Abstract

Adenoid cystic carcinoma (ACC) can often be controlled with surgery and postoperative adjuvant radiotherapy but is also characterized by late local recurrence and distant metastasis. No effective systemic therapeutic agents have been found to alter the natural history of ACC. Therefore, new therapeutic approaches are needed. In this study, we evaluated whether vandetanib (Zactima), a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, had antitumor efficacy in vitro and in an orthotopic nude mouse model of human ACC. The in vitro effects of vandetanib were assessed in three ACC cell lines on cell growth, apoptosis, and VEGFR-2 and EGFR phosphorylation levels. The in vivo antitumor activity of vandetanib was examined in nude mice bearing parotid gland ACC tumors. The mice were treated for 4 weeks with vandetanib (50 mg/kg/d) or placebo (control). Tumors were resected at necropsy, and immunohistochemical and immunofluorescence staining were done. In vitro, vandetanib caused dose-dependent inhibition of VEGFR-2 and EGFR phosphorylation in ACC cells. Vandetanib also inhibited the cell proliferation and induced their dose-dependent apoptosis. In vivo, mice in the vandetanib group had tumor volumes significantly lower than those in the control group (P < 0.01). In addition, immunohistochemical staining showed a decrease in microvessel density and an increase in apoptosis of both tumor cells and endothelial cells within the tumor xenografts. These results suggest that vandetanib inhibits the growth of ACC in vitro and in vivo, making it a promising novel agent for the treatment of ACC.

Highlights

  • Adenoid cystic carcinoma (ACC) can often be controlled with surgery and postoperative adjuvant radiotherapy but is characterized by late local recurrence and distant metastasis

  • To determine whether vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) are overexpressed in salivary gland cancer cell lines, we studied vascular endothelial growth factor receptors (VEGFR)-2, EGFR-2, mitogen-activated protein kinase (MAPK), and Akt expression levels in ACC2, ACC3, and ACCM cells

  • We found that EGFR was expressed in all the ACC cells, with the highest level of EGFR expression observed in the ACC3 cell line

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Summary

Introduction

Adenoid cystic carcinoma (ACC) can often be controlled with surgery and postoperative adjuvant radiotherapy but is characterized by late local recurrence and distant metastasis. We evaluated whether vandetanib (Zactima), a potent inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinases, had antitumor efficacy in vitro and in an orthotopic nude mouse model of human ACC. Results: In vitro, vandetanib caused dose-dependent inhibition of VEGFR-2 and EGFR phosphorylation in ACC cells. Numerous preclinical and clinical studies on molecular targeted therapy have shown that this therapeutic approach has great promise in the treatment of various malignant tumors [8]. We observed that VEGF/VEGFR-2 is overexpressed in human ACC tissues [12] It has been reported in numerous studies that EGFR, a tyrosine kinase receptor, plays a critical role in tumor cell proliferation, invasion, metastasis, and survival [13, 14]. In ACC tissues, EGFR expression has been reported to range from 10% to 85% [13, 16]

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