title: Early assessment of tumor response to gefitinib treatment by noninvasive optical imaging of tumor vascular endothelial growth factor expression in animal models.
abstract: Epidermal growth factor receptor (EGFR) expression is upregulated in many types of tumors, and the EGFR tyrosine kinase inhibitor gefitinib has high potential as an anticancer drug. However, accumulating clinical evidence has indicated that only a subset of patients benefit from gefitinib treatment. This study aimed to determine whether optical imaging of vascular endothelial growth factor (VEGF) expression can be an early biomarker for tumor response to gefitinib therapy.
  
  
  METHODS
  A VEGF-targeting fluorescent probe Dye-BevF(ab')2 was prepared and tested in vivo. Longitudinal optical imaging studies using Dye-BevF(ab')2 were performed in both 22B (gefitinib-resistant) and A549 (gefitinib-responsive) tumor models at different times (days 0, 2, and 5) before and after gefitinib treatment. The imaging results were validated by ex vivo immunofluorescence staining and enzyme-linked immunosorbent assay.
  
  
  RESULTS
  Dye-BevF(ab')2 exhibited high specificity for VEGF in vivo. There was no significant change in the Dye-BevF(ab')2 uptake in gefitinib-treated 22B tumors, compared with the control group. In contrast, the A549 tumor uptake of Dye-BevF(ab')2 in the gefitinib-treated group was significantly lower on days 2 and 5 than that in the control group and at the baseline. An in vivo gefitinib treatment study confirmed that 22B tumors were gefitinib-resistant, whereas A549 tumors were gefitinib-responsive. Immunofluorescence staining and enzyme-linked immunosorbent assay confirmed that changes in the Dye-BevF(ab')2 uptake were correlated with VEGF expression levels in tumors.
  
  
  CONCLUSIONS
  Optical imaging of VEGF expression with Dye-BevF(ab')2 can be used for the early assessment of tumor response to gefitinib therapy. This approach may also be valuable for preclinical high-throughput screening of novel antiangiogenic drugs.
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing, China.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
authors.forename: Xianlei
authors.initials: X
authors.lastname: Sun
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Huiyun
authors.initials: H
authors.lastname: Zhao
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000077156:Gefitinib; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D057054:Molecular Imaging; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D055095:Optics and Photonics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D019394:Ki-67 Antigen; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; D000077156:Gefitinib
keywords: EGFR; VEGF; angiogenesis; molecular imaging; therapy response