Combination of anti-IGF-1R antibody A12 and ionizing radiation in upper respiratory tract cancers.
OBJECTIVE
The IGF1/IGF-1R signaling pathway has emerged as a potential determinant of radiation resistance in human cancer cell lines. Therefore we investigated the potency of monoclonal anti-IGF-1R antibody, A12, to enhance radiation response in upper respiratory tract cancers.


METHODS
Cell lines were assessed for IGF-1R expression and IGF1-dependent response to A12 or radiation using viability and clonogenic cancer cell survival assays. In vivo response of tumor xenografts to 10 or 20 Gy and A12 (0.25-2 mg × 3) was assessed using growth delay assays. Combined treatment effects were also analyzed by immunohistochemical assays for tumor cell proliferation, apoptosis, necrosis, and vascular endothelial growth factor expression at Days 1 and 6 after start of treatment.


RESULTS
A12 enhanced the radiosensitivity of HN5 and FaDu head-and-neck carcinomas in vitro (p < 0.05) and amplified the radioresponse of FaDu xenografts in a dose-dependent manner, with enhancement factors ranging from 1.2 to 1.8 (p < 0.01). Immunohistochemical analysis of FaDu xenografts demonstrated that A12 inhibited tumor cell proliferation (p < 0.05) and vascular endothelial growth factor expression. When A12 was combined with radiation, this resulted in apoptosis induction that persisted until 6 days from the start of treatment and in increased necrosis at Day 1 (p < 0.01, respectively). Combined treatment with A12 and radiation resulted in additive or subadditive growth delay in H460 or A549 xenografts, respectively.


CONCLUSIONS
The results of this study strengthen the evidence for investigating how anti-IGF-1R strategies can be integrated into radiation and radiation-cetuximab regimen in the treatment of cancer of the upper aerodigestive tract cancers.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson, Cancer Center, Houston, TX 77030, USA.
Oliver
O
Riesterer
Qiuan
Q
Yang
Uma
U
Raju
Mylin
M
Torres
David
D
Molkentine
Nalini
N
Patel
David
D
Valdecanas
Luka
L
Milas
K Kian
KK
Ang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000532:radiotherapy; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D042461:Vascular Endothelial Growth Factor A; C557414:cixutumumab; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1