Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models

Tanaka,Nozomu; Sakamoto,Kazuki; Okabe,Hiroyuki; Fujioka,Akio; Yamamura,Keisuke; Nakagawa,Fumio; Nagase,Hideki; Yokogawa,Tatsushi; Oguchi,Kei; Ishida,Keiji; Osada,Akiko; Kazuno,Hiromi; Yamada,Yukari; Matsuo,Kenichi

doi:10.3892/or.2014.3487

December-2014 Volume 32 Issue 6

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December-2014 Volume 32 Issue 6

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Article Open Access

Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models

Authors:
- Nozomu Tanaka
- Kazuki Sakamoto
- Hiroyuki Okabe
- Akio Fujioka
- Keisuke Yamamura
- Fumio Nakagawa
- Hideki Nagase
- Tatsushi Yokogawa
- Kei Oguchi
- Keiji Ishida
- Akiko Osada
- Hiromi Kazuno
- Yukari Yamada
- Kenichi Matsuo
View Affiliations / Copyright

Affiliations: Taiho Pharmaceutical Co., Ltd., Tsukuba Research Center, Tsukuba, Ibaraki 300-2611, Japan, Taiho Pharmaceutical Co., Ltd., Tokushima Research Center, Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan

Copyright: © Tanaka et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].
Pages: 2319-2326
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Published online on: September 17, 2014

https://doi.org/10.3892/or.2014.3487
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Abstract

TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models

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