title: Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation.
abstract: Vandetanib (ZactimaTM) is a novel, orally available inhibitor of both vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinase. In the present study, a line of transgenic mice with a mouse Egfr gene mutation (delE748-A752) corresponding to a human EGFR mutation (delE746-A750) was established. The transgenic mice developed atypical adenomatous hyperplasia to adenocarcinoma of the lung at around 5 weeks of age and died of lung tumors at approximately 17 weeks of age. In the mice treated with vandetanib (6mg/kg/day), these lung tumors disappeared and the phosphorylations of EGFR and VEGFR-2 were reduced in lung tissues to levels comparable to those of non-transgenic control mice. The median overall survival time of the transgenic mice was 28 weeks in the vandetanib-treated group and 17 weeks in the vehicle-treated group. Vandetanib significantly prolonged the survival of the transgenic mice (log-rank test, p＜ 0.01); resistance to vandetanib occurred at 20 weeks of age and the animals died from their lung tumors at about 28 weeks of age. These data suggest that vandetanib could suppress the progression of tumors harboring an activating EGFR mutation.
authors.affiliation: Department of Haematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.sawaoh0327@gmail.com.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Osawa
authors.forename: Kadoaki
authors.initials: K
authors.lastname: Ohashi
authors.forename: Toshio
authors.initials: T
authors.lastname: Kubo
authors.forename: Eiki
authors.initials: E
authors.lastname: Ichihara
authors.forename: Saburo
authors.initials: S
authors.lastname: Takata
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Takata
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006965:Hyperplasia / Q000145:classification / Q000188:drug therapy / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors; C452423:vandetanib