title: Up-regulation of HER2 by gemcitabine enhances the antitumor effect of combined gemcitabine and trastuzumab emtansine treatment on pancreatic ductal adenocarcinoma cells.
abstract: BACKGROUND
  Although pancreatic ductal adenocarcinomas (PDAs) widely express HER2, the expression level is generally low. If HER2 expression in PDA cells could be enhanced by treatment with a given agent, then combination therapy with that agent and trastuzumab emtansine (T-DM1), a chemotherapeutic agent that is a conjugate of trastuzumab, might lead to significant antitumor effects against PDA.
  
  
  METHODS
  Cell proliferation was examined by spectrophotometry. HER2 expression was examined by flow cytometry, immunoblot and quantitative reverse transcription polymerase chain reaction. T-DM1 binding to cells was examined by flow cytometry and enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Out of 5 tested human PDA cell lines, including MIA PaCa-2, three showed increases in HER2 expression after gemcitabine (GEM) treatment. The binding of T-DM1 to GEM-treated MIA PaCa-2 cells was higher than to untreated MIA PaCa-2 cells. Treatment with GEM and T-DM1 showed synergic cytotoxic effects on MIA PaCa-2 cells in vitro. Cells in the G2M phase of the cell cycle were retained after GEM treatment and showed higher levels of HER2 expression, possibly contributing to the synergic effect of GEM and T-DM1.
  
  
  CONCLUSIONS
  Combined treatment with GEM and T-DM1 might confer a potent therapeutic modality against PDA as a result of GEM-mediated HER2 up-regulation.
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan. shinkan1070@gmail.com.
authors.forename: Shin
authors.initials: S
authors.lastname: Kan
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan. shigeo_koido@hotmail.com.|Division of Gastroenter ology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. shigeo_koido@hotmail.com.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koido
authors.affiliation: Department of Advanced Immunotherapeutics, Kitasato University School of Pharmacy, Tokyo, Japan. okamotom@pharm.kitasato-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Okamoto
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan. kz.hayashi@gmail.com.|Division of Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. kz.hayashi@gmail.com.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan. mito@jikei.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ito
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan. ykama@jikei.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kamata
authors.affiliation: Shimbashi Medical Checkup Office, Jikei University Hospital, Tokyo, Japan. pericyte@hotmail.co.jp.
authors.forename: Hideo
authors.initials: H
authors.lastname: Komita
authors.affiliation: Division of Oncology and Hematology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. nagasaki@jikei.ac.jp.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Nagasaki
authors.affiliation: Division of Oncology, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan. hommas@live.jp.
authors.forename: Sadamu
authors.initials: S
authors.lastname: Homma
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000080044:Ado-Trastuzumab Emtansine; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000080044:Ado-Trastuzumab Emtansine; D061067:Antibodies, Monoclonal, Humanized; D003841:Deoxycytidine; D008453:Maytansine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine; C508053:ERBB2 protein, human