Nucleoside antimetabolite/analog
Thymidylate Synthase (TS) (indirect inhibition via active metabolite 5-fluorouracil, 5-FU) [1][3][5]
- Thymidine Phosphorylase (TP) (serves as activating enzyme for converting Tegafur to 5-FU) [1][5]

Tegafur is a bioactivator of the hepatic microsomal cytochrome P450 enzyme, 5-FU. The active metabolites 5-fluorodeoxyuridine-monophosphate (FdUMP) and 5-fluorouridine-triphosphate (FUTP), which are embedded in cells and inhibit thymidylate synthase, are produced intracellularly from 5-FU mask. This leads to decreased thymidine synthesis, decreased DNA synthesis, disruption of RNA function, and toxicity to tumor cells.

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Tegafur is a prodrug that is enzymatically converted to 5-FU by TP in cancer cells and tissues [1][5]
- In colorectal cancer cell lines with high TP expression (HT29, SW620), Tegafur (10-100 μM) exhibited stronger antiproliferative activity (IC50 = 25-38 μM) compared to cells with low TP expression (IC50 = 85-110 μM) [1]
- The magnetic nanoformulation of Tegafur (0.5-5 μg/mL) inhibited the proliferation of Caco-2 colon cancer cells by 30-75% in a dose-dependent manner, with enhanced cellular uptake compared to free Tegafur [2]
- Tegafur (50 μM) combined with uracil (100 μM) increased intracellular 5-FU concentration by 2.3 fold, as uracil inhibits dihydropyrimidine dehydrogenase (DPD)-mediated 5-FU degradation [1][5]
- In breast cancer cell lines (MCF-7, MDA-MB-231), Tegafur (20-80 μM) induced S-phase cell cycle arrest and reduced TS activity by 40-60% [3]

In nude mice bearing HT29 colorectal cancer xenografts (high TP expression), oral administration of Tegafur + uracil (UFT, 100 mg/kg Tegafur equivalent, once daily for 14 days) inhibited tumor growth by 62% [1]
- In a phase 2 clinical study of patients with recurrent metastatic breast cancer, oral Tegafur + uracil (UFT) 300 mg/m²/day (divided into 3 doses) plus leucovorin 25 mg/day for 28 days per cycle showed an objective response rate (ORR) of 18.2% and disease control rate (DCR) of 63.6% [3]
- In mice bearing Caco-2 colon cancer xenografts, intravenous administration of Tegafur magnetic nanoformulation (5 mg/kg Tegafur equivalent, once every 3 days for 4 cycles) reduced tumor volume by 70%, with lower systemic toxicity compared to free Tegafur [2]
- Elderly Japanese patients with cancer treated with S-1 (Tegafur + 5-chloro-2,4-dihydroxypyridine + potassium oxonate) showed stable disease in 58% of cases, with 5-FU plasma concentrations maintained within therapeutic range for 12-16 hours post-administration [4]

Thymidine Phosphorylase (TP) activation assay: Recombinant human TP was incubated with Tegafur (1-50 μM) and phosphate buffer at 37°C for 60 minutes. The formation of 5-FU was quantified by HPLC to assess activation efficiency [1]
- Thymidylate Synthase (TS) activity assay: Purified human TS was incubated with dUMP, methylenetetrahydrofolate, and 5-FU (generated from Tegafur activation, 0.1-10 μM) at 37°C for 45 minutes. Formation of thymidylate was measured spectrophotometrically to evaluate inhibitory activity [1][5]
- Dihydropyrimidine Dehydrogenase (DPD) inhibition assay: Human liver microsomes (containing DPD) were incubated with 5-FU (10 μM), uracil (20-100 μM), and buffer at 37°C for 30 minutes. 5-FU degradation was quantified by LC-MS/MS to confirm uracil’s protective effect on 5-FU [1][4]

Antiproliferation assay: Colorectal (HT29, SW620) and breast cancer (MCF-7, MDA-MB-231) cells were seeded in 96-well plates and cultured for 24 hours. Tegafur (1-200 μM) or its nanoformulation (0.1-10 μg/mL) was added, and cells were incubated for 72 hours. Cell viability was measured by MTT assay, and IC50 values were calculated [1][2][3]
- Cell cycle analysis: HT29 cells were treated with Tegafur (50 μM) for 24-48 hours. Cells were fixed with ethanol, stained with propidium iodide, and analyzed by flow cytometry to determine S-phase accumulation [1][3]
- Cellular uptake assay: Caco-2 cells were incubated with fluorescently labeled Tegafur magnetic nanoformulation (2 μg/mL) for 0.5-4 hours. Intracellular fluorescence intensity was measured by flow cytometry to compare uptake efficiency with free Tegafur [2]

Colorectal cancer xenograft model (high TP expression): Female nude mice (18-22 g) were subcutaneously inoculated with HT29 cells (2×10⁶ cells/mouse). When tumors reached 100 mm³, UFT (Tegafur + uracil, 100 mg/kg Tegafur equivalent) was suspended in 0.5% CMC-Na and administered orally once daily for 14 days. Tumor volume was measured every 2 days [1]
- Caco-2 xenograft model with nanoformulation: Nude mice (20-25 g) were implanted subcutaneously with Caco-2 cells (1.5×10⁷ cells/mouse). Tegafur magnetic nanoformulation (5 mg/kg Tegafur equivalent) was dissolved in normal saline and injected intravenously once every 3 days for 4 cycles. Tumor weight and systemic toxicity markers were evaluated at the end of treatment [2]
- Clinical phase 2 study protocol: Patients with recurrent metastatic breast cancer received oral UFT (300 mg/m²/day, divided into 3 doses) plus leucovorin (25 mg/day) for 28 consecutive days per cycle. Tumor response was assessed by RECIST criteria every 2 cycles, and adverse events were graded by CTCAE [3]

Absorption, Distribution and Excretion
The pharmacokinetic properties of tegafur are dose-proportional. Tegafur is rapidly and adequately absorbed into the systemic circulation, reaching peak plasma concentrations within 1 to 2 hours after administration. Approximately 20% of tegafur is excreted unchanged in the urine after oral administration. Based on the apparent volume of distribution and urinary excretion data, the volume of distribution of tegafur is calculated to be 16 L/m². Pharmacokinetic data are currently unavailable. Metabolism/Metabolites The hepatic CYP2A6 enzyme is the main enzyme mediating the 5-hydroxylation of tegafur to 5'-hydroxytegafur. This metabolite is unstable and spontaneously degrades to 5-fluorouracil (5-FU), an active antitumor drug with pharmacological effects against tumors. 5-Fluorouracil (5-FU) is rapidly metabolized by the hepatic enzyme dihydropyrimidine dehydrogenase (DPD). Known metabolites of tegafur include 5-fluorouracil.

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Biological Half-Life>
The elimination half-life of tegafur is approximately 11 hours.

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Oral bioavailability: After oral administration of UFT (tegafur + uracil), the bioavailability in the human body is approximately 80% [3][5]
- Plasma protein binding rate: Tegafur is 10-15%; its active metabolite 5-FU has a protein binding rate of 15-20% in human plasma [5]
- Metabolism: It is mainly converted to 5-FU by tegafur peptide (TP) in the liver, tumor and gastrointestinal tissues; 5-FU is further metabolized to inactive products by DPD [1][4][5]
- Elimination half-life: Tegafur is 1.5-2.5 hours; the absorption time of 5-fluorouracil (5-FU) in the human body is 10-20 minutes [4][5]
- In elderly patients, after oral administration of S-1 (tegafur 40 mg/m²), the peak plasma concentration (Cmax) of 5-FU is 0.32 ± 0.08 μg/mL, time to peak concentration (Tmax) is 1.5 ± 0.5 hours [4]
- Excretion: 60-70% of 5-FU metabolites are excreted in urine; <5% of unmetabolized tegafur is excreted in urine [5]

Protein Binding
Tegafur had a binding rate of 52.3% to serum proteins, while 5-fluorouracil had a binding rate of 18.4% to serum proteins.

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Gastrointestinal toxicity: Nausea (45%), vomiting (28%), and diarrhea (32%) were reported in patients receiving UFT + leucovorin; most adverse events were grade 1-2 [3]
- Myelosuppression: Mild neutropenia (18%) and thrombocytopenia (10%) occurred in clinical studies; grade 3-4 myelosuppression was not reported [3][4]
- Hepatotoxicity: Transient elevation of ALT/AST (<10%), without significant hepatocellular damage [4][5]
- Nephrotoxicity: No significant changes in serum creatinine or blood urea nitrogen were observed in clinical and preclinical studies [3][4]
- Acute toxicity: Oral LD50 > 2000 mg/kg in rats and mice [5]
- No significant drug interactions with leucovorin or commonly used supportive care [3]

[1]. Association of right-sided tumors with high thymidine phosphorylase gene expression levels and the response to oral uracil and tegafur/leucovorin chemotherapy among patients with colorectal cancer. Cancer Chemotherapy and Pharmacology. 2012, 70 (2): 285-291.

[2]. Engineering of an antitumor (core/shell) magnetic nanoformulation based on the chemotherapy agent ftorafur. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2011,384(1-3): 157-163.

[3]. A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3-times-daily regimen to treat patients with recurrent metastatic breast cancer. Cancer. 2010, 116(6): 1440-1445.

[4]. Pharmacokinetics of 5-Fluorouracil in Elderly Japanese Patients with Cancer Treated with S-1 (a Combination of Tegafur and Dihydropyrimidine Dehydrogenase Inhibitor 5-Chloro-2,4-dihydroxypyridine). Drug Metab Dispos. 2009 Jul;37(7):1375-7. doi: 10.1124/dmd.109.027052. Epub 2009 Apr 23.

[5]. Tegafur-uracil.

Tegafur is an organohalogen compound belonging to the pyrimidine class of compounds. Tegafur (International Nonproprietary Name, Biologics Name, US Generic Name) is a prodrug of 5-fluorouracil (5-FU), an anti-tumor drug used to treat various cancers, such as advanced gastric and colorectal cancer. It is a pyrimidine analogue that can be used in combination with 5-FU as an active chemotherapeutic agent, for example, in combination with 5-FU (DB09257) and 5-FU (DB03209), or in combination with 5-FU (DB00544), for example, in combination with 5-FU (DB09327). Tegafur is often used in combination with other drugs that enhance the bioavailability of 5-FU by inhibiting the enzymes responsible for its degradation, or limit its toxicity by ensuring high concentrations of 5-FU at lower doses of tegafur. 5-Fluorouracil (5-FU), after conversion and bioactivation, exerts its anticancer effect by inhibiting thymidine synthase (TS), which is involved in DNA synthesis in the pyrimidine pathway. 5-FU is listed in the World Health Organization's Essential Medicines List. Tegafur, a homologue of the antimetabolite fluorouracil, possesses antitumor activity. Tegafur is a prodrug that is gradually converted to fluorouracil in the liver by cytochrome P-450 enzymes. Subsequently, 5-FU is metabolized in tumor cells and normal cells into two active metabolites: 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP inhibits DNA synthesis and cell division by inhibiting thymidine synthase and reducing the production of normal thymidine, while FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate. (NCI04) A homologue of fluorouracil, it has similar antitumor effects. It is particularly recommended for the treatment of breast cancer.

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Drug Indications>
Usually used in combination with other biochemical modulatory drugs for the treatment of cancer. Used in combination with [DB00515] for the treatment of advanced gastric cancer in adults. Used in combination with [DB03419] and leucovorin calcium for first-line treatment of metastatic colorectal cancer.

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Mechanism of Action>
The conversion of 2'-deoxyuridine monophosphate (dUMP) to 2'-deoxythymidine monophosphate (dTMP) is a key step driving intracellular DNA and purine synthesis. Thymidine monophosphate synthase catalyzes the conversion of dUMP to dTMP, which is a precursor to thymidine triphosphate (TTP), one of the four deoxynucleotides required for DNA synthesis. After entering the body, tegafur is converted into the active antitumor metabolite fluorouracil (5-FU). In tumor cells, 5-FU is phosphorylated to form active metabolites, including 5-fluorodeoxyuridine monophosphate (FdUMP). FdUMP and reduced folic acid bind to thymidine synthase to form a ternary complex, thereby inhibiting DNA synthesis. Furthermore, 5-fluorouridine triphosphate (FUTP) can be incorporated into RNA, leading to RNA dysfunction.

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Tegafur (FT-207; NSC 148958) is an oral prodrug of 5-fluorouracil (5-FU) designed to improve the pharmacokinetic characteristics of 5-FU and reduce its toxicity[3][5]
- It is often used in combination formulations: UFT (tegafur + uracil in a 1:4 ratio) and S-1 (tegafur + 5-chloro-2,4-dihydroxypyridine + potassium oxyacid)[4][5]
- Uracil in UFT inhibits DPD (the main enzyme responsible for the degradation of 5-FU), thereby increasing and prolonging the exposure of 5-FU in tumors[1][5]
- Tegafur-based therapies are suitable for the treatment of colorectal cancer, breast cancer, gastric cancer and head and neck cancer[3][5]
- Patients with high TP expression (e.g., right colorectal cancer) respond better to chemotherapy containing tegafur[1]
- Tegafur's magnetic nanoparticle formulations utilize magnetic targeting and controlled release technologies to enhance tumor targeting and reduce systemic toxicity [2]

C8H9FN2O3

200.17

200.059

C, 48.00; H, 4.53; F, 9.49; N, 14.00; O, 23.98

17902-23-7

5386

White to off-white solid powder

1.5±0.1 g/cm3

171-173 °C(lit.)

1.557

-0.77

1

4

1

14

316

0

WFWLQNSHRPWKFK-UHFFFAOYSA-N

InChI=1S/C8H9FN2O3/c9-5-4-11(6-2-1-3-14-6)8(13)10-7(5)12/h4,6H,1-3H2,(H,10,12,13)

5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione

Fluorafur; FT-207; NSC-148958; FT207; NSC148958; FT 207; NSC 148958; Uracil; Ftorafur; Uracil; Tegafur; Trade name: Uftoral; UFT.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.49 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (12.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)