Oncotarget

Research Papers:

Trifluridine/tipiracil overcomes the resistance of human gastric 5-fluorouracil-refractory cells with high thymidylate synthase expression

Kazuaki Matsuoka _, Fumio Nakagawa, Takashi Kobunai and Teiji Takechi

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Oncotarget. 2018; 9:13438-13450. https://doi.org/10.18632/oncotarget.24412

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Abstract

Kazuaki Matsuoka1, Fumio Nakagawa2, Takashi Kobunai1 and Teiji Takechi1

1Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan

2Applied Pharmacology Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan

Correspondence to:

Kazuaki Matsuoka, email: kazu-matsuoka@taiho.co.jp

Keywords: trifluridine/tipiracil; TAS-102; 5-FU resistant cells; gastric cancer

Received: June 17, 2016     Accepted: January 30, 2018     Published: February 05, 2018

ABSTRACT

Trifluridine/tipiracil (FTD/TPI or TFTD, also known as TAS-102) is a combination of the antineoplastic thymidine analog, FTD, and thymidine phosphorylase inhibitor, TPI (molar ratio 1:0.5). FTD/TPI was approved in Japan, the United States, and the European Union for the treatment of unresectable advanced or recurrent colorectal cancer. We evaluated the in vitro and in vivo efficacy and mechanisms of action of FTD and FTD/TPI against 5-fluorouracil (5-FU)-resistant MKN45/5FU, MKN74/5FU, and KATOIII/5FU human gastric cancer cells overexpressing thymidylate synthase (TS) and their respective parent cell lines. MKN45/5FU and KATOIII/5FU cells were not cross-resistant to FTD, whereas MKN45/5FU cells were 3.7-fold more resistant than the parental cells in vitro. FTD was also incorporated into genomic DNA in a concentration-dependent manner in 5-FU-resistant and parental cells. Additionally, deoxyuridine monophosphate levels in MKN45/5FU cells after 24-h FTD treatment were 3.0-fold higher than those in parental cells, and FTD treatment for 72 h induced G2/M arrest in MKN45/5FU cells, unlike the S phase arrest in MKN45 cells. Thus, TS-overexpressing MKN45/5FU cells, but not MKN74/5FU and KATOIII/5FU cells, showed partial cross-resistance to FTD. However, FTD/TPI (administered orally twice a day) exhibited antitumor activity to the same extent in MKN45 and MKN45/5FU xenograft mouse models, overcoming in vitro cross-resistance to FTD. DNA incorporation rather than TS inhibition seems to be the main action of FTD under these in vivo conditions. Thus, FTD/TPI is a promising chemotherapeutic agent against gastric cancers recurring following 5-FU therapy.


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