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Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and
M M van der Eb1, S J Cramer, Y Vergouwe
1Department of Surgery, Leiden University Medical Center, The Netherlands.
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.
Insights
Gene therapy using herpes simplex virus thymidine kinase (HSVtk) suicide gene and ganciclovir shows promise for colorectal liver metastases. However, severe liver toxicity was observed in rats, highlighting the need for careful liver function monitoring in patients.
Area of Science:
- Oncolytic Virotherapy
- Gene Therapy
- Hepatology
Background:
- Suicide gene therapy, utilizing enzyme-prodrug systems like herpes simplex virus thymidine kinase (HSVtk) and ganciclovir (GCV), has shown efficacy in preclinical models for solid tumors.
- Adenovirus vectors (Ad) are commonly employed for gene delivery in cancer therapy, including HSVtk gene transfer.
Purpose of the Study:
- To evaluate the efficacy and toxicity of adenovirus-mediated HSVtk gene therapy combined with ganciclovir for rat colorectal liver metastases.
- To investigate the impact of hepatic HSVtk expression on liver function and survival in both tumor-bearing and tumor-free rats.
Main Methods:
- Adenovirus vectors (Ad.CMV.TK) encoding the HSVtk gene were administered to rats with colorectal liver metastases via in situ tumor cell transduction and intraportal injection.
- The sensitivity of tumor cells and the toxicity of the HSVtk-GCV system were assessed following ganciclovir administration.
Main Results:
- The HSVtk-GCV system demonstrated the validity of the gene therapy approach for targeting colorectal liver metastases.
- Severe liver dysfunction and mortality were observed in rats upon ganciclovir administration, irrespective of tumor presence, due to hepatic HSVtk expression.
- These findings challenge the assumption that non-mitotic tissues are unaffected by adenovirus-mediated HSVtk transfer and subsequent ganciclovir treatment.
Conclusions:
- Adenovirus-mediated HSVtk gene therapy combined with ganciclovir can induce significant liver toxicity, even in non-dividing liver cells.
- Close monitoring of liver function is crucial for patients participating in gene therapy trials involving adenoviral vectors expressing the HSVtk gene, due to the hepatotropic nature of these vectors.