Effect of vandetanib on lung tumorigenesis in transgenic mice carrying an activating Egfr gene mutation

Masahiro Osawa, Kadoaki Oohashi, Toshio Kubo, Eiki Ichihara, Saburo Takata, Nagio Takigawa, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)243-254
Number of pages12
JournalActa Medica Okayama
Volume70
Issue number4
Publication statusPublished - 2016

Fingerprint

Transgenic Mice
Carcinogenesis
Genes
Epidermal Growth Factor Receptor
Lung
Mutation
Tumors
Vascular Endothelial Growth Factor Receptor-2
Neoplasms
Phosphorylation
Protein-Tyrosine Kinases
Hyperplasia
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Animals
Tissue
Survival

Keywords

  • EGFR
  • Nonsmall cell lung cancer
  • Transgenic mouse
  • Vandetanib
  • VEGFR

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Effect of vandetanib on lung tumorigenesis in transgenic mice carrying an activating Egfr gene mutation. / Osawa, Masahiro; Oohashi, Kadoaki; Kubo, Toshio; Ichihara, Eiki; Takata, Saburo; Takigawa, Nagio; Takata, Minoru; Tanimoto, Mitsune; Kiura, Katsuyuki.

In: Acta Medica Okayama, Vol. 70, No. 4, 2016, p. 243-254.

Research output: Contribution to journalArticle

Osawa, Masahiro ; Oohashi, Kadoaki ; Kubo, Toshio ; Ichihara, Eiki ; Takata, Saburo ; Takigawa, Nagio ; Takata, Minoru ; Tanimoto, Mitsune ; Kiura, Katsuyuki. / Effect of vandetanib on lung tumorigenesis in transgenic mice carrying an activating Egfr gene mutation. In: Acta Medica Okayama. 2016 ; Vol. 70, No. 4. pp. 243-254.
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