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EGFR-inhibition enhances apoptosis in irradiated human head and neck xenograft tumors independent of effects on DNA repair.
- Source :
-
Radiation research [Radiat Res] 2013 Oct; Vol. 180 (4), pp. 414-21. Date of Electronic Publication: 2013 Sep 23. - Publication Year :
- 2013
-
Abstract
- Epidermal growth factor receptor (EGFR) inhibition using cetuximab improves the efficacy of radiotherapy in only a subgroup of head and neck squamous cell carcinoma (HNSCC) patients. Therefore, to improve patient selection a better understanding of tumor characteristics that affect treatment is necessary. Here, we investigated the effect of cetuximab on repair of radiation-induced DNA damage in a HNSCC xenograft model, which shows a synergistic effect to cetuximab and radiotherapy (SCCNij185) and a HNSCC model, which shows no additive effect of cetuximab to radiotherapy (SCCNij153). In both tumor models, clear increases were seen in the number of 53BP1 and Rad51 foci after irradiation. 53BP1 foci were present at comparable levels in hypoxic and normoxic tumor areas of the tumor xenografts, while the number of Rad51 foci was significantly higher in normoxic areas compared to hypoxic areas (P < 0.05). In both SCCNij185 and SCCNij153 xenografts an increased number of 53BP1 foci was observed in tumors treated with cetuximab and radiotherapy compared to radiotherapy alone. In SCCNij185 this increase was statistically significant in normoxic tumor areas (P = 0.04) and in SCCNij153 in both hypoxic and normoxic areas (P = 0.007 and P = 0.02, respectively). The number of Rad51 foci was not significantly different when cetuximab was added to radiotherapy compared to radiotherapy alone. Levels of pEGFR and pERK1/2 were decreased when cetuximab was added to radiotherapy in SCCNij185, but not in SCCNij153. Apoptosis was also only increased in SCCNij185 tumors at 4 days after cetuximab and radiotherapy treatment (P < 0.01). In conclusion, cetuximab inhibited DNA repair in both HNSCC models, but this effect was not predictive for the radiosensitizing effect of cetuximab in vivo. This lack of correlation may be related to differential effects of cetuximab and radiotherapy on ERK1/2 signaling and a decreased induction of apoptosis by cetuximab and radiotherapy in the resistant model.
- Subjects :
- Animals
Antibodies, Monoclonal, Humanized therapeutic use
Cell Hypoxia drug effects
Cell Hypoxia radiation effects
Cell Line, Tumor
Cetuximab
Combined Modality Therapy
DNA Damage
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm radiation effects
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms genetics
Head and Neck Neoplasms radiotherapy
Humans
Intracellular Signaling Peptides and Proteins metabolism
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Phosphoproteins metabolism
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
Tumor Suppressor p53-Binding Protein 1
Xenograft Model Antitumor Assays
Antibodies, Monoclonal, Humanized pharmacology
Apoptosis drug effects
Apoptosis radiation effects
DNA Repair drug effects
DNA Repair radiation effects
ErbB Receptors antagonists & inhibitors
Head and Neck Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1938-5404
- Volume :
- 180
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Radiation research
- Publication Type :
- Academic Journal
- Accession number :
- 24059677
- Full Text :
- https://doi.org/10.1667/RR3349.2