An antimetabolite is a chemical that
inhibits the use of a
metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
, 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
antifolate
Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionin ...
s that interfere with the use of
folic acid; thus,
competitive inhibition
Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected ...
can occur, and the presence of antimetabolites can have
toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
effects on cells, such as halting
cell growth
Cell growth refers to an increase in the total mass of a cell, including both cytoplasmic, nuclear and organelle volume. Cell growth occurs when the overall rate of cellular biosynthesis (production of biomolecules or anabolism) is greater than ...
and
cell division
Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there a ...
, so these compounds are used as
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
for cancer.
Function
Cancer treatment
Antimetabolites can be used in
cancer treatment
Cancer can be treated by surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy (including immunotherapy such as monoclonal antibody therapy) and synthetic lethality, most commonly as a series of separate treatments (e.g ...
, as they interfere with DNA production and therefore cell division and tumor growth. Because cancer cells spend more time dividing than other cells, inhibiting cell division harms tumor cells more than other cells. Antimetabolite drugs are commonly used to treat leukemia, cancers of the breast, ovary, and the gastrointestinal tract, as well as other types of cancers.
In the
Anatomical Therapeutic Chemical Classification System
The Anatomical Therapeutic Chemical (ATC) Classification System is a drug classification system that classifies the active ingredients of drugs according to the organ or system on which they act and their therapeutic, pharmacological and chemical ...
antimetabolite cancer drugs are classified under L01B.
Antimetabolites generally impair DNA replication machinery, either by incorporation of chemically altered nucleotides or by depleting the supply of deoxynucleotides needed for DNA replication and cell proliferation.
Examples of cancer drug antimetabolites include, but are not limited to the following:
*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, panc ...
(5-FU)
*6-
Mercaptopurine (6-MP)
*
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.
Co ...
(Xeloda®)
*
Cytarabine
Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by i ...
(Ara-C®)
*
Floxuridine
Floxuridine (also ''5-fluorodeoxyuridine'') is an oncology drug that belongs to the class known as antimetabolites. Specifically, floxuridine is a pyrimidine analog, classified as a deoxyuridine. The drug is usually administered via an artery, an ...
*
Fludarabine
Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate,
sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatmen ...
*
Gemcitabine
Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by ...
(Gemzar®)
*
Hydroxycarbamide
Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and ...
*
Methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
*
Pemetrexed
Pemetrexed, sold under the brand name Alimta among others, is a chemotherapy medication for the treatment of pleural mesothelioma and non-small cell lung cancer (NSCLC)..
It is available as a generic medication.
Medical use
In February 2004 ...
(Alimta®)
*
Phototrexate
Phototrexate is a photochromic antifolate drug developed at the Institute for Bioengineering of Catalonia (IBEC, The Barcelona Institute of Science and Technology). In particular, it is a photopharmacological agent that behaves as light-regulat ...
Anti-metabolites masquerade as a
purine (
azathioprine
Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, a ...
,
mercaptopurine) or 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 othe ...
, chemicals that become the building-blocks of DNA. They prevent these substances from becoming incorporated into DNA during the
S phase (of the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
), stopping normal development and cell division. Anti-metabolites also affect RNA synthesis. However, because
thymidine
Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. ...
is used in DNA but not in RNA (where
uracil is used instead), inhibition of thymidine synthesis via
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 deoxynucle ...
selectively inhibits DNA synthesis over RNA synthesis.
Due to their efficiency, these drugs are the most widely used
cytostatics
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
. Competition for the binding sites of
enzymes that participate in essential biosynthetic processes and subsequent incorporation of these biomolecules into
nucleic acids, inhibits their normal tumor cell function and triggers
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes includ ...
, the cell death process. Because of this mode of action, most antimetabolites have high cell cycle specificity and can target arrest of cancer cell DNA replication.
Antibiotics
Antimetabolites may also be
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...
s, such as
sulfanilamide drugs, which inhibit
dihydrofolate
Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid ( vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidines, which a ...
synthesis in bacteria by competing with
para-aminobenzoic acid
4-Aminobenzoic acid (also known as ''para''-aminobenzoic acid or PABA because the two functional groups are attached to the benzene ring across from one another in the ''para'' position) is an organic compound with the formula H2NC6H4CO2H. PABA i ...
(PABA). PABA is needed in enzymatic reactions that produce folic acid, which acts as a coenzyme in the synthesis of purines and pyrimidines, the building-blocks of DNA. Mammals do not synthesize their own folic acid so they are unaffected by PABA inhibitors, which selectively kill bacteria. Sulfanilamide drugs are not like the antibiotics used to treat infections. Instead, they work by changing the DNA inside cancer cells to keep them from growing and multiplying. Antitumor antibiotics are a class of antimetabolite drugs that are cell cycle nonspecific. They act by binding with DNA molecules and preventing RNA (ribonucleic acid) synthesis, a key step in the creation of proteins, which are necessary for cancer cell survival.
Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in copying DNA during the
cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
.
Examples of anthracyclines include:
*
Daunorubicin
Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. It ...
*
Doxorubicin (Adriamycin®)
*
Epirubicin
Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in t ...
*
Idarubicin
Idarubicin or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy gr ...
Anti-tumor antibiotics that are not anthracyclines include:
*
Actinomycin-D
*
Bleomycin
-13- (1''H''-imidazol-5-yl)methyl9-hydroxy-5- 1''R'')-1-hydroxyethyl8,10-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazapentadec-1-yl}-2,4'-bi-1,3-thiazol-4-yl)carbonyl]amino}propyl)(dimethyl)sulfonium
, chemical_formula =
, C=55 , H=84 , N=1 ...
*
Mitomycin-C
*
Mitoxantrone
*
Phototrexate
Phototrexate is a photochromic antifolate drug developed at the Institute for Bioengineering of Catalonia (IBEC, The Barcelona Institute of Science and Technology). In particular, it is a photopharmacological agent that behaves as light-regulat ...
Other uses
Antimetabolites, particularly
mitomycin C
Mitomycin C is a mitomycin that is used as a chemotherapeutic agent by virtue of its antitumour activity.
Medical uses
It is given intravenously to treat upper gastro-intestinal cancers (e.g. esophageal carcinoma), anal cancers, and breast c ...
(MMC), are commonly used in America and Japan as an addition to
trabeculectomy, a surgical procedure to treat
glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...
.
Antimetabolites have been shown to decrease
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
of operative sites. Thus, its use following external
dacryocystorhinostomy
Dacryocystorhinostomy (DCR) is a surgical procedure to restore the flow of tears into the nose from the lacrimal sac when the nasolacrimal duct does not function.
Process
Traditional
A small incision is made on the side of the nose and some bone ...
, a procedure for the management of
nasolacrimal duct obstruction
Nasolacrimal duct obstruction is the obstruction of the nasolacrimal duct and may be either congenital or acquired. Obstruction of the nasolacrimal duct leads to the excess overflow of tears called epiphora.
Sign and symptoms
Excessive tear ...
, is being researched.
Intraoperative antimetabolite application, namely
mitomycin C
Mitomycin C is a mitomycin that is used as a chemotherapeutic agent by virtue of its antitumour activity.
Medical uses
It is given intravenously to treat upper gastro-intestinal cancers (e.g. esophageal carcinoma), anal cancers, and breast c ...
(MMC) and
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, panc ...
(5-FU), is currently being tested for its effectiveness of managing
pterygium
Pterygium (plural ''pterygia'' or ''pterygiums'') refers to any wing-like triangular membrane occurring in the neck, eyes, knees, elbows, ankles or digits.
The term comes from the Greek word ''pterygion'' meaning "wing".
Types
* Popliteal ptery ...
.
Types
Main categories of these drugs include:
*
base analogues (altered
nucleobases) – structures that can substitute for a normal
nucleobases in
nucleic acids. This means that these molecules are structurally similar enough to the basic components of DNA that they can be substituted in. However, since they are slightly different from the normal bases after they are incorporated into the DNA, the DNA production is halted and the cell dies.
**
purine analogue
Purine analogues are antimetabolites that mimic the structure of metabolic purines.
Examples
* Nucleobase analogues
**Thiopurines such as thioguanine are used to treat acute leukemias and remissions in acute granulocytic leukemias.
***Azathioprin ...
s – mimic the structure of metabolic
purines, the larger bases incorporated into DNA as
adenosine
Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building b ...
and
guanosine.
***Examples:
Azathioprine
Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, a ...
,
Thiopurine
The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders (e.g., Crohn's disease, rheumatoid arthritis), and organ transplant recipients.
Metabolism is catalyzed by S-meth ...
s, and
Fludarabine
Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate,
sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatmen ...
**
pyrimidine analogue
Pyrimidine analogues are antimetabolites which mimic the structure of metabolic pyrimidines.
Examples
* Nucleobase analogues
**Fluorouracil (5FU), which inhibits thymidylate synthase
**Floxuridine (FUDR)
** 6-azauracil (6-AU)
*Nucleoside analogues ...
s – mimic the structure of metabolic
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 othe ...
s, the smaller bases incorporated into DNA as
cytosine
Cytosine () (symbol C or Cyt) is one of the four nucleobases 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 attached (an amin ...
and
thymine
Thymine () (symbol T or Thy) is one of the four nucleobases 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 nuc ...
.
***Examples:
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, panc ...
,
Gemcitabine
Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by ...
, and
Cytarabine
Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by i ...
*
nucleoside analogue
Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates.
Nucleoside and nucl ...
s –
nucleoside alternatives that consist of a
nucleic acid analogue and a
sugar. This means these are the same bases as above, but with an added sugar group. For the nucleoside analogues either the base or the sugar component can be altered. They are similar enough to the molecules used to build cellular DNA that they are incorporated by the cell into its DNA, but different enough that after being added the cell's DNA they stop cell growth.
*
nucleotide analogue
Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates.
Nucleoside and nucl ...
s –
nucleotides alternatives that consist of a
nucleic acid, a
sugar, and 1–3
phosphates. This means these molecules look exactly like the pieces used to build DNA in a cell and can be incorporated into a growing cell's DNA. However, because they are analogues and therefore slightly different than regular nucleotides, causing the cell's growth to be halted and the cell to die.
*
antifolate
Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionin ...
s – chemicals that block the actions of
folic acid (vitamin B9) which is needed to build DNA and allow cells to grow.
See also
*
Antinutrient
Antinutrients are natural or synthetic compounds that interfere with the absorption of nutrients. Nutrition studies focus on antinutrients commonly found in food sources and beverages. Antinutrients may take the form of drugs, chemicals that natura ...
References
External links
Overviewat
University of Nebraska
A university () is an institution of higher (or tertiary) education and research which awards academic degrees in several academic disciplines. Universities typically offer both undergraduate and postgraduate programs. In the United States, th ...
{{Chemotherapeutic agents
*
Antineoplastic antimetabolites