Tegafur-uracil (UFT)

From discovery to approval

1. c. 1978 · Earliest report found

   A 1998 review says UFT was designed in 1978 by adding uracil to ftorafur; a 2009 review dates its invention by Fujii and colleagues to 1976. Two 1979 papers from the Japanese group describe uracil raising fluorouracil levels in tumours and slowing fluorouracil breakdown, with an optimal uracil to tegafur molar ratio of 4.^{[2][3][4][5][6]}

2. No approval is recorded on this site.

How it works

Tegafur releases fluorouracil in the body. Uracil is a moderate inhibitor of dihydropyrimidine dehydrogenase, the enzyme that breaks fluorouracil down, according to a 2013 review by the developer's scientists, so more fluorouracil stays available.^[1]

Where it came from and why

A 2009 review explains that plasma fluorouracil after oral tegafur was lower than with continuous infusion, so uracil, an inhibitor of fluorouracil degradation, was combined with it. The 1979 rat study found the best tumour to blood fluorouracil ratio at a uracil to tegafur ratio of 4.

Cancers

• Colorectal cancer

  Two large randomised trials, reviewed in 2001, compared oral tegafur-uracil plus calcium folinate with intravenous fluorouracil plus folinic acid in metastatic colorectal cancer.^[7]

Family and partners

Derived from: Tegafur

Worth knowing

• A 2001 review reports that in two trials in metastatic colorectal cancer (816 and 380 patients), oral tegafur-uracil with calcium folinate and intravenous fluorouracil with folinic acid had a median survival of about 12 months in both, with no significant difference in response rates.^[7]
• A 2001 review says UFT first entered phase I trials in Japan over 20 years earlier, and was approved for colorectal cancer in many European countries but not the US.^[8]
• A 2013 review by the developer's scientists says UFT has indications such as colorectal, non-small-cell lung, breast, gastric and liver cancers and is widely used in Japan, and that it is also used in Asia and the EU with limited indications.^[1]
• A 1979 in vitro study found that uracil inhibited fluorouracil degradation much more than its phosphorylation.^[5]
• A 1998 review reports objective response rates of about 40% in colorectal cancer when UFT was given with oral leucovorin, and about 25% as a single agent or with lower leucovorin doses.^[2]

References

1. Utsugi T. New challenges and inspired answers for anticancer drug discovery and development. Jpn J Clin Oncol. 2013;43(10):945-53. PubMedDOI
2. Sulkes A, Benner SE, Canetta RM. Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer. J Clin Oncol. 1998;16(10):3461-75. PubMedDOI
3. 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
4. Fujii S, Kitano S, Ikenaka K, Shirasaka T. Effect of coadministration of uracil or cytosine on the anti-tumor activity of clinical doses of 1-(2-tetrahydrofuryl)-5-fluorouracil and level of 5-fluorouracil in rodents. Gan. 1979;70(2):209-14. PubMed
5. Ikenaka K, Shirasaka T, Kitano S, Fujii S. Effect of uracil on metabolism of 5-fluorouracil in vitro. Gan. 1979;70(3):353-9. PubMed
6. 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
7. Wellington K, Goa KL. Oral tegafur/uracil. Drugs Aging. 2001;18(12):935-48; discussion 949-50. PubMedDOI
8. Twelves C, Jones R. Oral uracil-tegafur: an alternative to intravenous 5-fluorouracil?. Expert Opin Pharmacother. 2001;2(9):1495-505. PubMedDOI
9. Köhne CH, Peters GJ. UFT: mechanism of drug action. Oncology (Williston Park). 2000;14(10 Suppl 9):13-8. PubMed