PET imaging of early response to the tyrosine kinase inhibitor ZD4190
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We evaluated noninvasive positron emission tomography (PET) imaging for monitoring tumor response to the VEGFR-2 tyrosine kinase (TK) inhibitor ZD4190 during cancer therapy.
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 18F-FDG, 18F-FLT and 18F-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.
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, 18F-FPPRGD2 uptake was stable between days 0 and 7. In ZD4190-treated tumors, 18F-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 18F-FLT had also decreased on both day 1 and day 3 after initiation of ZD4190 treatment. No significant change in 18F-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.
The longitudinal imaging results demonstrated the usefulness of quantitative 18F-FLT and 18F-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.
KeywordsPositron emission tomography (PET) Antiangiogenic treatment 18F-FDG 18F-FLT 18F-FPPRGD2 Integrin Therapy response Tyrosine kinase inhibitor
This project was supported by the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), and the International Cooperative Program of the National Science Foundation of China (NSFC) (81028009). M.Y. is partly supported by the Outstanding Professionals Foundation of the Jiangsu Health Bureau (grant no. RC2007096). G.N. is currently an Imaging Sciences Training Program (ISTP) Fellow jointly supported by the Radiology and Imaging Sciences Department, NIH Clinical Center and the IRP/NIBIB, NIH. We acknowledge the NIH/CC cyclotron facility for isotope production and Dr. Henry S. Eden for proofreading the manuscript.
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