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Pyrimidine analogues and fluoropyrimidinesIn useRational designNeeds review

Tegafur-gimeracil-oteracil (S-1)

Also known as S-1, TS-1, Teysuno

An oral combination of tegafur, which releases fluorouracil, with two modulators: one slows fluorouracil breakdown, one lessens gastrointestinal toxicity. Developed in Japan; the EU product is authorised for advanced gastric cancer and, in selected patients, metastatic colorectal cancer.

From discovery to approval

  1. 1991 · First described

    A 2009 review by its lead scientist dates the invention of S-1 to 1991, combining tegafur, gimeracil (CDHP, found 1984) and oteracil (potassium oxonate, found 1987) at 1:0.4:1; the same review says he had devised the combination before the project began in November 1990. The first journal description found is the 1996 Anti-Cancer Drugs paper.[2][1][3][4][5]

  2. 1992 · First use in people · 1 years after first description

    A 2009 review by the lead scientist lists the onset of phase I clinical trials of S-1 as November 1992 in its timeline table (preclinical studies from March 1991, phase II from March 1994).[2]

  3. 2011-03-14 · EMA regular · 20 years after first description

    Advanced gastric cancer when given in combination with cisplatin; metastatic colorectal cancer as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, in adults who cannot continue another fluoropyrimidine because of hand-foot syndrome or cardiovascular toxicity (indication wording from the EPAR product page, which prints 'Marketing authorisation issued 14/03/2011'; the page may list later extensions). The page mentions neither conditional approval nor exceptional circumstances, so the type regular is an inference.[6]

How it works

Tegafur releases fluorouracil. Gimeracil (CDHP) is a potent reversible inhibitor of fluorouracil degradation, raising fluorouracil levels in blood and tumour. Oteracil (potassium oxonate) inhibits fluorouracil phosphorylation, mainly in the gastrointestinal tract, reducing gastrointestinal toxicity.[1]

Where it came from and why

The 1996 abstract says tegafur was combined with CDHP to raise fluorouracil activity and with potassium oxonate to reduce gastrointestinal injury without losing antitumour effect, in rats. A 2009 review adds that the aim was to sustain fluorouracil levels like continuous infusion with fewer gastrointestinal toxicities.

Cancers

  • Gastric cancer

    The EU product is authorised for advanced gastric cancer given with cisplatin; a 2009 review lists Japanese approval for gastric cancer in January 1999, and a Japanese phase III trial reported in 2007 tested adjuvant S-1 after gastric cancer surgery.[6]

  • Colorectal cancer

    The EU product is authorised for metastatic colorectal cancer as monotherapy or with oxaliplatin or irinotecan, with or without bevacizumab, in patients who cannot continue another fluoropyrimidine because of hand-foot syndrome or cardiovascular toxicity.[6]

  • Other cancers in Japan

    A 2009 review lists later Japanese approvals for head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers between 2001 and 2007; no regulator document was read.[2]

Family and partners

Derived from: Tegafur

Worth knowing

  • The EU marketing authorisation for Teysuno (tegafur, gimeracil, oteracil) was issued on 14 March 2011.[6]
  • A 2009 review by its developer says the new drug application for S-1 was filed in November 1997 and approval for gastric cancer in Japan came in January 1999 through priority review.[2]
  • The same review says the S-1 project was set up in November 1990 against internal views that fluorouracil was obsolete and that a three-component drug would be hard to approve.[2]
  • A 1998 Japanese-language report states that, at the minimum toxic dose in rats, S-1 had antitumour activity more than three times that of UFT against Yoshida sarcoma and Sato lung carcinoma.[3]
  • In a Japanese phase III trial reported in 2007, S-1 was tested as adjuvant chemotherapy for gastric cancer after surgery.[7]

References

  1. Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs. 1996;7(5):548-57. PubMedDOI
  2. Shirasaka T. Development history and concept of an oral anticancer agent S-1 (TS-1): its clinical usefulness and future vistas. Jpn J Clin Oncol. 2009;39(1):2-15. PubMedDOI
  3. Shirasaka T, Shimamoto Y, Kato T, Fukushima M. [Invention of a tumor-selective 5-fluorouracil derivative named S-1 by biochemical modulation of 5-fluorouracil]. Gan To Kagaku Ryoho. 1998;25(3):371-84. PubMed
  4. Maehara Y, Oki E, Ota M, Harimoto N, Ando K, Nakanishi R, et al. Lineage of drug discovery research on fluorinated pyrimidines: chronicle of the achievements accomplished by Professor Setsuro Fujii. Int J Clin Oncol. 2023;28(5):613-624. PubMedDOI
  5. Saif MW, Rosen LS, Saito K, Zergebel C, Ravage-Mass L, Mendelson DS. A phase I study evaluating the effect of CDHP as a component of S-1 on the pharmacokinetics of 5-fluorouracil. Anticancer Res. 2011;31(2):625-32. PubMed
  6. European Medicines Agency. Teysuno (tegafur, gimeracil, oteracil): European public assessment report, product page (marketing authorisation issued 14/03/2011). Page read 2026-10-26. Source
  7. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357(18):1810-20. PubMedDOI