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Monitoring Tumor Response after Liposomal Doxorubicin in Combination with Liposomal Vinorelbine Treatment Using 3′-Deoxy-3′-[18F]Fluorothymidine PET

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Abstract

Purpose

Surgical resection is the standard treatment for localized colorectal cancer, which is the most common type of gastrointestinal cancer. However, over 40 % cases are diagnosed metastasized and apparently inoperable. Systemic chemotherapy provides an alternative to these patients. This study aims to evaluate the therapeutic potential of liposomal doxorubicin (lipoDox) in combination with liposomal vinorelbine (lipoVNB) in a CT-26 colon carcinoma-bearing mouse model.

Procedures

The in vitro cytotoxicity of Dox and VNB on CT-26 cancer cells was determined by MTT and colony formation assays. Mice were subcutaneously inoculated with 2 × 105 of CT-26 cells in the right hind flank. When tumor size reached 200 ± 50 mm3, mice were assigned to receive different treatment protocols. The pharmacokinetics, micro single-photon emission computed tomography/x-ray computed tomography imaging, biodistribution, and immunohistochemical staining studies were performed to survey the therapeutic efficacy of each regimen.

Results

Based on the results of pharmacokinetic study, co-administration of lipoDox and lipoVNB did not affect their individual systemic distribution, while lipoDox retained longer in blood than lipoVNB did. Superior tumor growth retardation was observed in the group received lipoDox plus lipoVNB administration (1 mg/kg each, namely D1V1) than those injected with lipoDox plus VNB (1 mg/kg each, namely D1fV1). No severe side effects were detected in each group. The tumor-to-muscle ratio (T/M) derived from 3′-dexoy-3′-[18F]fluorothymidine ([18F]FLT) micro positron emission tomography (PET) images of D1V1- and D1fV1-treated mice and the controls on day 7 was 6.88 ± 0.54, 7.50 ± 0.84, and 9.87 ± 0.73, respectively, suggesting that D1V1 is a more efficacious regimen against CT-26 xenografts. The results of proliferating cell nuclear antigen (PCNA) immunohistochemical staining were consistent with those findings obtained from [18F]FLT microPET imaging.

Conclusion

This study demonstrated that lipoDox in combination with lipoVNB was more efficacious than clinically used regimen, lipoDox plus VNB, in the treatment of colon carcinoma and [18F]FLT-PET is a promising approach in monitoring the treatment outcome at early stage.

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Acknowledgments

The authors thank the financial support from Cheng Hsin General Hospital, Taiwan (CY10401); Department of Health, Taipei City Government, Taiwan (10301-62-010); and China Medical University, Taichung, Taiwan (CMU-104-N-08). The authors also appreciate the technical support from the Molecular and Genetic Imaging Core, Taiwan Mouse Clinic, which is funded by the National Research Program for Biopharmaceuticals (NRPB) at the Ministry of Science and Technology (MOST) of Taiwan.

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Authors and Affiliations

  1. Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan

    Chun-Yi Wu

  2. Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan

    Jo-Hsin Tang, Pei-Chia Chan, Jia-Je Li, Ren-Shyan Liu & Hsin-Ell Wang

  3. Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan

    Pei-Chia Chan, Jia-Je Li & Hsin-Ell Wang

  4. Department of Nuclear Medicine, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan

    Ming-Hsien Lin

  5. Department of Nuclear Medicine, Cheng Hsin General Hospital, Taipei, Taiwan

    Chih-Chieh Shen

  6. Department of Nuclear Medicine and National PET/Cyclotron Center, Taipei Veterans General Hospital, Taipei, Taiwan

    Ren-Shyan Liu

  7. Taiwan Mouse Clinic, National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan

    Ren-Shyan Liu

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  1. Chun-Yi Wu
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Correspondence to Chih-Chieh Shen or Hsin-Ell Wang.

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Wu, CY., Tang, JH., Chan, PC. et al. Monitoring Tumor Response after Liposomal Doxorubicin in Combination with Liposomal Vinorelbine Treatment Using 3′-Deoxy-3′-[18F]Fluorothymidine PET. Mol Imaging Biol 19, 408–420 (2017). https://doi.org/10.1007/s11307-016-1005-2

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