Elsevier

Cancer Treatment Reviews

Volume 41, Issue 9, November 2015, Pages 777-783
Cancer Treatment Reviews

New Drugs
TAS-102, a novel antitumor agent: A review of the mechanism of action

https://doi.org/10.1016/j.ctrv.2015.06.001Get rights and content

Highlights

  • TAS-102 is an oral fluorothymidine agent for the treatment of cancer.

  • TAS-102 is a combination of the thymidine analog trifluridine (FTD) and tipiracil.

  • Tipiracil, a thymidine phosphorylase inhibitor, improves FTD bioavailability.

  • Compared with 5-fluorouracil (5-FU), TAS-102 has a distinct mechanism of action and metabolism.

  • TAS-102 has demonstrated efficacy in 5-FU-refractory cancers.

Abstract

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.

Introduction

Inhibition of nucleoside metabolism is an important concept in cancer therapy. Fluoropyrimidines, such as 5-fluorouracil (5-FU) and its derivatives, are uracil-based nucleic acid analogs that inhibit thymidylate synthase (TS), which is a key enzyme in DNA synthesis, and are also incorporated into nucleic acids, causing RNA damage [1], [2]. Antifolates, such as raltitrexed and pemetrexed, are another class of antimetabolites that act by inhibiting the TS pathway [2], [3], [4]. Agents that target nucleoside metabolism have been pivotal to the treatment of cancer for decades and are still the basis of chemotherapeutic treatment in multiple neoplasms, such as 5-FU for colon and breast cancer and pemetrexed for lung cancer, and a number of new antimetabolites are currently in development for clinical use [2], [5].

5-FU and its derivatives are commonly used in the treatment of metastatic colorectal cancer (mCRC) as well as other cancers, including breast cancer [2], [5]. However, additional agents are needed due to the development of secondary resistance [5]. TAS-102 is an oral combination drug consisting of trifluridine (FTD), which is a thymidine-based nucleoside analog, and tipiracil hydrochloride (TPI), which improves the bioavailability of FTD by inhibiting its catabolism by thymidine phosphorylase (TP) [6]. TAS-102 has been approved for the treatment of mCRC in Japan, and recently demonstrated positive results in overall and progression-free survival with a favorable safety profile in the global phase 3 RECOURSE trial, which was conducted in patients with mCRC refractory or intolerant to standard therapies [7]. This review describes and discusses the mechanism of action of TAS-102, particularly noting how this new drug demonstrates efficacy in patients with 5-FU-refractory cancers.

Section snippets

Thymidylate synthase pathway and DNA synthesis

TS plays a central role in the synthesis of DNA. The importance of the TS pathway in cancer is underscored by the overexpression of TS in many different human malignancies, including breast and colorectal cancers, and the association between TS overexpression and poor prognosis [8]. The TS enzyme catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) [2], [9]. The conversion of dUMP to dTMP depends on 5,10-methylenetetrahydrofolate (5,10-CH2-THF),

Mechanism of action of 5-FU and 5-FU derivatives

The anticancer activity of 5-FU requires intracellular conversion of 5-FU to the active metabolites fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP), and fluorouridine triphosphate (FUTP) [2], [5] (Fig. 1 and Table 1). FdUMP is a tight-binding inhibitor of TS, and TS inhibition by FdUMP requires the formation of an irreversible ternary complex with TS and the methyl-group donor 5,10-CH2-THF [2], [5], [10], [11]. The downstream effects of TS inhibition include

5-FU and FTD: pyrimidine-based nucleoside analogs

5-FU and FTD were first synthesized by Heidelberger et al. in 1957 and 1964, respectively [30], [31]. 5-FU is a uracil-based nucleic acid analog with fluorine replacing hydrogen at the C-5 position [1], [5], [30]. FTD is a thymidine-based nucleoside analog with a trifluoromethyl group (CF3) replacing the methyl group at the C-5 position [1], [31]. Although both agents have the potential to inhibit TS and be incorporated into nucleic acids, the main clinically relevant cytotoxic mechanism of

Mechanism of action of TAS-102

TAS-102 is an oral combination of an antineoplastic thymidine-based nucleoside analog (FTD, trifluridine) and a TP inhibitor (TPI, tipiracil hydrochloride) at a 1:0.5 M ratio [6], [32], [33]. The elimination half-life of FTD after intravenous administration to humans is very rapid (18 min), due to the rapid degradation of FTD to its major metabolite, 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione [34]. In monkeys, the plasma FTD level after oral administration alone was very low, suggesting

TAS-102: overcoming resistance to 5-FU-based agents

FTD and 5-FU appear to have different mechanisms for resistance. While a number of different molecular mechanisms have been shown to mediate 5-FU resistance, we will focus on the resistance mechanisms that have been investigated for TAS-102 in order to draw comparisons between the two drugs. The enzymes involved in nucleoside metabolism are an important determinant of resistance to fluoropyrimidines.

The main mechanism of 5-FU resistance in DLD-1/5-FU (CRC cells) was a significant decrease in

Preclinical studies of TAS-102 in combination with other anticancer agents

A number of preclinical studies have been performed to investigate the combination of TAS-102 with other drugs commonly used for the treatment of mCRC [68], [69], [70]. In studies using human CRC cell lines, FTD combined with oxaliplatin or SN-38, the active metabolite of irinotecan, demonstrated synergistic effects on growth inhibition [68], [69], [71]. The tumor growth-inhibitory activity of TAS-102 in combination with oxaliplatin was significantly greater than that of either agent as

Pharmacokinetic data with TAS-102

Based on the preclinical findings above, initial dose-finding phase 1 studies employed daily dosing of TAS-102 in order to facilitate FTD incorporation into tumor cells. The results of these initial clinical studies indicated that TAS-102 was better tolerated when administered for 5 consecutive days rather than 14 consecutive days, and the dose regimen of 5 days a week with 2 days rest for 2 weeks, repeated every 4 weeks, was determined to be the optimal dose regimen [74], [75], [76], [77]. A phase

Efficacy and safety data with TAS-102

TAS-102 had been investigated in a number of phase 1 studies in patients with solid tumors [33], [74], [75], [76], [77]. In a phase 1 dose escalation study conducted in Japanese patients with solid tumors (N = 21; n = 18 CRC), TAS-102 at 30, 40, 50, 60, or 70 mg/m2 per day was given twice daily on days 1–5 and 8–12 in a 28-day cycle; median treatment duration was 68 days [76]. All patients with mCRC were refractory to 5-FU, irinotecan, and oxaliplatin; three patients with mCRC were refractory to

Toxicity considerations with TAS-102 compared with other 5-FU-based agents

The toxicity profile of TAS-102 differs from the known toxicity profiles of 5-FU and its derivatives. The incidence of 5-FU-associated AEs such as stomatitis, hand-foot syndrome, or cardiac toxicity is rather low with TAS-102 [7]. In addition, TAS-102, unlike 5-FU, can be administered in patients with a DPD deficiency. In contrast to 5-FU, FTD does not appear to be metabolized by DPD in humans; instead, TP is the primary enzyme involved in the catabolism of FTD [5], [23], [24], [34]. Therefore,

Conclusions

TAS-102 is a promising oral fluorothymidine agent for the treatment of mCRC. It has a unique mechanism of action compared with the 5-FU-based fluoropyrimidines currently used in anticancer treatments. The intracellular metabolic pathway for FTD, the trifluorothymidine component of TAS-102, is distinct from that of 5-FU and the oral 5-FU prodrugs S-1 and capecitabine. The second component, TPI, enhances the bioavailability of FTD by inhibiting its degradation by TP and may be beneficial in

Conflict of interest

Heinz-Josef Lenz has reported clinical trial support from Taiho. Sebastian Stintzing and Fotios Loupakis have reported no conflicts of interest.

Acknowledgements

The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication. All authors contributed to the research, writing, and reviewing of all drafts of this manuscript. All authors approved the final draft. Editorial support in the preparation of this publication was provided by Phase Five Communications, supported by Taiho Oncology Inc.

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