TY - JOUR
T1 - Combination of Anti-IGF-1R antibody A12 and ionizing radiation in upper respiratory tract cancers
AU - Riesterer, Oliver
AU - Yang, Qiuan
AU - Raju, Uma
AU - Torres, Mylin
AU - Molkentine, David
AU - Patel, Nalini
AU - Valdecanas, David
AU - Milas, Luka
AU - Ang, K. Kian
N1 - Funding Information:
Supported by P01 CA06294 ( K.K. Ang, L. Milas ); UICC American Cancer Society International Fellowship (O. Riesterer), University of Zurich, Switzerland , supplemented by the Stiftung für medizinische Forschung und Entwicklung, and the Emil Boral-Stiftung (O. Riesterer), and the Gilbert H. Fletcher Memorial Distinguished Chair (K.K. Ang).
PY - 2011/3/15
Y1 - 2011/3/15
N2 - Purpose: 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 and Materials: 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.
AB - Purpose: 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 and Materials: 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.
KW - A12
KW - Head-and-neck cancer
KW - Insulin-like growth factor receptor 1
KW - Lung cancer
KW - Radiation
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U2 - 10.1016/j.ijrobp.2010.10.003
DO - 10.1016/j.ijrobp.2010.10.003
M3 - Article
C2 - 21129859
AN - SCOPUS:79951943282
SN - 0360-3016
VL - 79
SP - 1179
EP - 1187
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 4
ER -