Liver Cancer
Copyright ©2005 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2005; 11(44): 6910-6919
Published online Nov 28, 2005. doi: 10.3748/wjg.v11.i44.6910
Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model
Florian Graepler, Marie-Luise Lemken, Wolfgang A Wybranietz, Ulrike Schmidt, Irina Smirnow, Christine D Groß, Martin Spiegel, Andrea Schenk, Hansjörg Graf, Ulrike A Lauer, Reinhard Vonthein, Michael Gregor, Sorin Armeanu, Michael Bitzer, Ulrich M. Lauer
Florian Graepler, Marie-Luise Lemken, Ulrike Schmidt, Irina Smirnow, Martin Spiegel, Andrea Schenk, Michael Gregor, Sorin Armeanu, Michael Bitzer, Ulrich M. Lauer, Wolfgang A. Wybranietz, Christine D. Groß, Department of Internal Medicine I, University Clinic Tübingen, Tübingen D-72076, Germany
Hansjörg Graf, Ulrike A. Lauer, Section of Experimental Radiology, University Clinic Tübingen, Tübingen D-72076, Germany
Reinhard Vonthein, Department of Medical Biometry, University Clinic Tübingen, Tübingen D-72076, Germany
Author contributions: All authors contributed equally to the work.
Supported by grants from German Research Foundation (LA649-20-2), Federal Ministry of Education, Science, Research and Technology (Fö. 01KS9602, Fö. 01KV9532), Interdisciplinary Clinical Research Center (IZKF) Tübingen, and the fortüne-program of the Medical Faculty of Eberhard-Karls-University Tübingen (F.1281127). W.A.W. supported by a scholarship from Pinguin Foundation (Henkel KGaA)
Correspondence to: Dr Florian Graepler, Department of Internal Medicine I, Medical University Clinic Tübingen, Otfried-Müller-Str. 10, Tübingen D-72076, Germany.
Telephone: +49-7071-2980651 Fax: +49-7071-294630
Received: April 26, 2005
Revised: May 23, 2005
Accepted: May 24, 2005
Published online: November 28, 2005

AIM: To investigate the effects of catalytically superior gene-directed enzyme prodrug therapy systems on a rat hepatoma model.

METHODS: To increase hepatoma cell chemosensitivity for the prodrug 5-fluorocytosine (5-FC), we generated a chimeric bifunctional SuperCD suicide gene, a fusion of the yeast cytosine deaminase (YCD) and the yeast uracil phosphoribosyltransferase (YUPRT) gene.

RESULTS: In vitro stably transduced Morris rat hepatoma cells (MH) expressing the bifunctional SuperCD suicide gene (MH SuperCD) showed a clearly marked enhancement in cell killing when incubated with 5-FC as compared with MH cells stably expressing YCD solely (MH YCD) or the cytosine deaminase gene of bacterial origin (MH BCD), respectively. In vivo, MH SuperCD tumors implanted both subcutaneously as well as orthotopically into the livers of syngeneic ACI rats demonstrated significant tumor regressions (P<0.01) under both high dose as well as low dose systemic 5-FC application, whereas MH tumors without transgene expression (MH naïve) showed rapid progression. For the first time, an order of in vivo suicide gene effectiveness (SuperCD>>YCD>>BCD>>>negative control) was defined as a result of a direct in vivo comparison of all three suicide genes.

CONCLUSION: Bifunctional SuperCD suicide gene expression is highly effective in a rat hepatoma model, thereby significantly improving both the therapeutic index and the efficacy of hepatocellular carcinoma killing by fluorocytosine.

Keywords: YCD/YUPRT fusion, Cytosine deaminase, GDEPT, Suicide gene therapy, Hepatoma therapy