Antimetabolites mimic the action of normal metabolites in the folic acid cycle and the metabolic pathway of purine and pyrimidine synthesis. Because the antimetabolites are slightly different, they either block a specific enzymatic conversion or the antimetabolite is converted into strange product. They act during the S-phase of the cell cycle.
Methotrexate is a competitive inhibitor of the dihydrofolate reductase enzyme. Indirectly this drug depletes the amount of tetrahydrofolate, which is required for the thymidylate synthase enzyme in order to synthesize thymidine for DNA synthesis. Methotrexate is used for the treatment of breast tumors, placenta cancer, bladder carcinomas, epithelial carcinomas and leukemias. The bone marrow, kidneys and mucosal epithelia are mostly harmed by methotrexate.
5-Fluorouracil (5-FU) needs to be activated to 5-fluoro-deoxyuracil-monophosphate. This metabolite binds the thymidine synthase enzyme and thus blocks the formation of thymidine for DNA synthesis. Capecitabine is an oral prodrug of 5-FU. 5-Fluorouracil is applied for colon cancer, stomach cancer, breast cancer, prostate cancer and epithelial carcinomas in the neck-head area. Important adverse effects of 5-fluorouracil are mucositis, myelosuppression and diarrhea.
Gemcitabine is another nucleoside analogue which requires activation. Its metabolite gemcitabine diphosphate inhibits the ribonucleotide reductase enzyme which is involved in the formation of deoxynucleoside triphosphates. Another metabolite, gemcitabine triphosphate competes with deoxycytidine triphosphate as building block for DNA. Insertion of gemcitabine triphosphate into the DNA completely inhibits further DNA synthesis. Like 5-FU, gemcitabine is applied for all kinds of carcinomas. The most occurring adverse effects are myelosuppression, nausea/vomiting, peripheral edema and flu-like symptoms.
Extra info: Fluorouracil inhibits the enzyme thymidylate synthetase. Only 20% of the fluorouracil is excreted in urine, the rest is metabolized by the liver. Fluorouracil is used to treat all sorts of carcinoma's.
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Extra info: Methotrexate inhibits the enzyme dihydrofolate reductase, while 5-fluorouracil inhibits the enzyme thymidylate synthase. 5- fluorouracil is best administered via i.v. injection.