**3. Trifluridine/tipiracil hydrochloride**

TAS-102 is a new oral anti-metabolite drug, a 1:0.5 mixture of a thymidine-based nucleoside analog, alpha,alpha,alpha-trifluorothymidine (trifluridine: FTD), and thymidine phosphorylase inhibitor (tipiracil hydrochloride: TPI) [20–23]. FTD inhibits thymidylate synthase (TS), the key enzyme involved in DNA synthesis, whereas trifluridine incorporates into DNA via phosphorylation and initiates DNA fragmentation [20–22]. TPI enhances the exposure to FTD, improves its bioavailability, and increases the durability of response to this agent [24, 25]. Pre-exposure to 5-FU was shown to enhance FTD incorporation into DNA and to increase antitumor activity of this agent, as shown by lesser viability and proliferation of cancer cells [26]. TAS-102 proved to be effective in GI malignancies with inherent or acquired resistance to 5-FU, as well as in 5-FU-sensitive tumors [20, 21]. TAS-102 has recently been approved as the third-line treatment for adults with refractory metastatic colorectal cancer, patients with contraindications to currently available standard chemotherapy and biological therapy in the EU and USA, and individuals with unresectable advanced or recurrent colorectal cancer in Japan. The standard regimen is 35 mg/m2 twice a day on days 1–5 and 8–12 of each 28-day cycle [24, 27].
