Tegafur is a
chemotherapeutic prodrug of
5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...
(5-FU) used in the treatment of cancers. It is a component of the combination drug
tegafur/uracil. When metabolised, it becomes 5-FU.
It was patented in 1967 and approved for medical use in 1972.
Medical uses
As a prodrug to 5-FU it is used in the treatment of the following cancers:
*
Stomach
The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
(when combined with
gimeracil and oteracil)
*
Breast
The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues.
In females, it serves as the mammary gland, which produces and sec ...
(with uracil)
*
Gallbladder
In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...
*
Lung (specifically adenocarcinoma, typically with uracil)
*
Colorectal (usually when combined with gimeracil and oteracil)
*
Head and neck
This article describes the anatomy of the head and neck of the human body, including the brain, bones, muscles, blood vessels, nerves, glands, nose, mouth, teeth, tongue, and throat.
Structure Bones
The head rests on the top part of the vertebra ...
*
Liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
(with uracil)
*
Pancreatic
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...
It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil.
[ These agents achieve this by inhibiting the enzyme ]dihydropyrimidine dehydrogenase
In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction
:5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+
Thus, the two substrates of this enzyme are 5,6-dihydrouracil an ...
(uracil/gimeracil) or orotate phosphoribosyltransferase
Orotate phosphoribosyltransferase (OPRTase) or orotic acid phosphoribosyltransferase is an enzyme involved in pyrimidine biosynthesis. It catalyzes the formation of orotidine 5'-monophosphate (OMP) from orotate and phosphoribosyl pyrophosphate. ...
(oteracil).[
]
Adverse effects
The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea).[ Gastrointestinal toxicity is the dose-limiting side effect of tegafur.][ Central neurotoxicity is more common with tegafur than with fluorouracil.][
]
Pharmacogenetics
The dihydropyrimidine dehydrogenase
In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction
:5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+
Thus, the two substrates of this enzyme are 5,6-dihydrouracil an ...
(DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...
, capecitabine
Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth.
Com ...
, and tegafur. Genetic variations within the DPD gene (''DPYD'') can lead to reduced or absent DPD activity, and individuals who are heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
or homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency. Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (t ...
, neurotoxicity
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
and hand-foot syndrome
Chemotherapy-induced acral erythema, also known as palmar-plantar erythrodysesthesia or hand-foot syndrome is reddening, swelling, numbness and desquamation (skin sloughing or peeling) on palms of the hands and soles of the feet (and, occasionally ...
.
Mechanism of action
It is a prodrug to 5-FU, which is a thymidylate synthase
Thymidylate synthase (TS) () is an enzyme that catalyzes the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Thymidine is one of the nucleotides in DNA. With inhibition of TS, an imbalance of deoxynucleo ...
inhibitor.[
]
Pharmacokinetics
It is metabolised to 5-FU by CYP2A6.
Interactive pathway map
See also
* Tegafur/uracil
* Tegafur/gimeracil/oteracil
References
{{Chemotherapeutic agents
Organofluorides
Prodrugs
Pyrimidinediones
Pyrimidine antagonists
Tetrahydrofurans
Fluoropyrimidines
Drugs in the Soviet Union