Editing Chemotherapy (section)

==== Antimetabolites ====
[[File:Deoxcytidine, Gemcitidine and Decitabine.png|thumb|[[Deoxycytidine]] (left) and two anti-metabolite drugs (center and right), [[gemcitabine]] and [[decitabine]]. The drugs are very similar but they have subtle differences in their [[chemical structure]].]]
{{Main|Antimetabolite}}
[[Anti-metabolite]]s are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are [[nucleotide]]s; a molecule comprising a [[nucleobase]], a sugar and a [[phosphate group]]. The nucleobases are divided into [[purine]]s ([[guanine]] and [[adenine]]) and [[pyrimidine]]s ([[cytosine]], [[thymine]] and [[uracil]]). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered [[chemical group]]s.<ref name="pmid19476376">{{cite journal | vauthors = Parker WB | title = Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer | journal = Chemical Reviews | volume = 109 | issue = 7 | pages = 2880–93 | date = July 2009 | pmid = 19476376 | pmc = 2827868 | doi = 10.1021/cr900028p }}</ref> These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting the enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, [[DNA damage]] can occur and programmed cell death ([[apoptosis]]) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case [[S-phase]] (the DNA synthesis phase). For this reason, at a certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the [[antifolate|anti-folates]], fluoropyrimidines, deoxynucleoside analogues and [[thiopurine]]s.<ref name=lind /><ref name="pmid19476376" />

The anti-folates include [[methotrexate]] and [[pemetrexed]]. Methotrexate inhibits [[dihydrofolate reductase]] (DHFR), an enzyme that regenerates [[tetrahydrofolate]] from [[dihydrofolate]]. When the enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for [[thymidylate]] and purine production, which are both essential for DNA synthesis and cell division.<ref name=Airley2009/>{{rp|55–59}}<ref name=Wood2005/>{{rp|11}} Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme [[thymidylate synthase]], but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and [[glycinamide ribonucleotide formyltransferase]].<ref name="pmid15217974">{{cite journal | vauthors = Adjei AA | title = Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent | journal = Clinical Cancer Research | volume = 10 | issue = 12 Pt 2 | pages = 4276s–4280s | date = June 2004 | pmid = 15217974 | doi = 10.1158/1078-0432.CCR-040010 | s2cid = 31467685 }}</ref> The fluoropyrimidines include [[fluorouracil]] and [[capecitabine]]. Fluorouracil is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death.<ref name=Wood2005/>{{rp|11}} Capecitabine is a [[prodrug]] of 5-fluorouracil that is broken down in cells to produce the active drug.<ref name="pmid12515569">{{cite journal | vauthors = Wagstaff AJ, Ibbotson T, Goa KL | title = Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer | journal = Drugs | volume = 63 | issue = 2 | pages = 217–36 | year = 2003 | pmid = 12515569 | doi = 10.2165/00003495-200363020-00009 }}</ref> The deoxynucleoside analogues include [[cytarabine]], [[gemcitabine]], [[decitabine]], [[azacitidine]], [[fludarabine]], [[nelarabine]], [[cladribine]], [[clofarabine]], and [[pentostatin]]. The thiopurines include [[thioguanine]] and [[mercaptopurine]].<ref name=lind /><ref name="pmid19476376" />