Fluorouracil
Encyclopedia
Fluorouracil (sold under the brand names Adrucil, Carac, Efudix, Efudex and Fluoroplex) is a drug
that is a pyrimidine analog which is used in the treatment of cancer
. It is a suicide inhibitor
and works through irreversible inhibition of thymidylate synthase
. It belongs to the family of drugs called antimetabolite
s. It is typically administered with leucovorin.
. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine
, which is a nucleoside required for DNA replication
. Thymidylate synthase
methylates deoxyuridine monophosphate (dUMP) into thymidine monophosphate
(dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death
.
Like many anti-cancer drugs, 5-FU's effects are felt system wide but fall most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery, such as cancer cells, but also other cells in parts of the body that are rapidly dividing, for example, the cells lining the digestive tract.
Some of its principal uses are in colorectal cancer
, and pancreatic cancer
, in which it has been the established form of chemotherapy
for decades (platinum
-containing drugs approved for human use in the US since 1978 are also very well established). It is sometimes used in the treatment of inflammatory breast cancer, an especially aggressive form of breast cancer.
5-FU is used in ophthalmic surgery, specifically to augment trabeculectomy
(an operation performed to lower the intraocular pressure in patients with glaucoma
) in patients deemed to be at high risk for failure. 5-FU acts as an anti-scarring agent in this regard, since excessive scarring at the trabeculectomy site is the main cause for failure of the surgery.
Fluorouracil can be used topically (as a cream) for treating actinic (solar) keratoses
and some types of basal cell carcinoma
s of the skin. It is often referred to by its trade names Efudex, Carac or Fluoroplex.
Due to fluorouracil's toxicity and the fact that it can be manufactured using the same reaction as uracil
, its precursor, 5-fluoroorotic acid, is commonly used in laboratories to screen against organisms capable of synthesizing uracil.
It is a key component in tegafur-uracil
.
Since uracil is a normal component of RNA, the rationale behind the development of the drug was that cancer cells, with their increased genetic instability, might be more sensitive to 'decoy' molecules that mimic the natural compound than normal cells. The scientific goal in this case was to synthesize a drug which demonstrated specific uracil antagonism. The drug proved to have anti-tumor capabilities.
When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. 5-Fluorouracil masquerades as uracil during the nucleic acid replication process. Because 5-fluorouracil is similar in shape to but does not perform the same chemistry as uracil, the drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping the growth of cancerous cells.
analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA
and RNA
, finally inducing cell cycle
arrest and apoptosis
by inhibiting the cell's ability to synthesize DNA. It is an S-phase
specific drug and only active during certain cell cycles. In addition to being incorporated in DNA and RNA, the drug has been shown to inhibit the activity of the exosome complex
, an exoribonuclease
complex of which the activity is essential for cell survival.
Capecitabine is a prodrug
that is converted into 5-FU in the tissues. It can be administered orally.
s include myelosuppression, mucositis
, dermatitis
, diarrhea
and cardiac toxicity.
5-FU injection and topical even in small doses cause both acute central nervous system
(CNS) damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin
sheaths.
When using a pyrimidine-based drug, users must be aware that some people have a genetic inability to metabolize them. Current theory points to nearly 8% of the population having dihydropyrimidine dehydrogenase (DPD) deficiency
. There are laboratory tests to determine the relative activity of the DPD enzyme. Many labs offer DPD testing: Laboratory Corporation of America was one of the first to make the test available commercially on a large scale (Test Number 511176). Myriad Genetic Laboratories in Salt Lake City, UT also offers a test. In addition to full sequence analysis of the DPYD gene, Myriad performs an analysis of the TYMS gene which accounts for moderate gastrointestinal toxicities. Coventry Diagnostics in Troy, MI
and DNAVision (Belgium
) have quantitative analyses. GenPath diagnostics in Elmwood Park, NJ is also offering this test as a part of their pharmacogenomics effort. Additionally, EntroGen now offers genotyping reagents to clinical laboratories interested in developing an in-house DPYD mutation screen. It is expected that with a potential 500,000 people in North America using the pyrimidine-based 5-FU, this form of testing will increase.
The typical starting dose of capecitabine is 2,500 mg/m2 per day in Europe and 2,000 mg/m2 per day in the US. Probably the main action of 5-FU occurs when a 5-FU metabolite binds to thymidylate synthase. This binding is stable only in the presence of methylenetetrahydrofolate. It is speculated that this may explain why people in the US—a country that mandates adding folic acid to some foods—apparently require a lower dose of capecitabine than people in Europe, where countries do not mandate added folic acid.
The body converts both folic acid and leucovorin to methylenetetrahydrofolate.
Each of those precursors amplified the effect of 5-FU in one animal study. However, another animal study seemed to indicate that, given the same 5-FU treatment, a special diet containing no folic acid worked better than the normal diet.
Folic acid may amplify the desired action and the toxicity of 5-FU.
The exact mechanism of interaction is unknown.
When 5-FU is given intravenously, it is typically mixed with leucovorin in order to increase 5-FU activity. Folic acid may work as well as leucovorin, but the one human study performed (with a high dose of folic acid, from 40 mg/m2 to 140 mg/m2) had disappointing results and concluded that further studies were needed. There is some confusion about whether the amount of folic acid in a normal diet and multivitamins is enough to interact badly with 5-FU.
One study showed that 79 percent of the patients who switched from 5-FU (with leucovorin) to Xeloda (capecitabine) had serious side effects. None of the patients who switched from Xeloda to 5-FU (with leucovorin) had serious side effects. The researchers were unsure why.
Trissel and colleagues have shown that 5-FU and leucovorin are physically incompatible when mixed in portable-pump reservoirs. Similarly, infusion of 5-FU and leucovorin via permanent indwelling catheters is complicated by catheter blockage due to calcium carbonate formation (Ardalan and Flores, 1995).
more readily than normal liver cells. Charles Heidelberger, who had earlier found that fluorine in fluoroacetic acid
inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffman-La Roche to synthesize fluorouracil. Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice. The original 1957 report in Nature has Heidelberger as lead author, along with N.K.Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R.J. Schnitzer, E. Pleven, and J. Scheiner.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that is a pyrimidine analog which is used in the treatment of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. It is a suicide inhibitor
Suicide inhibition
Suicide inhibition, also known as suicide inactivation or mechanism-based inhibition, is a form of irreversible enzyme inhibition that occurs when an enzyme binds a substrate analogue and forms an irreversible complex with it through a covalent bond during the "normal" catalysis reaction...
and works through irreversible inhibition of thymidylate synthase
Thymidylate synthase
Thymidylate synthetase is the enzyme used to generate thymidine monophosphate , which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair....
. It belongs to the family of drugs called antimetabolite
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 antifolates that interfere with the use of folic acid...
s. It is typically administered with leucovorin.
Uses
The chemotherapy agent 5-FU, which has been used against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase inhibitorThymidylate synthase inhibitor
Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy...
. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
, which is a nucleoside required for DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
. Thymidylate synthase
Thymidylate synthase
Thymidylate synthetase is the enzyme used to generate thymidine monophosphate , which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair....
methylates deoxyuridine monophosphate (dUMP) into thymidine monophosphate
Thymidine monophosphate
Thymidine monophosphate, also known as 5'-thymidylate, thymidylate, or TMP, is a nucleotide that is used as a monomer in DNA. It is an ester of phosphoric acid with the nucleoside thymidine. TMP consists of a phosphate group, the pentose sugar deoxyribose, and the nucleobase thymine...
(dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death
Thymineless death
Thymineless death is the phenomenon by which bacteria, yeasts and mammalian cells undergo irreversible cell death when they are starved of thymidine triphosphate , an essential precursor for DNA replication...
.
Like many anti-cancer drugs, 5-FU's effects are felt system wide but fall most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery, such as cancer cells, but also other cells in parts of the body that are rapidly dividing, for example, the cells lining the digestive tract.
Some of its principal uses are in colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
, and pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, in which it has been the established form of chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
for decades (platinum
Platinum
Platinum is a chemical element with the chemical symbol Pt and an atomic number of 78. Its name is derived from the Spanish term platina del Pinto, which is literally translated into "little silver of the Pinto River." It is a dense, malleable, ductile, precious, gray-white transition metal...
-containing drugs approved for human use in the US since 1978 are also very well established). It is sometimes used in the treatment of inflammatory breast cancer, an especially aggressive form of breast cancer.
5-FU is used in ophthalmic surgery, specifically to augment trabeculectomy
Trabeculectomy
Trabeculectomy is a surgical procedure used in the treatment of glaucoma to relieve intraocular pressure by removing part of the eye's trabecular meshwork and adjacent structures. It is the most common glaucoma surgery performed and allows drainage of aqueous humor from within the eye to underneath...
(an operation performed to lower the intraocular pressure in patients with glaucoma
Glaucoma
Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
) in patients deemed to be at high risk for failure. 5-FU acts as an anti-scarring agent in this regard, since excessive scarring at the trabeculectomy site is the main cause for failure of the surgery.
Fluorouracil can be used topically (as a cream) for treating actinic (solar) keratoses
Actinic keratosis
Actinic keratosis is a premalignant condition of thick, scaly, or crusty patches of skin. It is more common in fair-skinned people. It is associated with those who are frequently exposed to the sun, as it is usually accompanied by solar damage...
and some types of basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
s of the skin. It is often referred to by its trade names Efudex, Carac or Fluoroplex.
Due to fluorouracil's toxicity and the fact that it can be manufactured using the same reaction as uracil
Uracil
Uracil is one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A, G, C and U. The others are adenine, cytosine, and guanine. In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine.Uracil is a common and...
, its precursor, 5-fluoroorotic acid, is commonly used in laboratories to screen against organisms capable of synthesizing uracil.
It is a key component in tegafur-uracil
Tegafur-uracil
Tegafur-uracil is a chemotherapy drug used in the treatment of cancer, primarily bowel cancer. It is also called UFT or UFUR.-Development and regulation:...
.
Synthesis
5-FU was designed, synthesized and patented by Charles Heidelberger in 1957.Since uracil is a normal component of RNA, the rationale behind the development of the drug was that cancer cells, with their increased genetic instability, might be more sensitive to 'decoy' molecules that mimic the natural compound than normal cells. The scientific goal in this case was to synthesize a drug which demonstrated specific uracil antagonism. The drug proved to have anti-tumor capabilities.
When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. 5-Fluorouracil masquerades as uracil during the nucleic acid replication process. Because 5-fluorouracil is similar in shape to but does not perform the same chemistry as uracil, the drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping the growth of cancerous cells.
Mode of action
As a pyrimidinePyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, finally inducing cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
arrest and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
by inhibiting the cell's ability to synthesize DNA. It is an S-phase
S phase
S-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this...
specific drug and only active during certain cell cycles. In addition to being incorporated in DNA and RNA, the drug has been shown to inhibit the activity of the exosome complex
Exosome complex
The exosome complex is a multi-protein complex capable of degrading various types of RNA molecules...
, an exoribonuclease
Exoribonuclease
An exoribonuclease is an exonuclease ribonuclease, which are enzymes that degrade RNA by removing terminal nucleotides from either the 5' end or the 3' end of the RNA molecule...
complex of which the activity is essential for cell survival.
Capecitabine is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
that is converted into 5-FU in the tissues. It can be administered orally.
Adverse effects
Side effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s include myelosuppression, mucositis
Mucositis
Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal tract, but oral mucositis refers to the particular...
, dermatitis
Dermatitis
-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
and cardiac toxicity.
5-FU injection and topical even in small doses cause both acute central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
sheaths.
When using a pyrimidine-based drug, users must be aware that some people have a genetic inability to metabolize them. Current theory points to nearly 8% of the population having dihydropyrimidine dehydrogenase (DPD) deficiency
Dihydropyrimidine dehydrogenase deficiency
Dihydropyrimidine dehydrogenase deficiency is an autosomal recessivemetabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.Individuals with this condition may develop...
. There are laboratory tests to determine the relative activity of the DPD enzyme. Many labs offer DPD testing: Laboratory Corporation of America was one of the first to make the test available commercially on a large scale (Test Number 511176). Myriad Genetic Laboratories in Salt Lake City, UT also offers a test. In addition to full sequence analysis of the DPYD gene, Myriad performs an analysis of the TYMS gene which accounts for moderate gastrointestinal toxicities. Coventry Diagnostics in Troy, MI
Troy, Michigan
Troy is a city in Oakland County in the U.S. state of Michigan, and is a suburb of Detroit. The population was 80,980 at the 2010 census, making it the 11th-largest city in Michigan by population, and the largest city in Oakland County...
and DNAVision (Belgium
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
) have quantitative analyses. GenPath diagnostics in Elmwood Park, NJ is also offering this test as a part of their pharmacogenomics effort. Additionally, EntroGen now offers genotyping reagents to clinical laboratories interested in developing an in-house DPYD mutation screen. It is expected that with a potential 500,000 people in North America using the pyrimidine-based 5-FU, this form of testing will increase.
The typical starting dose of capecitabine is 2,500 mg/m2 per day in Europe and 2,000 mg/m2 per day in the US. Probably the main action of 5-FU occurs when a 5-FU metabolite binds to thymidylate synthase. This binding is stable only in the presence of methylenetetrahydrofolate. It is speculated that this may explain why people in the US—a country that mandates adding folic acid to some foods—apparently require a lower dose of capecitabine than people in Europe, where countries do not mandate added folic acid.
The body converts both folic acid and leucovorin to methylenetetrahydrofolate.
Each of those precursors amplified the effect of 5-FU in one animal study. However, another animal study seemed to indicate that, given the same 5-FU treatment, a special diet containing no folic acid worked better than the normal diet.
Folic acid may amplify the desired action and the toxicity of 5-FU.
The exact mechanism of interaction is unknown.
When 5-FU is given intravenously, it is typically mixed with leucovorin in order to increase 5-FU activity. Folic acid may work as well as leucovorin, but the one human study performed (with a high dose of folic acid, from 40 mg/m2 to 140 mg/m2) had disappointing results and concluded that further studies were needed. There is some confusion about whether the amount of folic acid in a normal diet and multivitamins is enough to interact badly with 5-FU.
One study showed that 79 percent of the patients who switched from 5-FU (with leucovorin) to Xeloda (capecitabine) had serious side effects. None of the patients who switched from Xeloda to 5-FU (with leucovorin) had serious side effects. The researchers were unsure why.
Trissel and colleagues have shown that 5-FU and leucovorin are physically incompatible when mixed in portable-pump reservoirs. Similarly, infusion of 5-FU and leucovorin via permanent indwelling catheters is complicated by catheter blockage due to calcium carbonate formation (Ardalan and Flores, 1995).
History
In 1954 Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracilUracil
Uracil is one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A, G, C and U. The others are adenine, cytosine, and guanine. In RNA, uracil binds to adenine via two hydrogen bonds. In DNA, the uracil nucleobase is replaced by thymine.Uracil is a common and...
more readily than normal liver cells. Charles Heidelberger, who had earlier found that fluorine in fluoroacetic acid
Fluoroacetic acid
Fluoroacetic acid is a compound with formula H. It is between acetic acid and trifluoroacetic acid....
inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffman-La Roche to synthesize fluorouracil. Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice. The original 1957 report in Nature has Heidelberger as lead author, along with N.K.Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R.J. Schnitzer, E. Pleven, and J. Scheiner.