title: Transforming growth factor alpha stimulation of mucosal tissue cultures from head and neck squamous cell carcinoma patients increases chemoresistance to cisplatin.
abstract: The monoclonal epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux) was recently approved by the European Medicines Agency for the treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) in combination with a platinum-based chemotherapy. Since the antibody has only a limited effect as a monotherapy, possible explanations for the synergistic effect with cisplatin are enhanced antibody-dependent cytoxicity and increased sensitivity to the drug. Most of our knowledge of EGFR biology in HNSCC is based on studies using EGFR inhibitors and/or antibodies. Our study was designed to evaluate the impact of EGFR stimulation on cisplatin-induced DNA damage. Therefore, tissue cultures were produced of tumor-free oropharyngeal mucosa biopsies of HNSCC patients and controls. In a previous study, overexpression of EGFR in tissue cultures from tumor patients compared to controls was confirmed by immunohistochemical staining. Twenty-four-hour stimulation of tissue cultures with transforming growth factor alpha (TGF-alpha), a specific EGFR ligand, resulted in a reduction of cisplatin-induced DNA damage by 35% in cases, whereas in controls TGF-alpha had no effect. This reflects a statistically significant increase in cellular chemoresistance to cisplatin following TGF-alpha stimulation and helps to further understand effects of EGFR antisense therapy in combination with chemotherapy.
authors.affiliation: Department of Otolaryngology and Head and Neck Surgery, Ludwig Maximilian University, Munich, Germany. philipp.baumeister@med.uni-muenchen.de
authors.forename: Philipp
authors.initials: P
authors.lastname: Baumeister
authors.forename: Maximilian
authors.initials: M
authors.lastname: Reiter
authors.forename: Sabina
authors.initials: S
authors.lastname: Schwenk-Zieger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Harréus
mesh_terms: D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000068818:Cetuximab; D002945:Cisplatin / Q000378:metabolism / Q000627:therapeutic use*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology; D009959:Oropharyngeal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D046509:Tissue Culture Techniques; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D000068818:Cetuximab; D002945:Cisplatin