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: J Balzarini, B Degrève, G Andrei, J Neyts, M Sandvold, F Myhren, E de Clercq
• Journal: Gene therapy (Gene Ther) Vol. 5 Issue 3 Pg. 419-26 (Mar 1998) ISSN: 0969-7128 [Print] England
• PMID: 9614564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Prodrugs
• ganciclovir elaidate
• Thymidine Kinase
• Ganciclovir

Topics

• Animals
• Antiviral Agents (metabolism, pharmacology)
• Cell Division (drug effects)
• Female
• Ganciclovir (analogs & derivatives, metabolism, pharmacology)
• Genetic Therapy
• Half-Life
• Herpesvirus 1, Human (drug effects, physiology)
• Humans
• Mammary Neoplasms, Experimental (metabolism, pathology)
• Mice
• Prodrugs (metabolism, pharmacology)
• Thymidine Kinase (genetics)
• Transfection
• Tumor Cells, Cultured
• Virus Replication (drug effects)