Tamoxifen (TMX)/fas induced growth inhibition of human cholangiocarcinoma (HCC) by gamma interferon (IFN-γ)

• Published in: Annals of surgery Vol. 235; no. 6; pp. 872 - 878
• Main Authors: VICKERS, Selwyn M, JHALA, Nirag C, AHN, Eun-Young, MCDONALD, Jay M, PAN, George, BLAND, Kirby I
• Format: Conference Proceeding Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott 01-06-2002
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; bcl-2 Homologous Antagonist-Killer Protein; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - genetics; Bile Ducts, Intrahepatic; Biological and medical sciences; Caspases - genetics; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; fas Receptor - genetics; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression - drug effects; Humans; Interferon-gamma - pharmacology; Interferon-gamma - therapeutic use; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Membrane Proteins - genetics; Mice; Scientific Papers; Tamoxifen - pharmacology; Tamoxifen - therapeutic use; Tumor Cells, Cultured - drug effects; Tumors; Up-Regulation - drug effects; Xenograft Model Antitumor Assays; Human; Cell culture; Induction; Antiestrogen; Hepatic disease; Metabolic pathway; Malignant tumor; Biliary tract disease; Experimental study; Tamoxifene; Chemotherapy; Treatment; Malignant cholangioma; Digestive diseases; Pretreatment; Non steroid compound; Gamma interferon
• ISSN: 0003-4932; 1528-1140
• DOI: 10.1097/00000658-200206000-00016

To evaluate the response of human cholangoicarcinoma cells to TMX treatment through the Fas pathway by pretreatment with IFN-gamma.
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.
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.
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.
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.