title: PET imaging of early response to the tyrosine kinase inhibitor ZD4190.
abstract: OBJECTIVE
  We evaluated noninvasive positron emission tomography (PET) imaging for monitoring tumor response to the VEGFR-2 tyrosine kinase (TK) inhibitor ZD4190 during cancer therapy.
  
  
  METHODS
  Orthotopic MDA-MB-435 tumor-bearing mice were treated with ZD4190 (100 mg/kg orally per day for three consecutive days). Tumor growth was monitored by caliper measurement. During the therapeutic period, longitudinal PET scans were acquired using (18)F-FDG, (18)F-FLT and (18)F-FPPRGD2 as imaging tracers to evaluate tumor glucose metabolism, tumor cell proliferation, and angiogenesis, respectively. Imaging metrics were validated by immunohistochemical analysis of Ki67, GLUT-1, F4/80, CD31, murine integrin β3, and human integrin αvβ3.
  
  
  RESULTS
  Three consecutive daily oral administrations of 100 mg/kg of ZD4190 were effective in delaying MDA-MB-435 tumor growth. A significant difference in tumor volume was observed on day 7 between the treatment group and the control group (p < 0.01). After the final treatment, tumor growth resumed after a short delay. In the control tumors, (18)F-FPPRGD2 uptake was stable between days 0 and 7. In ZD4190-treated tumors, (18)F-FPPRGD2 uptake had decreased significantly relative to baseline by 26.74 ± 8.12% (p < 0.05) on day 1 and by 41.19 ± 6.63% (p < 0.01) on day 3, then had returned to baseline on day 7. Tumor uptake of (18)F-FLT had also decreased on both day 1 and day 3 after initiation of ZD4190 treatment. No significant change in (18)F-FDG uptake in ZD4190-treated tumors was observed, however, compared with the control group. All of the imaging findings were supported by ex vivo analysis of related biomarkers.
  
  
  CONCLUSIONS
  The longitudinal imaging results demonstrated the usefulness of quantitative (18)F-FLT and (18)F-FPPRGD2 PET imaging in evaluating the early antiproliferative and antiangiogenic effects of ZD4190. The quantification data from the PET imaging were consistent with the pattern of initial growth inhibition with treatment, followed by tumor relapse after treatment cessation.
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Haokao
authors.initials: H
authors.lastname: Gao
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Yan
authors.forename: Xilin
authors.initials: X
authors.lastname: Sun
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Qimeng
authors.initials: Q
authors.lastname: Quan
authors.forename: Lixin
authors.initials: L
authors.lastname: Lang
authors.forename: Dale
authors.initials: D
authors.lastname: Kiesewetter
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D011849:Radioactive Tracers; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D039302:Integrin alphaVbeta3; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011849:Radioactive Tracers; D014230:Triazoles; C405268:ZD 4190; D040301:Vascular Endothelial Growth Factor Receptor-2; D005947:Glucose