title: Tamoxifen (TMX)/Fas induced growth inhibition of human cholangiocarcinoma (HCC) by gamma interferon (IFN-gamma).
abstract: OBJECTIVE
  To evaluate the response of human cholangoicarcinoma cells to TMX treatment through the Fas pathway by pretreatment with IFN-gamma.
  
  
  BACKGROUND
  Cholangiocarcinoma remains one of the most difficult tumors to treat in clinical medicine. Currently, there are no effective chemotherapy treatments for this disease. Surgery offers the only opportunity for a cure, with the majority of patients failing to qualify for such treatment. This study seeks to evaluate a potential new modality for treatment of this disease.
  
  
  METHODS
  Human cholangiocarcinoma cells were treated with anti Fas mab and sorted to two populations (Fas-positive and Fas-negative) by FAC analysis. In vitro individual cell populations were pretreated with IFN-gamma 250 units/mL x 18hs. The treated cells assayed for caspase 3, 7, 8, Bak, and for apoptosis with Annexin V after treatment with or without TMX. In Vivo 2 x 106 5 SK-ChA-1 Fas-negative cells were injected into nude mice for development of tumor xenografts. Mice received either no treatment or intra tumor IFN-gamma and/or intra peritoneal TMX.
  
  
  RESULTS
  More than 90% (90% +/- 3.5%) of Fas-positive and 70% (71 +/- 2.3%) of Fas-negative cells underwent apoptosis after TMX treatment when pretreated with IFN-gamma. In contrast, TMX alone and IFN-gamma alone stimulated apoptosis by only 22% (22 +/- 3%) P <.00013, and 17% (17 +/- 2%) P <.0001 in Fas-ve cells respectively. In vivo human cholangiocarcinomas xenograft growth was significantly inhibited by a combination of TMX + IFN-gamma compared to controls P <.0007.
  
  
  CONCLUSIONS
  TMX exposure to human cholangiocarcinoma after pretreatment with IFN-gamma allows for induction of apoptosis in vitro and significant inhibition tumor xenograft growth. The combination of these two compounds may provide novel treatment regimen for cholangiocarcinoma.
authors.affiliation: Department of Surgery, The University of Alabama at Birmingham and Veterans Administration Medical Center, USA. smv@uab.edu
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
authors.forename: Nirag C
authors.initials: NC
authors.lastname: Jhala
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Ahn
authors.forename: Jay M
authors.initials: JM
authors.lastname: McDonald
authors.forename: George
authors.initials: G
authors.lastname: Pan
authors.forename: Kirby I
authors.initials: KI
authors.lastname: Bland
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics; D001653:Bile Ducts, Intrahepatic; D020169:Caspases / Q000235:genetics; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494773:Bak1 protein, mouse; D008565:Membrane Proteins; C411023:anti-Fas monoclonal antibody; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019014:fas Receptor; D013629:Tamoxifen; D007371:Interferon-gamma; D020169:Caspases