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Cancer Treat Rev. 2015 Nov;41(9):777-83. doi: 10.1016/j.ctrv.2015.06.001. Epub 2015 Jun 6.

TAS-102, a novel antitumor agent: a review of the mechanism of action.

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USC Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, NOR 3456, Los Angeles, CA 90089-9173, United States. Electronic address:
Department of Hematology and Oncology, University Hospital Grosshadern, University of Munich (LMU), Marchioninistrasse 15, 81377 Munich, Germany. Electronic address:
Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Via Taddeo Alderotti 26/N, 50139 Firenze, Italy. Electronic address:


Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5-FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.


5-Fluorouracil; Fluoropyrimidines; Mechanism of action; Metastatic colorectal cancer; TAS-102; Thymidylate synthase

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