title: Evaluation of a gene-directed enzyme-product therapy (GDEPT) in human pancreatic tumor cells and their use as in vivo models for pancreatic cancer.
abstract: BACKGROUND
  Gene-directed enzyme prodrug therapy (GDEPT) is a two-step treatment protocol for solid tumors that involves the transfer of a gene encoding a prodrug-activating enzyme followed by administration of the inactive prodrug that is subsequently activated by the enzyme to its tumor toxic form. However, the establishment of such novel treatment regimes to combat pancreatic cancer requires defined and robust animal model systems.
  
  
  METHODS
  Here, we comprehensively compared six human pancreatic cancer cell lines (PaCa-44, PANC-1, MIA PaCa-2, Hs-766T, Capan-2, and BxPc-3) in subcutaneous and orthotopical mouse models as well as in their susceptibility to different GDEPTs.
  
  
  RESULTS
  Tumor uptake was 83% to 100% in the subcutaneous model and 60% to 100% in the orthotopical mouse model, except for Hs-766T cells, which did not grow orthotopically. Pathohistological analyses of the orthotopical models revealed an infiltrative growth of almost all tumors into the pancreas; however, the different cell lines gave rise to tumors with different morphological characteristics. All of the resultant tumors were positive for MUC-1 staining indicating their origin from glandular or ductal epithelium, but revealed scattered pan-cytokeratin staining. Transfer of the cytochrome P450 and cytosine deaminase suicide gene, respectively, into the pancreatic cancer cell lines using retroviral vector technology revealed high level infectibility of these cell lines and allowed the analysis of the sensitivity of these cells to the chemotherapeutic drugs ifosfamide and 5-fluorocytosine, respectively.
  
  
  CONCLUSIONS
  These data qualify the cell lines as part of valuable in vitro and in vivo models for the use in defined preclinical studies for pancreas tumor therapy.
authors: Institute of Virology, Department of Pathobiology, University of Veterinary Medicine, Vienna, Austria.
authors: Juraj
authors: J
authors: Hlavaty
authors: Helga
authors: H
authors: Petznek
authors: Harry
authors: H
authors: Holzmüller
authors: Angelika
authors: A
authors: Url
authors: Gerrit
authors: G
authors: Jandl
authors: André
authors: A
authors: Berger
authors: Brian
authors: B
authors: Salmons
authors: Walter H
authors: WH
authors: Günzburg
authors: Matthias
authors: M
authors: Renner
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D043525:Cytosine Deaminase / Q000235:genetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D057487:Enzyme Therapy; D005437:Flucytosine / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy; D006801:Humans; D007069:Ifosfamide / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: D014408:Biomarkers, Tumor; D003577:Cytochrome P-450 Enzyme System; D005437:Flucytosine; D043525:Cytosine Deaminase; D007069:Ifosfamide