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Research ArticleBasic Science Investigations

Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy

Liquan Gao, Hao Liu, Xianlei Sun, Duo Gao, Chenran Zhang, Bing Jia, Zhaohui Zhu, Fan Wang and Zhaofei Liu
Journal of Nuclear Medicine February 2016, 57 (2) 321-326; DOI: https://doi.org/10.2967/jnumed.115.158881
Liquan Gao
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Hao Liu
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Xianlei Sun
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Duo Gao
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Chenran Zhang
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Bing Jia
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Zhaohui Zhu
2Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, China; and
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Fan Wang
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
3Interdisciplinary Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
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Zhaofei Liu
1Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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  • FIGURE 1.
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    FIGURE 1.

    Dasatinib had no effect on A549-fLuc tumor growth inhibition. (A) Tumor growth curves of A549-fLuc tumor–bearing mice administered vehicle control or dasatinib daily for 6 d (n = 7/group). Inset, schedule of dasatinib treatment and molecular imaging experiments. (B) Representative bioluminescence images and tumor BLI signal intensity changes from baseline to after treatment in the A549-fLuc tumor–bearing mice (n = 7/group). Arrows indicate location of tumors.

  • FIGURE 2.
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    FIGURE 2.

    18F-FDG PET imaging revealed comparable tumor cell metabolism in A549-fLuc tumors with or without dasatinib treatment. (A) Representative small-animal PET images and relative tumor 18F-FDG uptake (posttreatment/baseline ratios) in A549-fLuc tumor–bearing mice (n = 5/group). Arrows indicate location of tumors. (B) Quantified GLUT-1 fluorescence intensity and quantified percentage of Ki-67–positive cells of the A549-fLuc tumor tissues with or without dasatinib treatment.

  • FIGURE 3.
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    FIGURE 3.

    99mTc-3PRGD2 SPECT/CT imaging revealed decreased murine integrin β3 expression and inactivated integrin αvβ3 after dasatinib treatment. (A and B) Representative small-animal SPECT/CT images (A) and relative tumor 99mTc-3PRGD2 uptake (posttreatment/baseline ratios; B) in A549-fLuc tumor–bearing mice (n = 5/group). Arrows indicate location of tumors. (C) Quantified human integrin αvβ3 fluorescence intensity and quantified density of murine integrin β3–positive vessels in dasatinib-treated and control A549-fLuc tumor tissues. (D) 125I-c(RGDyK) radioligand binding assay in dasatinib-treated and control A549-fLuc tumor cells. *P < 0.05. ***P < 0.001.

  • FIGURE 4.
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    FIGURE 4.

    NIRF imaging using Dye755-Ran revealed antiangiogenic effects of dasatinib. (A) Representative NIRF images and relative tumor Dye755-Ran uptake (posttreatment/baseline ratios) in A549-fLuc tumor–bearing mice (n = 7/group). Arrows indicate location of tumors. (B) Quantified human VEGF fluorescence intensity in dasatinib-treated and control A549-fLuc tumor tissues. (C) Representative Matrigel plugs harvested from nude mice after 7 d of inoculation. Control (−) = Matrigel only; control (+) = Matrigel mixed with dimethyl sulfoxide (vehicle control) and growth factors; dasatinib = Matrigel mixed with dasatinib and growth factors. *P < 0.05. **P < 0.01.

  • FIGURE 5.
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    FIGURE 5.

    Significant improvements were observed in in vivo antitumor effects when combining dasatinib and DTX. (A) Tumor growth curves of A549-fLuc tumor–bearing mice that received daily administration of vehicle control, dasatinib, DTX, or dasatinib plus DTX (Das + DTX) for 6 d (n = 7/group). Inset, schedule of combination treatment and molecular imaging experiments. (B) Immunofluorescence staining of Ki-67 and quantified percentage of Ki-67–positive cells in A549-fLuc tumor tissues harvested from mice treated with vehicle (control), dasatinib (Das), DTX, and dasatinib plus DTX (Das + DTX) daily for 6 d. (C) Quantified tumor uptake (percentage injected dose per gram) of 18F-FDG, tumor-to-muscle ratios of 99mTc-3PRGD2, and tumor fluorescence intensity (radiance efficacy) of Dye755-Ran in A549-fLuc tumor–bearing nude mice with or without dasatinib plus docetaxel (Das + DTX) treatment for 6 d (n = 5/group). *P < 0.05. **P < 0.01. ***P < 0.001.

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Journal of Nuclear Medicine: 57 (2)
Journal of Nuclear Medicine
Vol. 57, Issue 2
February 1, 2016
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Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy
Liquan Gao, Hao Liu, Xianlei Sun, Duo Gao, Chenran Zhang, Bing Jia, Zhaohui Zhu, Fan Wang, Zhaofei Liu
Journal of Nuclear Medicine Feb 2016, 57 (2) 321-326; DOI: 10.2967/jnumed.115.158881

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Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy
Liquan Gao, Hao Liu, Xianlei Sun, Duo Gao, Chenran Zhang, Bing Jia, Zhaohui Zhu, Fan Wang, Zhaofei Liu
Journal of Nuclear Medicine Feb 2016, 57 (2) 321-326; DOI: 10.2967/jnumed.115.158881
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Keywords

  • Image-guided therapy
  • angiogenesis
  • Tumor Response
  • Dasatinib
  • Src family of kinases
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