An antimetabolite is a chemical that
inhibits the use of a
metabolite, which is another chemical that is part of normal
metabolism.[1] 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; thus,
competitive inhibition can occur, and the presence of antimetabolites can have
toxic effects on cells, such as halting
cell growth and
cell division, so these compounds are used in
chemotherapy for cancer.[2]
Function
Cancer treatment
Antimetabolites can be used in
cancer treatment,[3] 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.[4] In the
Anatomical Therapeutic Chemical Classification System 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:
Anti-metabolites masquerade as a
purine (
azathioprine,
mercaptopurine) or a
pyrimidine, 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), stopping normal development and cell division.[6] Anti-metabolites also affect RNA synthesis. However, because
thymidine is used in DNA but not in RNA (where
uracil is used instead), inhibition of thymidine synthesis via
thymidylate synthase selectively inhibits DNA synthesis over RNA synthesis.
Due to their efficiency, these drugs are the most widely used
cytostatics. 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, 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.[7]
Antibiotics
Antimetabolites may also be
antibiotics, such as
sulfanilamide drugs, which inhibit
dihydrofolate synthesis in bacteria by competing with
para-aminobenzoic acid (PABA).[8] 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.[9]
Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in copying DNA during the
cell cycle.[4]
Antimetabolites, particularly
mitomycin C (MMC), are commonly used in America and Japan as an addition to
trabeculectomy, a surgical procedure to treat
glaucoma.[11]
Intraoperative antimetabolite application, namely
mitomycin C (MMC) and
5-fluorouracil (5-FU), is currently being tested for its effectiveness of managing
pterygium.[13]
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.
nucleoside analogues –
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 analogues –
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 from regular nucleotides, causing the cell's growth to be halted and the cell to die.
antifolates – chemicals that block the actions of
folic acid (vitamin B9) which is needed to build DNA and allow cells to grow.
^Smith AL (1997). Oxford dictionary of biochemistry and molecular biology. Oxford [Oxfordshire]: Oxford University Press. p. 43.
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^Peters GJ, van der Wilt CL, van Moorsel CJ, Kroep JR, Bergman AM, Ackland SP (2000). "Basis for effective combination cancer chemotherapy with antimetabolites". Pharmacology & Therapeutics. 87 (2–3): 227–253.
doi:
10.1016/S0163-7258(00)00086-3.
PMID11008002.
^
abMatera C, Gomila AM, Camarero N, Libergoli M, Soler C, Gorostiza P (November 2018). "Photoswitchable Antimetabolite for Targeted Photoactivated Chemotherapy". Journal of the American Chemical Society. 140 (46): 15764–15773.
doi:
10.1021/jacs.8b08249.
hdl:2445/126377.
PMID30346152.
S2CID53043366.
^Mashita T, Kowada T, Takahashi H, Matsui T, Mizukami S (June 2019). "Light-Wavelength-Based Quantitative Control of Dihydrofolate Reductase Activity by Using a Photochromic Isostere of an Inhibitor". ChemBioChem. 20 (11): 1382–1386.
doi:
10.1002/cbic.201800816.
PMID30656808.
S2CID58567138.