title: Anticancer effects of gemcitabine are enhanced by co-administered iRGD peptide in murine pancreatic cancer models that overexpressed neuropilin-1.
abstract: BACKGROUND
  Impaired drug transport is an important factor that reduces the efficacy of anticancer agents against pancreatic cancer. Here, we report a novel combination chemotherapy using gemcitabine (GEM) and internalised-RGD (iRGD) peptide, which enhances tumour-specific drug penetration by binding neuropilin-1 (NRP1) receptor.
  
  
  METHODS
  A total of five pancreatic cancer murine models (two cell line-based xenografts (CXs) and three tumour grafts (TGs)) were treated with either GEM (100 mg kg(-1), q3d × 4) alone or GEM plus iRGD peptide (8 μmol kg(-1)). Evaluation of NRP1 expression in xenografts and 48 clinical cancer specimens was performed by immunohistochemistry (IHC).
  
  
  RESULTS
  We identified a subset of pancreatic cancer models that showed NRP1 overexpression sensitive to iRGD co-administration. Treatment with GEM plus iRGD peptide resulted in a significant tumour reduction compared with GEM monotherapy in CXs, but not remarkable in TGs. Potential targets of iRGD were characterised as cases showing NRP1 overexpression (IHC-2+/3+), and these accounted for 45.8% of the clinical specimens.
  
  
  CONCLUSIONS
  Internalised RGD peptide enhances the effects of co-administered drugs in pancreatic cancer models, its efficacy is however only appreciable in those employing cell lines. Therefore, the clinical application needs to be given careful consideration.
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Akashi
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Oda
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ohara
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Miyamoto
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kurokawa
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Enomoto
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Diagnostic Radiology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Satake
authors.affiliation: Department of Surgery, Clinical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, 305-8575 Ibaraki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ohkohchi
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D039942:Neuropilin-1 / Q000096:biosynthesis*; D009842:Oligopeptides / Q000008:administration & dosage; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D009842:Oligopeptides; D003841:Deoxycytidine; D039942:Neuropilin-1; C047981:arginyl-glycyl-aspartic acid; D000093542:Gemcitabine