In Vivo Enhancement of Tumor Radioresponse by C225 Antiepidermal Growth Factor Receptor Antibody

Overexpression of epidermal growth factor receptor (EGFR) has been correlated with tumor resistance to cytotoxic agents, including radiation (T. Akimoto et al., Clin. Cancer Res., 5: 2884–2890, 1999), and thus is a candidate target for anticancer treatment. This study investigated whether treatment...

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Bibliographic Details
Published in:	Clinical cancer research 2000-02, Vol.6 (2), p.701-708
Main Authors:	MILAS, L, MASON, K, HUNTER, N, PETERSEN, S, YAMAKAWA, M, KIAN ANG, MENDELSOHN, J, ZHEN FAN
Format:	Article
Language:	eng
Subjects:	Animals Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Humanized Antineoplastic agents Antineoplastic Agents - therapeutic use Apoptosis - drug effects Apoptosis - radiation effects Biological and medical sciences Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - pathology Carcinoma, Squamous Cell - radiotherapy Cetuximab Combined Modality Therapy Combined treatments (chemotherapy of immunotherapy associated with an other treatment) Humans Male Medical sciences Mice Mice, Nude Necrosis Pharmacology. Drug treatments Receptor, Epidermal Growth Factor - antagonists & inhibitors Recombinant Fusion Proteins - therapeutic use Transplantation, Heterologous
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Summary:	Overexpression of epidermal growth factor receptor (EGFR) has been correlated with tumor resistance to cytotoxic agents, including radiation (T. Akimoto et al., Clin. Cancer Res., 5: 2884–2890, 1999), and thus is a candidate target for anticancer treatment. This study investigated whether treatment with C225 anti-EGFR antibody would improve tumor response to radiotherapy. Nude mice bearing 8-mm-diameter A431 tumor xenografts in the hind leg were treated with C225 antibody, 18 Gy of single-dose local tumor irradiation, or both. C225 was given i.p. at a dose of 1 mg/mouse 6 h before irradiation or 6 h before and 3 and 6 days after irradiation. Delay in tumor growth was the treatment end point. C225 dramatically improved the efficacy of local tumor irradiation, particularly when multiple injections of C225 were administered. Tumor radioresponse was enhanced by a factor of 1.59 by a single dose and by a factor of 3.62 by 3 doses of C225. Histological analyses of tumors revealed that C225 caused a striking increase in central tumor necrosis associated with hemorrhage and vascular thrombosis when combined with radiotherapy. In addition, C225 induced heavy tumor infiltration with granulocytes, increased tumor cell terminal differentiation, and inhibited tumor angiogenesis. We conclude that C225 anti-EGFR antibody enhances tumor radioresponse by multiple mechanisms that may involve direct and indirect actions on tumor cell survival.
ISSN:	1078-0432 1557-3265