title: Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts.
abstract: BACKGROUND
  Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-epidermal growth factor receptor (EGFR) and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts.
  
  
  METHODS
  Nude mice, bearing human pancreatic carcinoma xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) or gemcitabine, and tumor growth was observed.
  
  
  CONCLUSIONS
  In first-line therapy, mice survival was significantly longer in the 2mAbs group compared with gemcitabine (P < 0.0001 for BxPC-3, P = 0.0679 for MiaPaCa-2 and P = 0.0019 for Capan-1) and with controls (P < 0.0001). In second-line therapy, tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival compared with mice receiving continuous gemcitabine injections (P = 0.008 for BxPC-3, P = 0.05 for MiaPaCa-2 and P < 0.001 for Capan-1). Therapeutic benefit of 2mAbs was observed despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab')(2) fragments from 2mAbs induced significant tumor growth inhibition, compared with controls (P = 0.001), indicating that the 2mAbs had an Fc fragment-independent direct action on tumor cells. This preclinical study demonstrated a significant improvement of survival and tumor regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first- and second-line treatments, compared with gemcitabine, independently of the K-Ras status.
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Larbouret
authors.forename: B
authors.initials: B
authors.lastname: Robert
authors.forename: C
authors.initials: C
authors.lastname: Bascoul-Mollevi
authors.forename: F
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: A
authors.initials: A
authors.lastname: Ho-Pun-Cheung
authors.forename: S
authors.initials: S
authors.lastname: Morisseau
authors.forename: I
authors.initials: I
authors.lastname: Navarro-Teulon
authors.forename: J-P
authors.initials: JP
authors.lastname: Mach
authors.forename: A
authors.initials: A
authors.lastname: Pèlegrin
authors.forename: D
authors.initials: D
authors.lastname: Azria
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D003841:Deoxycytidine; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000093542:Gemcitabine