title: Antitumor activity of ZD6474, a vascular endothelial growth factor-2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor, in combination with SC-236, a cyclooxygenase-2 inhibitor.
abstract: OBJECTIVE
  The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor (VEGF) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. Enhanced cyclooxygenase-2 (COX-2) expression has been linked to cancer cell proliferation, EGFR activation, VEGF secretion, and tumor-induced angiogenesis. ZD6474 is an orally available, small molecule, dual VEGF receptor-2 (VEGFR-2) and EGFR tyrosine kinase inhibitor. We investigated the activity of ZD6474 in combination with SC-236, a selective COX-2 inhibitor, to determine the antitumor activity of the simultaneous blockade of EGFR, COX-2, and VEGF functions.
  
  
  METHODS
  The antitumor activity in vitro and in vivo of ZD6474 and/or SC-236 was tested in human cancer cell lines with a functional EGFR autocrine pathway.
  
  
  RESULTS
  The combination of ZD6474 and SC-236 determined supra-additive growth inhibition in all cancer cell lines tested. In nude mice bearing established human colon (GEO) or lung adenocarcinoma (A549) cancer xenografts and treated with ZD6474 and/or SC-236 for 3 weeks, a reversible tumor growth inhibition was seen with each agent, whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents. A long-term, 10-week treatment with ZD6474 plus SC-236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor-bearing mice and in 4 of 10 A549 tumor-bearing mice.
  
  
  CONCLUSIONS
  This study provides a rationale for evaluating the simultaneous blockade of EGFR, COX-2, and VEGF signaling as cancer therapy in a clinical setting.
authors.affiliation: Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale F Magrassi e A Lanzara, Seconda Università degli Studi di Napoli, Via S. Pansini 5, 80131 Naples, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Tuccillo
authors.forename: Marco
authors.initials: M
authors.lastname: Romano
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
authors.forename: Ferdinando
authors.initials: F
authors.lastname: De Vita
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fontanini
authors.forename: Raffaele A
authors.initials: RA
authors.lastname: Bianco
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D016861:Cyclooxygenase Inhibitors; D066246:ErbB Receptors; D010880:Piperidines; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C452423:vandetanib