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: Jing Gong, David J Yang, Saady Kohanim, Laura S Angelo, Razelle Kurzrock
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 8 Issue 23 Pg. 2239-47 (Dec 2009) ISSN: 1555-8576 [Electronic] United States
• PMID: 19823028 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Indium Radioisotopes
• Protein Kinase Inhibitors
• Quinazolines
• ethylene dicysteine
• Technetium
• EGFR protein, mouse
• ErbB Receptors
• Cysteine
• Gefitinib

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cysteine (analogs & derivatives, pharmacology)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Female
• Flow Cytometry
• Gefitinib
• Humans
• Immunoprecipitation
• Indium Radioisotopes
• Mice
• Mice, Nude
• Molecular Imaging
• Neoplasms, Glandular and Epithelial (diagnostic imaging, drug therapy, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Quinazolines (pharmacology)
• Radionuclide Imaging
• Technetium (pharmacology)
• Tissue Distribution (drug effects)
• Xenograft Model Antitumor Assays