Abstract 369: Treatment with vandetanib can overcome resistance of head and neck squamous cell carcinoma cells to cisplatin and radiation in an orthotopic animal model
Authors: Sano Daisuke , Matsumoto Fumihiko , Valdecanas David R. , Zhao Mei , Molkentine David P. , Papadimitrakopoulou Vali , Heymach John V. , Raju Uma , Milas Luka , Myers Jeffrey N. 
Published: February 2011

Objective

Despite advances in treatment, the survival of patients with Head and neck squamous cell carcinoma (HNSCC) has not significantly improved over the past several decades. While concurrent chemotherapy with cisplatin and radiation has become a standard of care for many patients with HNSCC, some HNSCCs are resistant and persist/recur after this type of treatment. To determine whether we could overcome this resistance, we evaluated whether vandetanib, an inhibitor of tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) could augment the anti-tumor activity of concurrent chemotherapy with cisplatin and radiation in pre-clinical in vitro and in vivo models of human HNSCC

Method

To determine the effects of cisplatin and irradiation on HNSCC cell proliferation in vitro, we first performed MTT assays with cisplatin and clonogenic survival assay with radiation using 18 HNSCC cell lines. We chose HN5 as a relatively cisplatin & irradiation-resistant cell line. Clonogenic survival assays with irradiaton + cisplatin on HN5 were also performed to see the interaction between cisplatin and irradiation. We used an orthotopic nude mouse model of HNSCC by injecting human HN5 lines into the tongue of the mouse. Nine days after cell inoculation, the animals were randomly divided into 8 groups to receive vehicle, cisplatin (1 mg/kg, intravenously, once a week for 2 weeks), vandetanib (20 mg/kg, daily oral gavage, for 2 weeks), vandetanib plus cisplatin, irradiation (5 Gy at day 10), cisplatin plus irradiation, vandetanib plus irradiation, or vandetanib plus cisplatin plus irradiation. We assessed in vivo effects of the treatment by tumor size.

Results

Cisplatin GI50 values spanned a 10-fold range from 1.031 to 10.58 μM and the surviving fraction at 2 Gy (SF2) values ranged from 0.22 to 0.8 with 18 HNSCC cell lines. The GI50 value of vandetanib was 9.084 μM and the SF2 value was 0.75 for HN5 which indicated this line was a relatively cisplatin and irradiation-resistant cell line. In the clonogenic survival assay with iradiation and cisplatin on HN5, cisplatin did not improve radiosensitivity. At day 35 after cell inoculation, the treatment with cisplatin alone, vandetanib alone, vandetanib plus cisplatin, irradiation alone, cisplatin plus irradiation, vandetanib plus irradiation, and vandetanib plus cisplatin plus irradiation reduced tumor size by 5.0% (P=0.6843), 41.9% (P=0.0370), 49.2% (P &lt;0.0001), 8.28% (P =0.3190), 30% (P =0.0926), 52.1% (P =0.0001) and 63.9% (P &lt;0.0001), respectively, compared with control mice.

Conclusion

These data indicate that the addition of vandetanib to combination therapy with cisplatin and radiation may be effective in overcoming cisplatin-radiation resistance HNSCC and has the potential as a novel therapeutic startegy for patients with advanced HNSCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 369.