Abstract
Anaplastic thyroid carcinoma (ATC) remains one of the most lethal known human cancers. Targeted molecular therapy with cetuximab, a monoclonal antibody against epidermal growth factor receptor, offers new treatment potentials for patient with ATC. Cetuximab has also been reported to have synergistic effects when combined with irinotecan, a topoisomerase inhibitor. Therefore, we hypothesized that cetuximab and irinotecan would be effective in inhibiting the growth and progression of ATC in a murine orthotopic model. The in vitro antiproliferative effects of cetuximab and irinotecan on ATC cell line ARO were examined. We also studied the in vivo effects of cetuximab and irinotecan on the growth, invasion, and metastasis of orthotopic ATC tumors in nude mice. The in vivo antitumor efficacy of cetuximab/irinotecan combination was also compared with that of doxorubicin. Cetuximab alone did not show any antiproliferative or proapoptotic effect on this cell line. However, when combined with irinotecan, cetuximab potentiated the in vitro antiproliferative and proapoptotic effect of irinotecan. Cetuximab, irinotecan, and cetuximab/irinotecan combination resulted in 77%, 79%, and 93% in vivo inhibition of tumor growth, respectively. Incidences of lymph node metastasis, laryngeal invasion, and tumor microvessel density were also significantly decreased in these treatment groups. Furthermore, the cetuximab/irinotecan combination was significantly more effective than doxorubicin in inhibiting the growth of orthotopic ATC xenografts. Combination therapy with cetuximab/irinotecan inhibits the growth and progression of orthotopic ATC xenografts in nude mice. Given the lack of curative options for patients with ATC, combination therapy with cetuximab and irinotecan treatment warrants further study.
Highlights
Carcinomas of the thyroid gland account for f1% of all new malignant diseases in the United States [1]
We show that the coadministration of cetuximab and irinotecan significantly inhibited the growth, invasion, metastasis, and angiogenesis of orthotopic anaplastic thyroid carcinoma (ATC) xenografts in nude mice
We used 2% fetal bovine serum (FBS) in our medium to minimize the effect of exogenous EGF, it may be argued that there are still sufficient EGF or other growth factors in 2% FBS to overcome the effect of the cetuximab
Summary
Carcinomas of the thyroid gland account for f1% of all new malignant diseases in the United States [1]. EGFR pathway using monoclonal antibodies and smallmolecule inhibitors has shown antiproliferative effects on ATC cell lines in vitro [9, 10]. The administration of gefinitib (Iressa), a small-molecule inhibitor of the EGFR tyrosine kinase, to nude mice bearing s.c. ATC xenografts resulted in significant inhibition of tumor growth. Kim et al showed that AEE788, a dual inhibitor of EGFR and vascular endothelial growth factor receptor tyrosine kinases, produced significant cytostatic and cytotoxic effects on ATC cell lines in vitro and inhibited the growth of s.c. ATC xenografts in nude mice [12]. Preclinical studies have shown that cetuximab is able to inhibit the growth of colon, head and neck, and pancreatic carcinoma xenografts in nude mice (15 – 17). A randomized, phase III clinical trial showed that cetuximab prolongs the survival of patients with untreated head and neck cancers in combination with radiotherapy compared with treatment with radiotherapy alone [18]
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