Antimetabolite

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The drug methotrexate (bottom) is an antimetabolite that interferes with the metabolism of folic acid (top) Methotrexate vs folate.svg
The drug methotrexate (bottom) is an antimetabolite that interferes with the metabolism of folic acid (top)

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]

Contents

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]

Examples of anthracyclines include:

Anti-tumor antibiotics that are not anthracyclines include: [4]

Other uses

Antimetabolites, particularly mitomycin C (MMC), are commonly used in America and Japan as an addition to trabeculectomy, a surgical procedure to treat glaucoma. [11]

Antimetabolites have been shown to decrease fibrosis of operative sites. Thus, its use following external dacryocystorhinostomy, a procedure for the management of nasolacrimal duct obstruction, is being researched. [12]

Intraoperative antimetabolite application, namely mitomycin C (MMC) and 5-fluorouracil (5-FU), is currently being tested for its effectiveness of managing pterygium. [13]

Types

Main categories of these drugs include: [14] [15]

Nucleotides 1.svg

See also

Related Research Articles

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are 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 of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">Nucleobase</span> Nitrogen-containing biological compounds that form nucleosides

Nucleobases are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic building blocks of nucleic acids. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are called primary or canonical. They function as the fundamental units of the genetic code, with the bases A, G, C, and T being found in DNA while A, G, C, and U are found in RNA. Thymine and uracil are distinguished by merely the presence or absence of a methyl group on the fifth carbon (C5) of these heterocyclic six-membered rings. In addition, some viruses have aminoadenine (Z) instead of adenine. It differs in having an extra amine group, creating a more stable bond to thymine.

<span class="mw-page-title-main">Nucleoside</span> Any of several glycosylamines comprising a nucleobase and a sugar molecule

Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase and a five-carbon sugar whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and one or more phosphate groups. In a nucleoside, the anomeric carbon is linked through a glycosidic bond to the N9 of a purine or the N1 of a pyrimidine. Nucleotides are the molecular building blocks of DNA and RNA.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Folinic acid</span> Derivative of folic acid used in cancer treatment

Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.

<span class="mw-page-title-main">Pemetrexed</span> Chemical compound

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)..

<span class="mw-page-title-main">Vidarabine</span> Chemical compound

Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

<span class="mw-page-title-main">Mercaptopurine</span> Chemical compound

Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's disease, and ulcerative colitis. For acute lymphocytic leukemia it is generally used with methotrexate. It is taken orally.

<span class="mw-page-title-main">History of cancer chemotherapy</span>

The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.

<span class="mw-page-title-main">Epirubicin</span> Chemical compound

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 the US and Pharmorubicin or Epirubicin Ebewe elsewhere.

<span class="mw-page-title-main">Nucleoside analogue</span> Biochemical compound

Nucleoside analogues are structural analogues of a nucleoside, which normally contain a nucleobase and a sugar. Nucleotide analogues are analogues of a nucleotide, which normally has one to three phosphates linked to a nucleoside. Both types of compounds can deviate from what they mimick in a number of ways, as changes can be made to any of the constituent parts. They are related to nucleic acid analogues.

<span class="mw-page-title-main">Floxuridine</span> Chemical compound

Floxuridine 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, and most often used in the treatment of colorectal cancer. The quality of life and survival rates of individuals that receive continuous hepatic artery infusion of floxuridine for colorectal cancer metastases is significantly higher than control groups. Floxuridine can also be prescribed for the treatment of kidney and stomach cancers. In vitro uses of floxuridine include 5-minute treatments of fluorouracil, floxuridine, and mitomycin to increase cell proliferation in Tenon's capsule fibroblasts.

<span class="mw-page-title-main">Raltitrexed</span> Chemical compound

Raltitrexed is an antimetabolite drug used in cancer chemotherapy. It is an inhibitor of thymidylate synthase, and is manufactured by AstraZeneca.

Purine analogues are antimetabolites that mimic the structure of metabolic purines.

Pyrimidine analogues are antimetabolites which mimic the structure of metabolic pyrimidines.

A nucleic acid inhibitor is a type of antibacterial that acts by inhibiting the production of nucleic acids. There are two major classes: DNA inhibitors and RNA inhibitors. The antifungal flucytosine acts in a similar manner.

<span class="mw-page-title-main">Carmofur</span> Chemical compound

Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lipophilic-masked analog of 5-FU that can be administered orally.

<span class="mw-page-title-main">Doxifluridine</span> Nucleoside analog prodrug

Doxifluridine is a second generation nucleoside analog prodrug developed by Roche and used as a cytostatic agent in chemotherapy in several Asian countries including China and South Korea. Doxifluridine is not FDA-approved for use in the USA. It is currently being evaluated in several clinical trials as a stand-alone or combination therapy treatment.

<span class="mw-page-title-main">Fluorodeoxyuridylate</span> Chemical compound

Fluorodeoxyuridylate, also known as FdUMP, 5-fluoro-2'-deoxyuridylate, and 5-fluoro-2'-deoxyuridine 5'-monophosphate, is a molecule formed in vivo from 5-fluorouracil and 5-fluorodeoxyuridine.

References

  1. ↑ Smith AL (1997). Oxford dictionary of biochemistry and molecular biology. Oxford [Oxfordshire]: Oxford University Press. p. 43. ISBN   978-0-19-854768-6.
  2. ↑ 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. PMID   11008002.
  3. ↑ Antineoplastic+Antimetabolites at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  4. 1 2 3 "How Chemotherapy Drugs Work". American Cancer Society.
  5. 1 2 Matera 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 . PMID   30346152. S2CID   53043366.
  6. ↑ Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" Archived 2020-05-03 at the Wayback Machine in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach Archived 2013-10-04 at the Wayback Machine . 11 ed. 2008.
  7. ↑ Avendano C, Menendez CJ (2015). Medicinal Chemistry of Anticancer Drugs (2nd ed.). Elsevier Science.
  8. ↑ Silverman RB (2004). The Organic Chemistry of Drug Design and Drug Action (2nd ed.).
  9. ↑ "Types of Chemotherapy Drugs". SEER Training Modules.
  10. ↑ 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. PMID   30656808. S2CID   58567138.
  11. ↑ Siriwardena D, Edmunds B, Wormald RP, Khaw PT (July 2004). "National survey of antimetabolite use in glaucoma surgery in the United Kingdom". The British Journal of Ophthalmology. 88 (7): 873–876. doi:10.1136/bjo.2003.034256. PMC   1772249 . PMID   15205228.
  12. ↑ Gage-White L, LaMear WR, Paleri V, Robson A, Bearn (August 1, 2003). "Surgical Approaches and Antimetabolite Use in Dacryocystorhinostomy: A Meta-Analysis". Otolaryngology–Head and Neck Surgery. 129 (2): P205. doi:10.1016/S0194-5998(03)01253-1. S2CID   72098513.
  13. ↑ Kareem AA, Farhood QK, Alhammami HA (2012). "The use of antimetabolites as adjunctive therapy in the surgical treatment of pterygium". Clinical Ophthalmology. 6: 1849–1854. doi: 10.2147/OPTH.S38388 . PMC   3497463 . PMID   23152665.
  14. ↑ Woolley DW (March 1987). A Study of Antimetabolites. New York: John Wiley & Sons, Inc. ISBN   9780471960300.
  15. ↑ Leumann CJ (April 2002). "DNA analogues: from supramolecular principles to biological properties". Bioorganic & Medicinal Chemistry. 10 (4): 841–854. doi:10.1016/S0968-0896(01)00348-0. PMID   11836090.
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