Tegafur/uracil

Tegafur-uracil is a chemotherapy drug used in the treatment of cancer, primarily bowel cancer. It is also called UFT or UFUR.[1]

Development and regulation

The UFT combination was developed in Japan during the 1980s using tegafur, a pro-5FU drug. 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.[2] "[P]atients appeared strongly to prefer treatment with [oral] UFT/LV over [intravenous] 5-FU/LV."[3] 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.[4] 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.[5]

Description

UFT is a first generation DIF, or DPD (dihydropyrimidine dehydrogenase) inhibitory fluoropyrimidine drug. UFT is an oral agent which combines uracil, a competitive inhibitor of DPD, with the 5-FU prodrug tegafur in a 4:1 molar ratio.

Mechanism of action

Excess uracil competes with 5-FU for DPD, thus inhibiting 5-FU catabolism. The tegafur is taken up by the cancer cells and breaks down into 5-FU, a substance that kills tumor cells. The uracil causes higher amounts of 5-FU to stay inside the cells and kill them. Ftorafur is a type of antimetabolite. The 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. Tetrahydrofuran metabolites from the tegafur metabolism, unique among 5-FU based drugs, have also been shown to improve the antiangiogenic and cytocidal performances of 5-FU, particularly in patients with over expressed HIF-1.

Trial results

Trials using UFT for cancer treatment include pancreatic cancer, colorectal cancer,[6][7] liver cancer,[8] adenocarcinoma of the lung[9] and breast cancer[10][11] with significant gains over existing treatments, with reduced side effects, improved quality of life, improved disease free survival and/or overall survival. In Japan, China and Korea, papers cite improved success utilizing UFT with folinic acid (leucovrin), cimetidine and/or Polysaccharide-K (PSK, Krestin), in trials with advanced colorectal cancer, and individual cases of refractory and recurrent solid tumors with dismal prognoses. Papers show low dose neoadjuvant treatments with UFT backbones have been successfully used up to within hours of colorectal cancer surgery. Other trials show adjuvant chemotherapy with UFT backbones have been successfully started within 24 hours of colorectal cancer surgery, although two weeks after surgery was previously standard in Japan.

UFT has been administered on a long term basis for 6 months to over 11 years at 300-400 mg per day in divided doses (metronomic dosing), in cycles of 5 days dosed at 300 mg/m2 per day, followed by the weekend off, or in cycles of 28 days dosed at 300–600 mg/m2 per day, followed by a week off. The low side effect profile of UFT in cocktails routinely allows continuous, extended treatments of several years for recurrent, refractory, "hopeless" cases of various epithelial cancers.

Manufacturing and marketing

Tegafur-uracil is marketed by companies including Merck Serono, Korea United and 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.[12]

References

  1. ↑ Tegafur-uracil (Uftoral) : Cancerbackup
  2. ↑ Akasu T, Moriya Y, Ohashi Y, Yoshida S, Shirao K, Kodaira S (April 2006). "Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial". Jpn. J. Clin. Oncol. 36 (4): 237–44. doi:10.1093/jjco/hyl014. PMID 16675478.
  3. ↑ http://www.hta.ac.uk/execsumm/summ732.shtml
  4. ↑ http://www.drugs.com/clinical_trials/merck-asco-2007-new-data-demonstrate-value-uft-important-option-patients-metastatic-colorectal-1141.html
  5. ↑ Capecitabine and tegafur uracil for metastatic colorectal cancer, Technical appraisal 61
  6. ↑ Akasu T, Moriya Y, Ohashi Y, Yoshida S, Shirao K, Kodaira S (April 2006). "Adjuvant chemotherapy with uracil-tegafur for pathological stage III rectal cancer after mesorectal excision with selective lateral pelvic lymphadenectomy: a multicenter randomized controlled trial". Jpn. J. Clin. Oncol. 36 (4): 237–44. doi:10.1093/jjco/hyl014. PMID 16675478.
  7. ↑ Casado E, Pfeiffer P, Feliu J, González-Barón M, Vestermark L, Jensen HA (August 2008). "UFT (tegafur-uracil) in rectal cancer". Ann. Oncol. 19 (8): 1371–8. doi:10.1093/annonc/mdn067. PMID 18381370.
  8. ↑ Ishikawa T (May 2008). "Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma". World J Gastroenterol 14 (18): 2797–2801. doi:10.3748/wjg.14.2797. PMC 2710718. PMID 18473401.
  9. ↑ Kato H, Ichinose Y, Ohta M, et al. (April 2004). "A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung". N. Engl. J. Med. 350 (17): 1713–21. doi:10.1056/NEJMoa032792. PMID 15102997.
  10. ↑ Watanabe T, Sano M, Takashima S, et al. (March 2009). "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". J. Clin. Oncol. 27 (9): 1368–74. doi:10.1200/JCO.2008.18.3939. PMID 19204202.
  11. ↑ Nakayama T, Noguchi S (2010). "Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan". Oncologist 15 (1): 26–36. doi:10.1634/theoncologist.2009-0255. PMC 3227888. PMID 20080863.
  12. ↑ Merck at ASCO 2007: New Data Demonstrate the Value of UFT as an Important Treatment Option for Patients With Metastatic Colorectal Cancer, June 2007, Merck's press-release

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