Thymidylate synthase inhibitor

Last updated

Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy. [1] This inhibition prevents the methylation of C5 of deoxyuridine monophosphate (dUMP) thereby inhibiting the synthesis of deoxythymidine monophosphate (dTMP). The downstream effect is promotion of cell death because cells would not be able to properly undergo DNA synthesis if they are lacking dTMP, a necessary precursor to dTTP. [2] Five agents were in clinical trials in 2002: raltitrexed, pemetrexed, nolatrexed, Plevitrexed( ZD9331/BGC9331 ), and GS7904L. [3]

Examples include

Related Research Articles

<span class="mw-page-title-main">Chemotherapy</span> Treatment of cancer using drugs that inhibit cell division or kill cells

Chemotherapy is a type of cancer treatment that uses one or more anti-cancer drugs as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer, which is called medical oncology.

<span class="mw-page-title-main">Uridine monophosphate synthase</span> Protein-coding gene in the species Homo sapiens

The enzyme Uridine monophosphate synthase catalyses the formation of uridine monophosphate (UMP), an energy-carrying molecule in many important biosynthetic pathways. In humans, the gene that codes for this enzyme is located on the long arm of chromosome 3 (3q13).

Fluorouracil, 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, pancreatic cancer, breast cancer, and cervical cancer. As a cream it is used for actinic keratosis, basal cell carcinoma, and skin warts.

<span class="mw-page-title-main">Thymidine kinase</span> Enzyme found in most living cells

Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:

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; 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.

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

Capecitabine, sold under the brand name Xeloda among others, is a anticancer 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.

<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.

<span class="mw-page-title-main">Thymidylate synthase</span> Enzyme

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 deoxynucleotides and increased levels of dUMP arise. Both cause DNA damage.

<span class="mw-page-title-main">5,10-Methylenetetrahydrofolate</span> Chemical compound

5,10-Methylenetetrahydrofolate (N5,N10-Methylenetetrahydrofolate; 5,10-CH2-THF) is cofactor in several biochemical reactions. It exists in nature as the diastereoisomer [6R]-5,10-methylene-THF.

<span class="mw-page-title-main">Thymidylate synthase (FAD)</span>

In enzymology, a thymidylate synthase (FAD) (EC 2.1.1.148) is an enzyme that catalyzes the chemical reaction

<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">OSI-7904</span> Chemical compound

OSI-7904 is a noncompetitive liposomal thymidylate synthase inhibitor. OSI-7904 is a benzoquinazoline folate analog with antineoplastic activity. As a thymidylate synthase inhibitor, OSI-7904 noncompetitively binds to thymidylate synthase, resulting in inhibition of thymine nucleotide synthesis and DNA replication.

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

{{Drugbox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 451224667 | IUPAC_name = (2S)-methyl 2-((((2R,3S,5R)-5-(5-((E)-2-bromovinyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate | image = Thymectacin.svg | alt = Skeletal formula of thymectacin | width = 260 | image2 = Thymectacin-3D-spacefill.png | alt2 = Space-filling model of the thymectacin molecule | width2 = 240

Wafik El-Deiry is an American physician and cancer researcher who is the Associate Dean for Oncologic Sciences at the Warren Alpert Medical School, Brown University, Director of the Cancer Center at Brown University, and the Director of the Joint Program in Cancer Biology at Brown University and its affiliated hospitals. He was previously deputy director of Translational Research at Fox Chase Cancer Center, where he was also co-Leader of the Molecular Therapeutics Program.

<span class="mw-page-title-main">Thymidylate kinase</span>

Thymidylate kinase catalyzes the phosphorylation of thymidine 5'-monophosphate (dTMP) to form thymidine 5'-diphosphate (dTDP) in the presence of ATP and magnesium:

<span class="mw-page-title-main">Trifluridine/tipiracil</span> Combination medication

Trifluridine/tipiracil (FTD–TPI), sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

<span class="mw-page-title-main">ONX-0801</span> Chemical compound

ONX-0801 is an experimental drug that has been developed to target ovarian cancer. It is a folate receptor alpha mediated thymidylate synthase inhibitor.

Professor Kenneth Reginald Harrap (1931-2017) was a British oncological biochemist.

<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. Jackman AL, Calvert AH (November 1995). "Folate-based thymidylate synthase inhibitors as anticancer drugs". Annals of Oncology. 6 (9): 871–81. doi: 10.1093/oxfordjournals.annonc.a059353 . PMID   8624289.
  2. Ackland SP, Clarke SJ, Beale P, Peters GJ (December 2006). "Thymidylate synthase inhibitors". Update on Cancer Therapeutics. 1 (4): 403–427. doi:10.1016/j.uct.2006.09.001.
  3. "Thymidylate synthase inhibitors as anticancer agents: from bench to bedside" . Retrieved 2009-01-28.
  4. Liu Y, Wu W, Hong W, Sun X, Wu J, Huang Q (April 2014). "Raltitrexed-based chemotherapy for advanced colorectal cancer". Clinics and Research in Hepatology and Gastroenterology. 38 (2): 219–25. doi:10.1016/j.clinre.2013.11.006. PMID   24388340.
  5. Papamichael D (1999). "The use of thymidylate synthase inhibitors in the treatment of advanced colorectal cancer: current status". The Oncologist. 4 (6): 478–87. doi: 10.1634/theoncologist.4-6-478 . PMID   10631692.
  6. Gibbs DD, Theti DS, Wood N, Green M, Raynaud F, Valenti M, Forster MD, Mitchell F, Bavetsias V, Henderson E, Jackman AL (December 2005). "BGC 945, a novel tumor-selective thymidylate synthase inhibitor targeted to alpha-folate receptor-overexpressing tumors". Cancer Research. 65 (24): 11721–8. doi: 10.1158/0008-5472.CAN-05-2034 . PMID   16357184.
  7. Ricart AD, Berlin JD, Papadopoulos KP, Syed S, Drolet DW, Quaratino-Baker C, Horan J, Chick J, Vermeulen W, Tolcher AW, Rowinsky EK, Rothenberg ML (December 2008). "Phase I, pharmacokinetic and biological correlative study of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, and cisplatin in patients with solid tumors". Clinical Cancer Research. 14 (23): 7947–55. doi: 10.1158/1078-0432.CCR-08-0864 . PMID   19047127.