title: Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases.
abstract: OBJECTIVE
  The epidermal growth factor receptor (EGFR) autocrine pathway plays an important role in cancer cell growth. Vascular endothelial growth factor A (VEGF-A) is a key regulator of tumor-induced endothelial cell proliferation and vascular permeability. ZD6474 is an orally available, small molecule inhibitor of VEGF receptor-2 (VEGFR-2), EGFR and RET tyrosine kinase activity. We investigated the activity of ZD6474 in combination with cetuximab, an anti-EGFR blocking monoclonal antibody, to determine the anti-tumor activity of EGFR blockade through the combined use of two agents targeting the receptor at different molecular sites in cancer cells and of VEGFR-2 blockade in endothelial cells.
  
  
  METHODS
  The anti-tumor activity in vitro and in vivo of ZD6474 and/or cetuximab was tested in human cancer cell lines with a functional EGFR autocrine pathway.
  
  
  RESULTS
  The combination of ZD6474 and cetuximab determined synergistic growth inhibition in all cancer cell lines tested as assessed by the Chou and Talalay method. In nude mice bearing established human colon carcinoma (GEO) or lung adenocarcinoma (A549) xenografts and treated with ZD6474 and/or cetuximab for 4 weeks, a reversible tumor growth inhibition was caused by each drug. In contrast, a more significant tumor growth delay resulted from the combination of the two agents with an approximately 100-110 days increase in mice median overall survival as compared to single agent treatment.
  
  
  CONCLUSIONS
  This study provides a rationale for evaluating in a clinical setting the double blockade of EGFR in combination with inhibition of VEGFR-2 signaling as cancer therapy.
authors: Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara," Seconda Università degli Studi di Napoli, Napoli, Italy.
authors: Maria Pia
authors: MP
authors: Morelli
authors: Tina
authors: T
authors: Cascone
authors: Teresa
authors: T
authors: Troiani
authors: Concetta
authors: C
authors: Tuccillo
authors: Roberto
authors: R
authors: Bianco
authors: Nicola
authors: N
authors: Normanno
authors: Marco
authors: M
authors: Romano
authors: Bianca Maria
authors: BM
authors: Veneziani
authors: Gabriella
authors: G
authors: Fontanini
authors: S Gail
authors: SG
authors: Eckhardt
authors: Sabino
authors: S
authors: De Pacido
authors: Giampaolo
authors: G
authors: Tortora
authors: Fortunato
authors: F
authors: Ciardiello