title: In vivo analysis of insulin-like growth factor type 1 receptor humanized monoclonal antibody MK-0646 and small molecule kinase inhibitor OSI-906 in colorectal cancer.
abstract: The development and characterization of effective anticancer drugs against colorectal cancer (CRC) is of urgent need since it is the second most common cause of cancer death. The study was designed to evaluate the effects of two IGF-1R antagonists, MK-0646, a recombinant fully humanized monoclonal antibody and OSI-906, a small molecule tyrosine kinase inhibitor on CRC cells. Xenograft study was performed on IGF-1R-dependent CRC cell lines for analyzing the antitumor activity of MK-0646 and OSI-906. Tumor proliferation and apoptosis were assessed using Ki67 and TUNEL assays, respectively. We also performed in vitro characterization of MK-0646 and OSI-906 treatment on CRC cells to identify mechanisms associated with drug-induced cell death. Exposure of the GEO and CBS tumor xenografts to MK-0646 or OSI-906 led to a decrease in tumor growth. TUNEL analysis showed an increase of approximately 45-55% in apoptotic cells in both MK-0646 and OSI-906 treated tumor samples. We report the novel finding that treatment with IGF-1R antagonists led to downregulation of X-linked inhibitor of apoptosis (XIAP) protein involved in cell survival and inhibition of cell death. In conclusion, IGF-1R antagonists (MK-0646 and OSI-906) demonstrated single agent inhibition of subcutaneous CRC xenograft growth. This was coupled to pro-apoptotic effects resulting in downregulation of XIAP and inhibition of cell survival. We report a novel mechanism by which MK-0646 and OSI-906 elicits cell death in vivo and in vitro. Moreover, these results indicate that MK-0646 and OSI-906 may be potential anticancer candidates for the treatment of patients with IGF-1R-dependent CRC.
authors.affiliation: Eppley Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA.
authors.forename: Premila D
authors.initials: PD
authors.lastname: Leiphrakpam
authors.forename: Ekta
authors.initials: E
authors.lastname: Agarwal
authors.forename: Michelle
authors.initials: M
authors.lastname: Mathiesen
authors.forename: Katie L
authors.initials: KL
authors.lastname: Haferbier
authors.forename: Michael G
authors.initials: MG
authors.lastname: Brattain
authors.forename: Sanjib
authors.initials: S
authors.lastname: Chowdhury
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011719:Pyrazines / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007093:Imidazoles; D011719:Pyrazines; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C569480:dalotuzumab; D017526:Receptor, IGF Type 1