title: Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration.
abstract: The use of so-called 'suicide' genes to activate prodrugs has been effective in animal models for several solid tumor types and is now in phase I and II clinical trials. We have exploited adenovirus vectors (Ad) for transfer and expression of the herpes simplex virus thymidine kinase (HSVtk) gene to render rat colorectal liver metastases sensitive to the anti-herpetic agent ganciclovir (GCV). The efficacy and toxicity of this enzyme-prodrug combination were tested after in situ transduction of rat colorectal tumor cells and after intraportal administration of the vector Ad.CMV.TK. Our results demonstrate the validity of the approach but reveal that hepatic expression of HSVtk, both in tumor bearing and in tumor-free rats, provokes severe liver dysfunction and mortality upon GCV administration. These data show, that in contrast to the common assumption, normally non-mitotic tissues too, can be affected by adenovirus-mediated HSVtk transfer and subsequent GCV treatment. Given the hepatotropic nature of systemically administered adenovirus type 2- and 5-derived vectors, it will be essential to monitor liver functions of patients included in all gene therapy trials involving adenoviral vectors with the HSVtk gene.
authors.affiliation: Department of Surgery, Leiden University Medical Center, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: van der Eb
authors.forename: S J
authors.initials: SJ
authors.lastname: Cramer
authors.forename: Y
authors.initials: Y
authors.lastname: Vergouwe
authors.forename: F H
authors.initials: FH
authors.lastname: Schagen
authors.forename: J H
authors.initials: JH
authors.lastname: van Krieken
authors.forename: A J
authors.initials: AJ
authors.lastname: van der Eb
authors.forename: I H
authors.initials: IH
authors.lastname: Borel Rinkes
authors.forename: C J
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: R C
authors.initials: RC
authors.lastname: Hoeben
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000963:Antimetabolites / Q000009:adverse effects / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000503:physiopathology; D015774:Ganciclovir / Q000009:adverse effects / Q000627:therapeutic use; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D005814:Genes, Viral; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000009:adverse effects; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000503:physiopathology*; D008113:Liver Neoplasms / Q000503:physiopathology / Q000556:secondary* / Q000628:therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D000963:Antimetabolites; D013937:Thymidine Kinase; D015774:Ganciclovir