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Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil

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Abstract

Purpose

Trifluridine (FTD) is the active component of the nucleoside chemotherapeutic drug trifluridine/tipiracil (FTD/TPI), which is approved worldwide for the treatment of patients with metastatic gastrointestinal cancer. FTD exerts cytotoxic effects via its incorporation into DNA, but FTD has not been detected in the tumor specimens of patients. The purpose of this study was to detect FTD in tumors resected from metastatic colorectal cancer (mCRC) patients who were administered FTD/TPI. Another purpose was to investigate the turnover rate of FTD in tumors and bone marrow in a mouse model.

Methods

Tumors and normal tissue specimens were obtained from mCRC patients who were administered FTD/TPI or placebo at Kyushu University Hospital. Tumors and bone marrow were resected from mice with peritoneal dissemination treated with FTD/TPI. To detect and quantitate FTD incorporated into DNA, immunohistochemical staining of paraffin-embedded specimens (IHC-p staining) and slot-blot analysis of DNA purified from these tissues were performed using an anti-BrdU antibody. IHC-p staining of proliferation and apoptosis markers was also performed.

Results

FTD was detected in metastatic tumors obtained from mCRC patients who were administered FTD/TPI, but who had discontinued the treatment several weeks before surgery. In a peritoneal dissemination mouse model, FTD was still detected in tumors 13 days after the cessation of FTD/TPI treatment, but had disappeared from bone marrow within 6 days.

Conclusion

These results indicate that FTD persists longer in tumors than in bone marrow, which may cause a sustained antitumor effect with tolerable hematotoxicity.

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Abbreviations

BrdU:

Bromodeoxyuridine

FTD:

Trifluridine

FTD/TPI:

Trifluridine/tipiracil

IHC-p staining:

Immunohistochemical staining of paraffin-embedded tumor tissue

mCRC:

Metastatic colorectal cancer

PBMCs:

Peripheral blood mononuclear cells

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Acknowledgements

We thank Ms. Masako Kosugi and Atsuko Yamaguchi for their expert technical assistance, and Ms. Yuko Kubota and Miki Nakashima for their help with the immunohistochemical staining of clinical specimens. We also thank H. Nikki March, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yoshiaki Fujimoto, Ryota Nakanishi, Koji Ando, Eiji Oki, Yoshihiko Maehara & Masaki Mori

  2. Translational Research Laboratory, Taiho Pharmaceutical Co. Ltd., Tokushima, Japan

    Mamoru Nukatsuka, Kazuaki Matsuoka & Takeshi Wakasa

  3. Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

    Takeshi Wakasa & Hiroyuki Kitao

  4. Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan

    Yoshihiko Maehara

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  1. Yoshiaki Fujimoto
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  2. Ryota Nakanishi
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Correspondence to Hiroyuki Kitao.

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Conflict of interest

M.N., K.M., and T.W. are employees of Taiho Pharmaceutical Co. Ltd.; H.K. is a staff member of the Joint Research Department funded by Taiho Pharmaceutical Co. Ltd. located in Kyushu University. Y.M. received research funds from Taiho Pharmaceutical Co. Ltd. Other authors declare no competing interests.

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Fujimoto, Y., Nakanishi, R., Nukatsuka, M. et al. Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil. Cancer Chemother Pharmacol 85, 1029–1038 (2020). https://doi.org/10.1007/s00280-020-04072-6

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