Augmentation of radiation response by panitumumab in models of upper aerodigestive tract cancer.
OBJECTIVE
To examine the interaction between panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, and radiation in head-and-neck squamous cell carcinoma and non-small-cell lung cancer cell lines and xenografts.


METHODS
The head-and-neck squamous cell carcinoma lines UM-SCC1 and SCC-1483, as well as the non-small-cell lung cancer line H226, were studied. Tumor xenografts in athymic nude mice were used to assess the in vivo activity of panitumumab alone and combined with radiation. In vitro assays were performed to assess the effect of panitumumab on radiation-induced cell signaling, apoptosis, and DNA damage.


RESULTS
Panitumumab increased the radiosensitivity as measured by the clonogenic survival assay. Radiation-induced epidermal growth factor receptor phosphorylation and downstream signaling through mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) was inhibited by panitumumab. Panitumumab augmented radiation-induced DNA damage by 1.2-1.6-fold in each of the cell lines studied as assessed by residual gamma-H(2)AX foci after radiation. Radiation-induced apoptosis was increased 1.4-1.9-fold by panitumumab, as evidenced by Annexin V-fluorescein isothiocyanate staining and flow cytometry. In vivo, the combination therapy of panitumumab and radiation was superior to panitumumab or radiation alone in the H226 xenografts (p = 0.01) and showed a similar trend in the SCC-1483 xenografts (p = 0.08). In vivo, immunohistochemistry demonstrated the ability of panitumumab to augment the antiproliferative and antiangiogenic effects of radiation.


CONCLUSIONS
These studies have identified a favorable interaction in the combination of radiation and panitumumab in upper aerodigestive tract tumor models, both in vitro and in vivo. These data suggest that clinical investigations examining the combination of radiation and panitumumab in the treatment of epithelial tumors warrant additional pursuit.
Kruser
Tim J
TJ
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Armstrong
Eric A
EA
Ghia
Amol J
AJ
Huang
Shyhmin
S
Wheeler
Deric L
DL
Radinsky
Robert
R
Freeman
Daniel J
DJ
Harari
Paul M
PM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000532:radiotherapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D004249:DNA Damage / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects; D009060:Mouth Floor; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D000077544:Panitumumab; D010766:Phosphorylation / Q000187:drug effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018809:Proliferating Cell Nuclear Antigen; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077544:Panitumumab; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases
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