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

Ganciclovir (GCV) and its lipophilic elaidic acid ester prodrug E-GCV were evaluated for their antiherpetic, cytostatic and metabolic proper ties. E-GCV proved exquisitely inhibitory to the replication of herpes simplex virus type 1 (HSV-1) and HSV-2 in cell cultures (50% effectiv e concentration (EC50): 0.002 mu M). It was five- to 10-fold more effe ctive than its parent drug GCV. E-GCV was at least 2000-fold more cyto static to HSV-1 or HSV-2 thymidine kinase (tk) gene-transfected mammar y carcinoma FM3A tk(-)/HSVtk(+) tumor cells than to the corresponding non-transfected tumor cells. The cytostatic activity of E-GCV to the H SVtk gene-transfected tumor cells was far superior to that of GCV. Met abolic studies revealed that both GCV and E-GCV were converted to the mono-, di- and tri-phosphate derivatives of GCV to a markedly higher e xtent in FM3Atk(-)/HSV-1 tk(+) cells than in wild-type FM3A/0 cells. S trikingly, mono-, di- and tri-phosphate metabolites of GCV were retain ed for a substantially longer time in E-GCV-treated cells (half-life a pproximately 50 h) than in GCV-treated cells (half-life approximately 20 h). The longer retention time of the GCV metabolites most likely ex plains why E-GCV is superior to GCV against herpes simplex virus repli cation and HSVtk gene-transfected tumor cell proliferation. Taking int o account the marked stability of E-GCV in human plasma and its much h igher lipophilicity than GCV, E-GCV should be considered as an effecti ve lipophilic prodrug of GCV with a markedly enhanced cytostatic activ ity in HSVtk gene-transfected tumor cells compared with parental ganci clovir. Its usefulness in the combined gene/chemotherapy of HSVtk gene -transfected tumors should be further pursued.