Tegafur/uracil explained

Type:	combo
Component1:	Tegafur
Class1:	Antineoplastic agent
Component2:	Uracil
Class2:	Nucleobase
Imagel:	Tegafur.svg
Widthl:	100
Altl:	Structural formula of tegafur
Imager:	Uracil.svg
Widthr:	60
Altr:	Structural formula of uracil
Tradename:	Uftoral, others
Cas Number:	74578-38-4
Pubchem:	104747
Drugbank:	DB09327
Unii:	HMI5GR78FR

Tegafur/uracil (abbreviation: UFT^[1]) is a chemotherapy drug combination used in the treatment of cancer, primarily bowel cancer.

UFT is an oral formulation combining uracil (a competitive inhibitor of dihydropyrimidine dehydrogenase), and tegafur (a bioavailable 5-fluorouracil (5-FU) prodrug) in a 4:1 molar ratio.

Uracil has also been stated to help protect the gastrointestinal tract from 5-FU toxicity and the related metabolites, with less side effects than 5-FU and other 5-FU related (pro)drugs.

Pharmacology

Pharmacodynamics

Tetrahydrofuran metabolites of tegafur have been shown to exhibit antiangiogenic^[2] effects and improve cytocidal performance of 5-FU, particularly in patients with over-expressed HIF-1.

Pharmacokinetics

5-FU exhibits poor intestinal penetration^{[3] [4]} and significant intestinal^{[5] [6]} and hepatic first-pass metabolism by DPD, resulting in low and erratic systemic bioavailibility as well as formation of toxic metabolites.^[7] Tegafur, after being absorbed from the gastrointestinal tract and delivered to the liver by the portal venous system, is converted to the bioactive compound 5-FU by hepatic cytochrome P450 enzymes. Meanwhile, the surplus of uracil competitively inhibits hepatic DPD, preventing immediate inactivation of the just formed 5-FU.

Clinical trials

Trials using UFT for cancer treatment include pancreatic cancer, colorectal cancer,^[8] liver cancer,^[9] adenocarcinoma of the lung,^[10] and breast cancer,^{[11] [12]} with significant gains over existing treatments, including reduced side effects, improved quality of life, improved disease free survival and/or overall survival.

History

The UFT combination was developed in Japan during the 1980s. UFT is approved in over 50 countries as a cancer therapy, most commonly for advanced colorectal cancer to replace 5FU, and has a low cost.^[13] "[P]atients appeared strongly to prefer treatment with [oral] UFT/LV over [intravenous] 5-FU/LV."^[14] In Japan, UFT is approved for cancer treatments including tumors of the colon/rectum, lung, breast, stomach, head and neck, liver, gallbladder, bile duct, pancreas, bladder, prostate, and cervix.^[15] In the UK, tegafur/uracil with folinic acid is approved as first line treatment by the National Institute for Health and Clinical Excellence (NICE) for metastatic colorectal cancer.^[16]

Available forms

Tegafur/uracil is marketed by companies including Merck Serono, Korea United and Jeil, Taiho, mostly in Asia, Europe, South America, Central America and South Africa.

It is made by various manufacturers and sold under a variety of names including: Tegafur-uracil, UFT, Ftorafur, Tefudex, Ufur and Uftoral. The UFT brand version is authorized for marketing in over 50 countries. Between 1984 and 2006, over 30 million patients were treated with UFT.^[17]

Further reading

• Murad A, de Andrade CA, Delfino C, Arikian S, Doyle J, Sinha N . A pharmacoeconomic comparison of UFT and 5-FU chemotherapy for colorectal cancer in South America . Oncology . 11 . 9 Suppl 10 . 128–135 . September 1997 . 9348585 .
• Yoshitani S, Takashima S . Efficacy of postoperative UFT (Tegafur/Uracil) plus PSK therapies in elderly patients with resected colorectal cancer . Cancer Biotherapy & Radiopharmaceuticals . 24 . 1 . 35–40 . February 2009 . 19243246 . 10.1089/cbr.2008.0547 .
• Sakai T, Yamashita Y, Maekawa T, Mikami K, Hoshino S, Shirakusa T . Immunochemotherapy with PSK and fluoropyrimidines improves long-term prognosis for curatively resected colorectal cancer . Cancer Biotherapy & Radiopharmaceuticals . 23 . 4 . 461–467 . August 2008 . 18771350 . 10.1089/cbr.2008.0484 .
• Sadahiro S, Mitomi T, Noto T, Kumada K, Hiki Y, Yamakawa T, Amano T, Oki S, Otani Y, Oka H, Takahashi T, Takemiya S, Nishiyama K, Yamamura T, Tsuchiya S, Ogawa N . [Multicenter comparative study of the recurrence-inhibitory effect of oral fluoropyrimidine drugs in patients with colorectal cancer following curative resection] ]. Japanese . Gan to Kagaku Ryoho. Cancer & Chemotherapy . 32 . 7 . 997–1005 . July 2005 . 16044962 .
• Shirao K, Hoff PM, Ohtsu A, Loehrer PJ, Hyodo I, Wadler S, Wadleigh RG, O'Dwyer PJ, Muro K, Yamada Y, Boku N, Nagashima F, Abbruzzese JL . Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV . Journal of Clinical Oncology . 22 . 17 . 3466–3474 . September 2004 . 15277535 . 10.1200/JCO.2004.05.017 .
• Onoyama H, Urakawa T, Sugihara S, Hashimoto Y, Azumi Y, Takao S, Saitoh Y . [A noteworthy case of postoperative liver metastasis from gastric cancer which responded well to UFT therapy] . Japanese . Gan to Kagaku Ryoho. Cancer & Chemotherapy . 27 . 11 . 1731–1735 . October 2000 . 11057325 .
• Matsushita A, Hanazaki K, Noike T, Nakagawa K, Misawa R, Nakata T, Nomura K, Kobayashi A, Miwa S, Miyagawa S, Kawasaki S . [Complete disappearance with oral UFT administration of recurrent hepatocellular carcinoma of the remnant liver and multiple lung metastasis after hepatic resection] . Japanese . Gan to Kagaku Ryoho. Cancer & Chemotherapy . 30 . 9 . 1327–1332 . September 2003 . 14518415 .
• Ohashi Y, Watanabe M, Ikeda M, Nanami T, Yamazaki K, Yajima S, Oshima Y, Takeyama T, Ito M, Saito F . [Regression of metastatic hepatic cancer from gastric cancer by polysaccharide K and UFT administration--a case report] ]. Japanese . Gan to Kagaku Ryoho. Cancer & Chemotherapy . 35 . 13 . 2409–2412 . December 2008 . 19098413 .
• Nakagawa Y, Todoroki T, Morishita Y, Mori K, Nakahaashi C, Ohkohchi N, Matsumoto H . A long-term survivor after pancreaticoduodenectomy for metastatic undifferentiated carcinoma of an unknown primary . Hepato-Gastroenterology . 55 . 86-87 . 1557–1561 . 2008 . 19102342 .
• Ueda H, Tanaka H, Kida Y, Fukuchi H, Ichinose M . Adjuvant chemotherapy with tegafur/uracil administration after transcatheter arterial chemoembolization for advanced hepatocellular carcinoma . Oncology Reports . 19 . 5 . 1355–1361 . May 2008 . 18425398 . 10.3892/or.19.5.1355 . free .
• Lin PC, Chen WS, Chao TC, Yang SH, Tiu CM, Liu JH . Biweekly oxaliplatin plus 1-day infusional fluorouracil/leucovorin followed by metronomic chemotherapy with tegafur/uracil in pretreated metastatic colorectal cancer . Cancer Chemotherapy and Pharmacology . 60 . 3 . 351–356 . August 2007 . 17111120 . 10.1007/s00280-006-0377-4 . 29375226 .
• Ohwada S, Ikeya T, Yokomori T, Kusaba T, Roppongi T, Takahashi T, Nakamura S, Kakinuma S, Iwazaki S, Ishikawa H, Kawate S, Nakajima T, Morishita Y . Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer: a randomised controlled study . British Journal of Cancer . 90 . 5 . 1003–1010 . March 2004 . 14997197 . 2409633 . 10.1038/sj.bjc.6601619 .

Notes and References

1. Web site: 2011-02-02 . Tegafur-uracil . 2024-06-20 . NCI dictionaries . National Cancer Institute, U.S. Department of Health and Human Services . en.
2. Watanabe T . Evidence produced in Japan: tegafur-based preparations for postoperative chemotherapy in breast cancer . Breast Cancer . 20 . 4 . 302–309 . October 2013 . 23456736 . 3824200 . 10.1007/s12282-013-0451-9 .
3. Ahmad N, Albassam AA, Faiyaz Khan M, Ullah Z, Mohammed Buheazah T, Salman AlHomoud H, Ali Al-Nasif H . A novel 5-Fluorocuracil multiple-nanoemulsion used for the enhancement of oral bioavailability in the treatment of colorectal cancer . Saudi Journal of Biological Sciences . 29 . 5 . 3704–3716 . May 2022 . 35844373 . 9280251 . 10.1016/j.sjbs.2022.02.017 .
4. Kumar A, Singh Arya PK, Jindal A . 2024-03-05 . Modulation of intestinal permeability of 5-fluorouracil via phospholipid interaction based lipophilic complex designing and pharmacokinetic assessment . Journal of Dispersion Science and Technology . en . 1–13 . 10.1080/01932691.2024.2325398 . 0193-2691.
5. Gu J, Yuasa H, Hayashi Y, Watanabe J . First-pass metabolism of 5-fluorouracil in the perfused rat small intestine . Biological & Pharmaceutical Bulletin . 21 . 8 . 871–873 . August 1998 . 9743260 . 10.1248/bpb.21.871 .
6. Yuasa H, Gu J, Hayashi Y, Watanabe J . First-pass metabolism of 5-fluorouracil in rats . The Journal of Pharmacy and Pharmacology . 50 . 9 . 1019–1025 . September 1998 . 9811163 . 10.1111/j.2042-7158.1998.tb06917.x .
7. Eisenmann ED, Talebi Z, Sparreboom A, Baker SD . Boosting the oral bioavailability of anticancer drugs through intentional drug-drug interactions . Basic & Clinical Pharmacology & Toxicology . 130 Suppl 1 . Suppl 1 . 23–35 . January 2022 . 34117715 . 8665934 . 10.1111/bcpt.13623 .
8. Casado E, Pfeiffer P, Feliu J, González-Barón M, Vestermark L, Jensen HA . UFT (tegafur-uracil) in rectal cancer . Annals of Oncology . 19 . 8 . 1371–1378 . August 2008 . 18381370 . 10.1093/annonc/mdn067 . free .
9. Ishikawa T . Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma . World Journal of Gastroenterology . 14 . 18 . 2797–2801 . May 2008 . 18473401 . 2710718 . 10.3748/wjg.14.2797 . free .
10. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M . A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung . The New England Journal of Medicine . 350 . 17 . 1713–1721 . April 2004 . 15102997 . 10.1056/NEJMoa032792 . free .
11. Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y . Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial . Journal of Clinical Oncology . 27 . 9 . 1368–1374 . March 2009 . 19204202 . 10.1200/JCO.2008.18.3939 .
12. Nakayama T, Noguchi S . Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan . The Oncologist . 15 . 1 . 26–36 . 2010 . 20080863 . 3227888 . 10.1634/theoncologist.2009-0255 .
13. Akasu T, Moriya Y, Ohashi Y, Yoshida S, Shirao K, Kodaira S . Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial . Japanese Journal of Clinical Oncology . 36 . 4 . 237–244 . April 2006 . 16675478 . 10.1093/jjco/hyl014 . free .
14. Web site: Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: Systematic review and economic evaluation . www.hta.ac.uk . 15 January 2022 . https://web.archive.org/web/20091118110244/http://www.hta.ac.uk/execsumm/summ732.shtml . 18 November 2009 . dead.
15. Web site: Merck at ASCO 2007: New Data Demonstrate the Value of UFT as an Important Treatment Option for Patients With Metastatic Colorectal Cancer - Drugs.com MedNews. Drugs.com.
16. Capecitabine and tegafur uracil for metastatic colorectal cancer, Technical appraisal 61
17. https://www.drugs.com/clinical_trials/merck-asco-2007-new-data-demonstrate-value-uft-important-option-patients-metastatic-colorectal-1141.html Merck at ASCO 2007: New Data Demonstrate the Value of UFT as an Important Treatment Option for Patients With Metastatic Colorectal Cancer