title: Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine.
abstract: OBJECTIVE
  The purpose of the present study was to evaluate whether trastuzumab has antitumor effect against pancreatic cancer and whether this effect is concordant with levels of HER-2, which is reportedly overexpressed in pancreatic cancer. We also investigated whether the effect is potentiated in combined therapy with gemcitabine.
  
  
  METHODS
  Using immunohistochemistry and FACScan, we analyzed HER-2 expression in 16 pancreatic cancer cell lines. The in vitro antiproliferative effect of trastuzumab, alone and in combination with gemcitabine, was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vitro antibody-dependent cell-mediated cytotoxicity of trastuzumab was investigated by (51)Cr release assay. The in vivo antitumor effect of trastuzumab, alone and in combination with gemcitabine, was evaluated in nude mouse xenograft growth. The survival benefit was evaluated in a Capan-1 orthotopic implanted nude mouse model.
  
  
  RESULTS
  HER-2 expression of 2+ or more was observed in 10 and of 3+ in 2 of the 16 cell lines. No in vitro growth-inhibitory effect of trastuzumab was found in any cell line, but trastuzumab induced antibody-dependent cell-mediated cytotoxicity in proportion to HER-2 expression level. Trastuzumab inhibited tumor growth in Capan-1 (HER-2: 3+) xenografts and prolonged survival in the orthotopic model. These effects were increased by combined therapy with gemcitabine. In contrast, trastuzumab exhibited no antitumor effect against PANC-1 (HER-2: 1+) or SW1990 (HER-2: 2+) xenografts.
  
  
  CONCLUSIONS
  The antitumor effect of trastuzumab in pancreatic cancer with high HER-2 expression was shown in vitro and in vivo. Clinical application of trastuzumab is expected in pancreatic cancer with 3+ HER-2 expression.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kimura
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Sawada
authors.forename: Midori
authors.initials: M
authors.lastname: Komatsu
authors.forename: Masafumi
authors.initials: M
authors.lastname: Inoue
authors.forename: Kazuya
authors.initials: K
authors.lastname: Muguruma
authors.forename: Tamahiro
authors.initials: T
authors.lastname: Nishihara
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yamada
authors.forename: Masaichi
authors.initials: M
authors.lastname: Ohira
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine