Abstract | PURPOSE: EXPERIMENTAL DESIGN: The radiosensitizing effect of CP-751,871 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced damage was evaluated by immunofluorescence analysis of the histone gamma-H2AX and Rad51. RESULTS: A clonogenic survival assay revealed that CP-751,871 increased the sensitivity of NSCLC cells to radiation in vitro. CP-751,871 inhibited radiation-induced IGF-IR signaling, and potentiated the radiation-induced increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of the histone gamma-H2AX and Rad51 also showed that CP-751,871 inhibited the repair of radiation-induced DNA double-strand breaks. Finally, combination therapy with CP-751,871 and radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone. CONCLUSIONS: These results show that CP-751,871 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of CP-751,871 is likely attributable to the inhibition of DNA repair and enhancement of apoptosis that result from attenuation of IGF-IR signaling. Combined treatment with CP-751,871 and radiation thus warrants further investigation in clinical trials as a potential anticancer strategy.
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Authors | Tsutomu Iwasa, Isamu Okamoto, Minoru Suzuki, Erina Hatashita, Yuki Yamada, Masahiro Fukuoka, Koji Ono, Kazuhiko Nakagawa |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 15
Issue 16
Pg. 5117-25
(Aug 15 2009)
ISSN: 1557-3265 [Electronic] United States |
PMID | 19671857
(Publication Type: Journal Article)
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Chemical References |
- Antibodies, Monoclonal
- Immunoglobulins, Intravenous
- Protein Kinase Inhibitors
- Radiation-Sensitizing Agents
- Insulin-Like Growth Factor I
- Receptor, IGF Type 1
- figitumumab
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Topics |
- Animals
- Antibodies, Monoclonal
(pharmacology, therapeutic use)
- Carcinoma, Non-Small-Cell Lung
(pathology, radiotherapy)
- Female
- Humans
- Immunoglobulins, Intravenous
- Insulin-Like Growth Factor I
(antagonists & inhibitors, metabolism)
- Lung Neoplasms
(pathology, radiotherapy)
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Protein Binding
(drug effects)
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- Radiation-Sensitizing Agents
(pharmacology, therapeutic use)
- Receptor, IGF Type 1
(antagonists & inhibitors, metabolism)
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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