SEVERE HEPATIC-DYSFUNCTION AFTER ADENOVIRUS-MEDIATED TRANSFER OF THE HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE AND GANCICLOVIR ADMINISTRATION

The use of so-called 'suicide' genes to activate prodrugs has been eff ective in animal models for several solid tumor types and is now in ph ase I and II clinical trials. We have exploited adenovirus vectors (Ad ) for transfer and expression of the herpes simplex virus thymidine ki nase (HSVtk) gene to render rat colorectal liver metastases sensitive to the anti-herpetic agent ganciclovir (GCV). The efficacy and toxicit y of this enzyme-prodrug combination were tested after in situ transdu ction of rat colorectal tumor cells and after intraportal administrati on of the vector Ad.CMV.TK. Our results demonstrate the validity of th e approach but reveal that hepatic expression of HSVtk, both in tumor bearing and tumor-free rats, provokes severe liver dysfunction and mor tality upon GCV administration. These data show, that in contrast to t he common assumption, normally non-mitotic tissues too, can be affecte d 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 f unctions of patients included in all gene therapy trials involving ade noviral vectors with the HSVtk gene.