title: Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model.
abstract: OBJECTIVE
  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 naive) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine I, Medical University Clinic Tübingen, Germany. florian.graepler@uni-tuebingen.de
authors.forename: Florian
authors.initials: F
authors.lastname: Graepler
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Lemken
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Wybranietz
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schmidt
authors.forename: Irina
authors.initials: I
authors.lastname: Smirnow
authors.forename: Christine D
authors.initials: CD
authors.lastname: Gross
authors.forename: Martin
authors.initials: M
authors.lastname: Spiegel
authors.forename: Andrea
authors.initials: A
authors.lastname: Schenk
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Graf
authors.forename: Ulrike A
authors.initials: UA
authors.lastname: Lauer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Vonthein
authors.forename: Michael
authors.initials: M
authors.lastname: Gregor
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu
authors.forename: Michael
authors.initials: M
authors.lastname: Bitzer
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Lauer
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005437:Flucytosine / Q000378:metabolism / Q000627:therapeutic use*; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D009368:Neoplasm Transplantation; D010430:Pentosyltransferases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase