Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement

Hirokazu Ogino; Seiji Yano; Soji Kakiuchi; Tadaaki Yamada; Kenji Ikuta; Emiko Nakataki; Hisatsugu Goto; Masaki Hanibuchi; Yasuhiko Nishioka; Anderson Ryan; Saburo Sone

doi:10.1016/j.canlet.2008.02.018

Novel dual targeting strategy with vandetanib induces tumor cell apoptosis and inhibits angiogenesis in malignant pleural mesothelioma cells expressing RET oncogenic rearrangement

Cancer Lett. 2008 Jun 28;265(1):55-66. doi: 10.1016/j.canlet.2008.02.018. Epub 2008 Mar 24.

Authors

Hirokazu Ogino¹, Seiji Yano, Soji Kakiuchi, Tadaaki Yamada, Kenji Ikuta, Emiko Nakataki, Hisatsugu Goto, Masaki Hanibuchi, Yasuhiko Nishioka, Anderson Ryan, Saburo Sone

Affiliation

¹ Department of Internal Medicine and Molecular Therapeutics, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.

PMID: 18364248
DOI: 10.1016/j.canlet.2008.02.018

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a poor prognosis, therefore development of novel effective therapies is urgent. In the present study, we investigated the therapeutic efficacy of vandetanib (ZD6474), an inhibitor of VEGFR-2, EGFR and RET tyrosine kinases, in an orthotopic model of MPM. We found that a human MPM cell line, EHMES-10, expressed RET/PTC3 oncogenic rearrangement and a large amount of VEGF. Vandetanib induced the apoptosis and inhibited the proliferation of EHMES-10 cells in vitro (IC(50)=0.3 microM). Once-daily oral treatment with vandetanib inhibited tumor angiogenesis, and reduced significantly the growth of thoracic tumors and the production of pleural effusions, resulting in the prolonged survival of mice in EHMES-10 orthograft model. In contrast, the selective EGFR tyrosine kinase inhibitor, gefitinib, had no effect against EHMES-10 cells both in vitro and in vivo. Our results suggest that using vandetanib to target RET-dependent tumor cell proliferation and survival and VEGFR-2-dependent tumor angiogenesis may be promising against MPM expressing RET oncogenic rearrangement and VEGF.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiogenesis Inhibitors / pharmacology*
Angiogenesis Inhibitors / therapeutic use
Animals
Apoptosis*
Base Sequence
Cell Line, Tumor
Cell Proliferation / drug effects
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Gefitinib
Gene Rearrangement*
Humans
Male
Mesothelioma / blood supply
Mesothelioma / drug therapy*
Mesothelioma / metabolism
Mice
Mice, SCID
Molecular Sequence Data
Neoplasm Transplantation
Neovascularization, Pathologic
Piperidines / pharmacology*
Piperidines / therapeutic use
Pleural Neoplasms / blood supply
Pleural Neoplasms / drug therapy*
Pleural Neoplasms / metabolism
Proto-Oncogene Proteins c-ret / biosynthesis*
Proto-Oncogene Proteins c-ret / genetics
Quinazolines / pharmacology*
Quinazolines / therapeutic use
Transplantation, Heterologous
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Angiogenesis Inhibitors
Piperidines
Quinazolines
ErbB Receptors
Proto-Oncogene Proteins c-ret
RET protein, human
Vascular Endothelial Growth Factor Receptor-2
Gefitinib
vandetanib