Vandetanib Restores Head and Neck Squamous Cell Carcinoma Cells' Sensitivity to Cisplatin and Radiation In Vivo and In Vitro

Abstract

Purpose: We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC).Experimental Design: OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data.Results: Vandetanib plus cisplatin radiosensitized HNSCC cells in vitro and in vivo. The combination treatment with vandetanib, cisplatin, and radiation was superior to the rest of treatments (including the double combinations) in antitumoral effects, prolonging survival, decreasing cervical lymph node metastases in vivo. It also increased both tumor and tumor-associated endothelial cell apoptosis and decreased microvessel density in vivo. An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo. All vandetanib-containing treatments inhibited EGFR and Akt phosphorylation in vitro and in vivo.Conclusion: The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC. Further study of this regimen in clinical trials may be warranted.

On-demand intracellular amplification of chemoradiation with cancer-specific plasmonic nanobubbles

“…3d and Supplementary Fig. 3e) owing to the well-known synergy of drugs and X-rays 15,16 . To summarize, neither the tested therapeutic components alone, nor their standard combinations described above, prevented the growth of resistant and aggressive cancer cells.…”

“…This amplification can be explained through well-established macroeffects: the mutual enhancement of chemotherapy and radiation therapy 16,25–27 and the mechanical radio- and chemosensitization of tumors 28–33 . However, it is the cancer cell–specific nanocluster that efficiently colocalizes the above therapeutic events and thus synergistically amplifies their therapeutic effect only in cancer cells.…”

Anti-tumor and anti-invasion effects of a combination of 4-methylumbelliferone and ionizing radiation in human fibrosarcoma cells

“…An inhibitor of HA synthesis, 4-methylumbelliferone (MU), was identified as a possible countermeasure in prostate, lung and breast cancer cell models (5)(6)(7). To the best of our knowledge, there have been no published studies investigating the administration of MU in conjunction with the exposure of cancer cells to ionizing radiation (IR); however, the chemotherapy drugs cisplatin and paclitaxel have been clinically used along with radiotherapy in various solid tumors (8)(9)(10).…”

Current status of and future strategies for multimodality treatment of unresectable stage III nonsmall cell lung cancer

“…Combination therapy with vandetanib and radiotherapy markedly reduced tumour dissemination into the thoracic wall and was more effective than either modality alone or the combination of paclitaxel with radiotherapy [84]. Vandetanib also has radiosensitising effects on head and neck carcinoma cell lines and xenografts [85][86][87].…”