title: Antitumor effect of FP3 in combination with cetuximab on patient-derived             tumor tissue xenograft models of primary colon carcinoma and related lymphatic             and hepatic metastases.
abstract: FP3 is an engineered protein which contains the extracellular domain 2 of vascular endothelial growth factor (VEGF) receptor 1 (Flt-1) and the extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies have demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combined inhibition of VEGF and EGF signaling may act additively or synergistically. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with cetuximab. Xenografts were treated with FP3 and cetuximab, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR and PCNA in the tumor were examined by immunohistochemical staining, and levels of related cell signaling pathway proteins were examined by western blotting. FP3 in combination with cetuximab showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with cetuximab was lower compared to that of the control. Antitumor activity of FP3 in combination with cetuximab was significantly higher than that of each agent alone in two xenograft models (colon carcinoma lymphatic metastasis and hepatic metastasis). This study indicated that addition of FP3 to cetuximab significantly improved tumor growth inhibition in the PDTT xenograft models of colon carcinoma lymphatic and hepatic metastases. Combination anti-VEGF (FP3) and anti-EGFR (cetuximab) therapies may represent a novel therapeutic strategy for the management of metastatic colon carcinoma.
authors.affiliation: Department of Medical Oncology, The Affiliated Dongyang Hospital,                     Wenzhou Medical College, Dongyang, Zhejiang 322100, P.R. China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Dong
authors.forename: Ketao
authors.initials: K
authors.lastname: Jin
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hu
authors.forename: Fangmin
authors.initials: F
authors.lastname: Du
authors.forename: Huanrong
authors.initials: H
authors.lastname: Lan
authors.forename: Na
authors.initials: N
authors.lastname: Han
authors.forename: Zhaosheng
authors.initials: Z
authors.lastname: Ma
authors.forename: Bojian
authors.initials: B
authors.lastname: Xie
authors.forename: Binbin
authors.initials: B
authors.lastname: Cui
authors.forename: Lisong
authors.initials: L
authors.lastname: Teng
authors.forename: Feilin
authors.initials: F
authors.lastname: Cao
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D066246:ErbB Receptors / Q000032:analysis / Q000276:immunology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C557495:FP3 VEGF receptor Fc-fusion protein; D018809:Proliferating Cell Nuclear Antigen; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; D000068818:Cetuximab