title: Vandetanib improves anti-tumor effects of L19mTNFalpha in xenograft models of esophageal cancer.
abstract: OBJECTIVE
  Targeting the tumor vasculature by vascular disrupting agents (VDAs) has shown therapeutic activity in mouse models. In most cases, however, VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass. In this study, we investigated anti-tumor effects of L19mTNFα, a fusion protein composed of L19 (scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform, and murine TNFα, in xenograft models of esophageal cancer.
  
  
  METHODS
  We evaluated ED-B expression in esophageal cancer samples. Subsequently, we generated subcutaneous xenografts from primary tumors, treated them with the L19mTNFα scFv, and determined effects on tumor vasculature, viability and proliferation, and VEGF expression and infiltration by hematopoietic cells. To overcome tumor resistance, L19mTNFα scFv was combined with vandetanib, a tyrosine kinase inhibitor of VEGF receptor, epidermal growth factor receptor, and RET signaling.
  
  
  RESULTS
  ED-B was broadly expressed by esophageal cancer cell lines, as well as xenografts and primary surgical samples of esophageal cancer. Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis, indicating a VDA-like activity of this immunoconjugate. This event was followed, however, by rapid tumor growth recovery associated with increased expression of VEGF and recruitment of CD11b+Gr1+ myeloid cells into tumors. Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors, leading to a reduction of cell proliferation and increased necrosis, without apparent signs of toxicity.
  
  
  CONCLUSIONS
  These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer.
authors.affiliation: Istituto Oncologico Veneto-IRCCS, Padua, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Crescenzi
authors.forename: Luca
authors.initials: L
authors.lastname: Persano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zulato
authors.forename: Laura
authors.initials: L
authors.lastname: Borsi
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
authors.forename: Alberto
authors.initials: A
authors.lastname: Ruol
authors.forename: Ermanno
authors.initials: E
authors.lastname: Ancona
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005353:Fibronectins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D057127:Single-Chain Antibodies / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C067625:FN1 protein, human; D005353:Fibronectins; C558733:L19mTNFalpha protein; D010880:Piperidines; D011799:Quinazolines; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D014409:Tumor Necrosis Factor-alpha; C452423:vandetanib