Floxuridine (also ''5-fluorodeoxyuridine'') is an

oncology Oncology is a branch of medicine that deals with the study, treatment, diagnosis, and prevention of cancer. A medical professional who practices oncology is an ''oncologist''. The name's Etymology, etymological origin is the Greek word ὄγ ...

drug that belongs to the class known as

antimetabolite An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolat ...

s. Specifically, floxuridine is a

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...

analog, classified as a

deoxyuridine Deoxyuridine (dU) is a compound and a nucleoside. It belongs to a class of compounds known as Pyrimidine 2'-deoxyribonucleosides and closely resembles the chemical composition of uridine but without the presence of the 2' hydroxyl group. Idoxurid ...

. The drug is usually administered via an artery, and most often used in the treatment of

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

. The quality of life and survival rates of individuals that receive continuous

hepatic artery The common hepatic artery is a short blood vessel that supplies oxygenated blood to the liver, pylorus of the stomach, duodenum, pancreas, and gallbladder. It arises from the celiac artery and has the following branches: Additional images ...

infusion Infusion is the process of extracting chemical compounds or flavors from plant material in a solvent such as water, oil or alcohol, by allowing the material to remain suspended in the solvent over time (a process often called steeping). An inf ...

of floxuridine for

metastases Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

is significantly higher than control groups. Floxuridine can also be prescribed for the treatment of kidney and stomach

cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

uses of floxuridine include 5-minute treatments of

fluorouracil Fluorouracil (5-FU, 5-fluorouracil), 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, stoma ...

, floxuridine, and

mitomycin The mitomycins are a family of aziridine-containing Secondary metabolite, natural products isolated from ''Streptomyces caespitosus'' or ''Streptomyces lavendulae.'' They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin ...

to increase cell proliferation in

Tenon's capsule Tenon's capsule (), also known as the Tenon capsule, fascial sheath of the eyeball () or the fascia bulbi, is a thin membrane which envelops the eyeball from the optic nerve to the corneal limbus, separating it from the orbital fat and forming a ...

fibroblasts A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...

Biosynthesis

Immobilized ''

Aeromonas salmonicida ''Aeromonas salmonicida'' is a pathogenic bacterium that severely impacts salmonid populations and other species. It was first discovered in a Bavarian brown trout hatchery by Emmerich and Weibel in 1894. ''Aeromonas salmonicida's'' ability to in ...

'' ATCC 27013, when exposed to

thymidine Thymidine (nucleoside#List of nucleosides and corresponding nucleobases, symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine nucleoside, deoxynucleoside. Deoxythymidine is the DNA nuc ...

and 5-fluorouracil in phosphate buffer at room temperature for one hour, can synthesize floxuridine and

thymine Thymine () (symbol T or Thy) is one of the four nucleotide bases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine ...

Pharmacology

Floxuridine primarily works by stopping the growth of newly born cells. The drug essentially stops

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

from forming in new and rapidly developing cells, which is a sign of a cancerous cell. Therefore, the floxuridine kills the cancerous cells. For colorectal cancer and hepatic metastases, an average adult should be given an intra-arterial dosage of 0.1–0.6 mg/kg/day as a continuous

, continued until intolerable toxicity is reached (

white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

count < 3,500/mm³ or platelet count < 100,000/mm³). Lethal dosages for other species are below.

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose requ ...

is the lethal dose at which half of

organisms An organism is any living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have been pr ...

exposed to the drug die.

Pharmacodynamics

Floxuridine is a

analog that acts as an inhibitor of the

S-phase S phase (Synthesis phase) is the phase of the cell cycle in which DNA is DNA replication, replicated, occurring between G1 phase, G1 phase and G2 phase, G2 phase. Since accurate duplication of the genome is critical to successful cell division, ...

of cell division. This selectively kills rapidly dividing cells.

Antimetabolites An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolat ...

masquerade as

-like molecules which prevents normal pyrimidines from being incorporated into DNA during the S phase of the cell cycle.

Fluorouracil Fluorouracil (5-FU, 5-fluorouracil), 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, stoma ...

(the end-product of catabolism of floxuridine) blocks an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

which converts

cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...

nucleosides into the deoxy

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

. In addition, DNA synthesis is further inhibited because fluorouracil blocks the incorporation of the

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

into the DNA strand.

Mechanism of action

Floxuridine is rapidly catabolized to

5-fluorouracil Fluorouracil (5-FU, 5-fluorouracil), 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, stoma ...

, which is the active form of the drug. The primary effect is interference with DNA synthesis and to a lesser extent, inhibition of

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

formation through the drug's incorporation into

, thus leading to the production of fraudulent RNA. Fluorouracil also inhibits uracil riboside phosphorylase, which prevents the utilization of preformed

uracil Uracil () (nucleoside#List of nucleosides and corresponding nucleobases, symbol U or Ura) is one of the four nucleotide bases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via ...

in RNA synthesis. As well, the monophosphate of floxuridine, 5-fluoro-2'-deoxyuridine-5'-phosphate (FUDR-MP) inhibits the enzyme

thymidylate synthetase 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 deoxynucleot ...

. This leads to the inhibition of

methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...

of deoxyuridylic acid to thymidylic acid, thus interfering with

DNA synthesis DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occu ...

Route of elimination

The drug is excreted intact and as

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

, α-fluoro-β-ureidopropionic acid, dihydrofluorouracil, α-fluoro-β-guanidopropionic acid, and α-fluoro-β-alanine in the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

; it is also expired as respiratory

carbon dioxide Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...

Side effects

Side effects include:

Common (30% of patients)

* Low blood counts. The patient's white and

red blood cells Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

and

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

may temporarily decrease. This can put them at increased risk for infection,

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

and/or bleeding. * Mouth sores * Diarrhea (may be severe)

Less common (10–29% of patients)

* Poor

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

Hair loss Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...

* Elevated liver enzymes (temporary increase in

alkaline phosphatase The enzyme alkaline phosphatase (ALP, alkaline phenyl phosphatase, also abbreviated PhoA) is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryo ...

lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvic acid, pyruvate to lactic acid, lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that t ...

transaminase Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid con ...

, and

bilirubin Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...

). This is seen more with the intra-arterial infusion directly into the liver. * Hand-foot syndrome (Palmar-plantar erythrodysesthesia or PPE) -skin rash, swelling, redness, pain and/or peeling of the skin on the palms of hands and soles of feet *

Stomach ulcers Peptic ulcer disease is when the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus, gets damaged. An ulcer in the stomach is called a gastric ulcer, while ...

(This is seen more with the intra-arterial infusion).

Contact your health provider immediately

Fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...

of 100.4 °F (38 °C) or higher, chills (possible signs of infection).

Contact your health provider

Diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

(2 episodes in a 24-hour period) *

(interferes with ability to eat and unrelieved with prescribed medication) *

Vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

(vomiting more than 4–5 times in a 24-hour period) *

Mouth sores A mouth ulcer (aphtha), or sometimes called a canker sore or salt blister, is an Ulcer (dermatology), ulcer that occurs on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and by ma ...

(painful redness, swelling or ulcers) * Unusual bleeding or bruising * Black or tarry stools, or blood in your stools * Blood in the

* Yellowing of the skin or eyes * Tingling or burning, redness, swelling of the palms of the hands or soles of feet

Other

* Fertility for both men and women may be affected by floxuridine.

Use in research

Apart from its use in chemotherapy, floxuridine is also used in aging research employing a ''

C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...

'' model, namely to stop growth and to prevent reproduction. The latter is brought about by treatment of larvae close to maturity with low doses of floxuridine that, even though allowing normal maturation, causes reproducing individuals to lay eggs that are unable to hatch. This limits the population to a single generation allowing quantification of aging processes and measurement of

longevity Longevity may refer to especially long-lived members of a population, whereas ''life expectancy'' is defined Statistics, statistically as the average number of years remaining at a given age. For example, a population's life expectancy at birth ...

. It has, however, been indicated that floxuridin exposure by itself increases life expectancy potentially leading to flawed data in respective studies.

History

Floxuridine first gained

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

approval in December 1970 under the brand name FUDR. The drug was initially marketed by

Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Switzerland, Swiss multinational corporation, multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, ...

, which also did a lot of the initial work on

. The

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...

was an early developer of the drug. Roche sold its FUDR product line in 2001 to

F H Faulding F. H. Faulding & Co was a pharmaceutical company founded in Adelaide, Australia, in 1845 by Francis Hardey Faulding (23 August 1816 – 19 November 1868), a native of Swinefleet, near Goole in Yorkshire, son of Francis Faulding, a surgeon. ...

, which became Mayne Pharma.

Alternative names

Synonyms for floxuridine include: * 5 Fluorodeoxyuridine * 5-Fluorodeoxyuridine * 5-FUdR * Floxuridine * Fluorodeoxyuridine * FUdR * 50-91-9 * 2'-Deoxy-5-fluorouridine * 5-Fluoro-2'-deoxyuridine * 5-Fluorodeoxyuridine * FUDR * 5 Fluorodeoxyuridine * Fluorodeoxyuridine * Floxuridin * Fluoruridine deoxyribose * Deoxyfluorouridine * Floxiridina * Floxuridinum * 5-Fluorouracil deoxyriboside * 5-Fluoro-2-desoxyuridine * 5FdU * 5-Fluoro-2-deoxyuridine * beta-5-Fluoro-2'-deoxyuridine * FdUR * 5-fluoro-1-((2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1h,3h)-dione * FdUrd * 1-(2-Deoxy-beta-D-ribofuranosyl)-5-fluorouracil * Uridine, 2'-deoxy-5-fluoro- * 1beta-D-2'-Deoxyribofuranosyl-5-flurouracil * 1-beta-D-2'-Deoxyribofuranosyl-5-flurouracil * UNII-039LU44I5M * 5-Fluorouracil 2'-deoxyriboside * Floxuridinum NN-Latin* Floxiridina NN-Spanish* 5-FdUrd

References

{{Chemotherapeutic agents Pyrimidine antagonists Nucleosides Organofluorides Pyrimidones Hydroxymethyl compounds