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Inhibition of insulin-like growth factor 1 receptor by CP-751,871 radiosensitizes non-small cell lung cancer cells.

AbstractPURPOSE:
Therapeutic strategies that target the insulin-like growth factor I receptor (IGF-1R) hold promise for a wide variety of cancers. We have now investigated the effect of CP-751,871, a fully human monoclonal antibody specific for IGF-IR, on the sensitivity of human non-small cell lung cancer (NSCLC) cell lines to radiation.
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.
AuthorsTsutomu Iwasa, Isamu Okamoto, Minoru Suzuki, Erina Hatashita, Yuki Yamada, Masahiro Fukuoka, Koji Ono, Kazuhiko Nakagawa
JournalClinical 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
PMID19671857 (Publication Type: Journal Article)
Chemical References
  • Antibodies, Monoclonal
  • Immunoglobulins, Intravenous
  • Protein Kinase Inhibitors
  • Radiation-Sensitizing Agents
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • figitumumab
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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