title: Molecular imaging of gefitinib activity in an epidermal growth factor receptor (EGFR)-bearing xenograft model.
abstract: Finding noninvasive methods to discern which patients' tumors bear a specific target molecule, and are presumably more likely to respond, remains a critical challenge. An anti-phospho-tyrosine antibody was labeled with indium ((111)In) using ethylenedicysteine (EC) as a chelator ((111)In-EC-P-Tyr). We hypothesized that tumor phosphokinase activity would be discernible by imaging with (111)In-EC-P-Tyr. A xenograft of A431 cells, a human epithelial carcinoma cell line overexpressing epidermal growth factor receptor (EGFR), was employed. Biodistribution studies confirmed increased tumor/muscle ratios of (111)In-EC-P-Tyr in the A431 model. Imaging demonstrated that a marked decrease in tumor uptake of (111)In-EC-P-Tyr occurred after 3 d of gefitinib therapy in A431 cells (gefitinib-sensitive), but not in H441 cells (gefitinib-resistant). Our results indicate that (111)In-EC-P-Tyr can detect tumor phospho-tyrosine kinase activity in animal models. This type of agent merits investigation in the clinic to determine if it can predict patient responses to kinase inhibitors based on phosphokinase imaging.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.forename: David J
authors.initials: DJ
authors.lastname: Yang
authors.forename: Saady
authors.initials: S
authors.lastname: Kohanim
authors.forename: Laura S
authors.initials: LS
authors.lastname: Angelo
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D047468:Immunoprecipitation; D007205:Indium Radioisotopes; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging; D009375:Neoplasms, Glandular and Epithelial / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D011877:Radionuclide Imaging; D013667:Technetium / Q000494:pharmacology; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D007205:Indium Radioisotopes; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C109063:ethylene dicysteine; D013667:Technetium; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D003545:Cysteine; D000077156:Gefitinib