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Antiapoptotic Activity Is Dispensable for Insulin-like Growth Factor I Receptor-mediated Clonogenic Radioresistance after -Irradiation¹

Molecular Diagnosis and Therapeutics [M. T., D. Y., W. A., M. M.] and Oral and Maxillofacial Radiology [H. W., S. N., T. S.], Department of Oral Restitution, and Diagnostic Radiology and Oncology, Department of Head and Neck Reconstruction [M. T., D. Y., W. A., H. S.], Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Purpose: The purpose of this study was to evaluate the relationship between apoptotic activity and clonogenic radiosensitivity in vitro using an insulin-like growth factor I receptor (IGF-IR) signaling model, which is known to exert tumorigenic and antiapoptotic effects.

Experimental Design: We used mouse embryo fibroblast cell lines expressing either human IGF-IR [R+(Wt) and R+] or the marker gene alone [R-(puro)]; these cell lines were derived from R- cells, which are deficient in IGF-IR. After -irradiation, apoptotic activity was determined by the presence of DNA fragmentation and caspase-3-, -8-, and -9-like activities. Clonogenic radiosensitivity was determined by a colony-forming assay.

Results: R+(Wt) and R+ cells expressed similar levels of IGF-IR, transducing phosphorylation signals to major downstream substrates on insulin-like growth factor I stimulation. R+ cells were resistant to the induction of apoptosis after -irradiation; however, both R+(Wt) and R-(puro) cells demonstrated significant DNA fragmentation and increase in caspase-3-, -8-, and -9-like activities. Both R+(Wt) and R+ cells were radioresistant (to a similar extent) compared with R-(puro) cells as measured by a colony-forming assay. Clonogenic radioresistance was not influenced by the inhibition of Akt/protein kinase B through treatment with wortmannin at low concentrations specifically inhibiting phosphatidylinositol 3'-kinase.

Conclusions: Our findings indicate that apoptotic activity does not necessarily predict clonogenic survival after exposure to ionizing radiation. This study provides clinical implications in the evaluation of apoptotic activities observed during the course of radiotherapy to predict accurate tumor response or local control.

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