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


METHODS
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.
Iwasa
Tsutomu
T
Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
Okamoto
Isamu
I
Suzuki
Minoru
M
Hatashita
Erina
E
Yamada
Yuki
Y
Fukuoka
Masahiro
M
Ono
Koji
K
Nakagawa
Kazuhiko
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D016756:Immunoglobulins, Intravenous; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C525021:figitumumab