcinoma FM3A tk-/HSVtk+ tumor cells than to the corresponding nontransfected tumor cells. The cytostatic activity of E-GCV to the HSVtk gene-transfected tumor cells was far superior to that of GCV. Metabolic studies revealed that both GCV and E-GCV were converted to the mono-, di- and tri-phosphate derivatives of GCV to a markedly higher extent in FM3Atk-/HSV-1 tk+ cells than in wild-type FM3A/0 cells. Strikingly, mono-, di- and tri-phosphate metabolites of GCV were retained for a substantially longer time in E-GCV-treated cells (half-life approximately 50 h) than in GCV-treated cells (half-life approximately 20 h). The longer retention time of the GCV metabolites most likely explains why E-GCV is superior to GCV against herpes simplex virus replication and HSVtk gene-transfected tumor cell proliferation. Taking into account the marked stability of E-GCV in human plasma and its much higher lipophilicity than GCV, E-GCV should be considered as an effective lipophilic prodrug of GCV with a markedly enhanced cytostatic activity in HSVtk gene-transfected tumor cells compared with parental ganciclovir. Its usefulness in the combined gene/chemotherapy of HSVtk gene-transfected tumors should be further pursued.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: B
authors.initials: B
authors.lastname: Degrève
authors.forename: G
authors.initials: G
authors.lastname: Andrei
authors.forename: J
authors.initials: J
authors.lastname: Neyts
authors.forename: M
authors.initials: M
authors.lastname: Sandvold
authors.forename: F
authors.initials: F
authors.lastname: Myhren
authors.forename: E
authors.initials: E
authors.lastname: de Clercq
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015316:Genetic Therapy; D006207:Half-Life; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; C112547:ganciclovir elaidate; D013937:Thymidine Kinase; D015774:Ganciclovir