Cetuximab may inhibit tumor growth and angiogenesis induced by ionizing radiation: a preclinical rationale for maintenance treatment after radiotherapy.
BACKGROUND
The benefits of radiotherapy and cetuximab have encouraged evaluation of cetuximab after radiotherapy. The aims of this study were to preclinically evaluate the efficacy of cetuximab maintenance after radiotherapy and eventually determine its mechanisms of action.


METHODS
The A431 human carcinoma cell line was treated in culture with fractionated radiotherapy and cetuximab. The surviving cells were injected s.c. into nude mice to mimic microscopic residual disease. The animals were randomized to receive either cetuximab or saline solution. Tumor growth, cell proliferation (Ki-67), microvessel density (MVD), epidermal growth factor receptor (EGFR) and transforming growth factor (TGF-α) mRNA transcription, and vascular endothelial growth factor (VEGF) secretion were measured.


RESULTS
Tumors from irradiated cells had a faster growth rate, higher Ki-67 index, and greater angiogenesis than tumors from untreated cells. This aggressive phenotype was associated with in vitro radiation-induced extracellular signal-related kinase (ERK)-1/2 and Akt activation, greater EGFR and TGF-α transcription, and augmented VEGF secretion, all of which were inhibited by cetuximab. In cetuximab-treated mice with tumors arising from irradiated cells, time to volume was longer by a factor of 3.52, whereas the Ki-67 index and MVD were 1.57 and 1.49 times lower, respectively, a larger enhancement than seen in tumors from untreated cells. These findings suggest that cells surviving radiation may express factors that promote cell survival and induce an aggressive phenotype that may potentially be blocked by cetuximab maintenance therapy.


CONCLUSIONS
These results support the clinical evaluation of adjuvant therapy with cetuximab after radiotherapy in EGFR-dependent carcinomas.
Pueyo
Gemma
G
Laboratori de Recerca Translacional-IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Spain.
Mesia
Ricard
R
Figueras
Agnes
A
Lozano
Alicia
A
Baro
Marta
M
Vazquez
Silvia
S
Capella
Gabriel
G
Balart
Josep
J
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D003131:Combined Modality Therapy; D019610:Cytoprotection; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019394:Ki-67 Antigen; D066246:ErbB Receptors; D000068818:Cetuximab
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