Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas

Abstract

Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999-2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. 'S-1 and low-dose cisplatin therapy' without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, 'alternate-day S-1 regimen' may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. < or =Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1.

Figures

Figure 1.

Metabolic pathways of pyrimidine nucleotides and 5-FU. Main sites of action of 5-FU. 5-FU, 5-fluorouracil; FdUMP, 5-fluoro-2′- deoxyuridine 5′-monophosphate; F-β-Ala, alpha-fluoro-beta-alanine.

Figure 2.

Biological actions of Ura, CDHP and Oxo on the metabolic pathways of 5-FU, as well as the conversion of FT to 5-FU. FT, futraful; CDHP, 5-chloro-2,4-dihydroxypyridine; Oxo, potassium oxonate.

Figure 3.

Potent inhibitory activity of CDHP that is translated into increased plasma 5-FU concentrations after oral administration of FT and CDHP to rats as compared with FT and Ura (UFT) (19,39).

Figure 4.

14C-oxonic acid concentrations in blood and tissues of Yoshida sarcoma-bearing rats after oral administration of 14C-Oxo (potassium oxonate) (18).

Figure 5.

Antitumor activity of S-1 and UFT in Yoshida sarcoma-bearing rats (19,37). T/C, treatment/control; UFT, FU and uracil.

Figure 6.

5-FU concentrations in plasma of and tumor in Yoshida sarcoma-bearing rats after oral administration of S-1 (19,37).

Figure 7.

Plasma 5-FU concentrations in cancer patients after oral administration of S-1. Bold lines represent three patients who underwent total gastrectomy (40).

Figure 8.

Reductions in total daily doses of FT in an attempt to establish patient-friendly formulations.

Figure 9.

Incidences of hand–foot syndrome (HFS) in patients during treatment with different fluoropyrimidines. (A) Patients treated by continuous infusion of 5-FU or capecitabine are at significantly higher risk of developing all grades of HFS as compared with patients on bolus 5-FU or combination therapy containing a DPD inhibitor (UFT, S-1, or 5-FU/eniluracil). (B) Grade 3 or 4 symptoms were extremely rare in patients who received UFT, S-1, or 5-FU/eniluracil (36).