Antimetabolites are substances that are close in chemical structure to endogenous metabolic products and inhibit, as a result of competitive relations, certain biochemical processes, which is accompanied by a violation of cell function and inhibition of cell growth.
The antitumor activity of antimetabolites was discovered in the early 1960s. It turned out that methotrexate, which is an antimetabolite of folic acid, is effective in some human tumors, especially in choriocarcinoma in women and in acute leukemia. Later, other antimetabolites appeared in medical practice – analogs of purine and pyrimidine.
Antimetabolites used as antineoplastic agents include structural analogs of folic acid (methotrexate), purines (mercaptopurine, thioguanine, etc.), pyrimidines (fluorouracil, tegafur, cytarabine, etc.).
The cytostatic effect of all these compounds is associated with a violation of the synthesis of nucleic acids (DNA and RNA). Antimetabolites are phase-specific agents – they predominantly act in the S-phase of the cell cycle.
Folic acid antagonist is methotrexate. It binds to the active catalytic center and inhibits the activity of the enzyme dihydrofolate reductase, which reduces dihydrofolate to its active form – tetrahydrofolate, which is a coenzyme and plays the role of a carrier of one-carbon groups (methyl, methylene, metenyl, etc.) in many enzymatic reactions. Lack of tetrahydrofolate leads to disruption of the synthesis of thymidylate, pyrimidine nucleotides, amino acids serine and methionine, resulting in inhibition of the synthesis of DNA, RNA and protein. Since methotrexate acts in the S-phase of the cell cycle, it is most active against tissues with a high rate of cell proliferation, such as tumor tissue, bone marrow, cells of the gastrointestinal tract mucosa, urinary bladder, etc. Methotrexate has a wide spectrum of antitumor activity. The main indications for its appointment are leukemias, lymphomas, uterine chorionepithelioma, breast cancer, lung cancer, ovarian cancer, bladder cancer, etc.
The antitumor effect of pyrimidine analogs is due to their transformation in tumor cells into active inhibitors of enzymes – thymidylate synthetase (fluorouracil and its analogs, raltitrexide, etc.), DNA polymerase (cytarabine), ribonucleotide reductase (hydroxycarbamide, etc.), involved in nucleic acid synthesis.
Fluorouracil (an antimetabolite of uracil) was created in 1962. The activity of fluorouracil is due to its biotransformation in tissues into active forms. In the process of intracellular transformations of 5-fluorouracil (5-FU), cytostatically active metabolites (5-fluoro? 2′-deoxyuridine monophosphate and 5-fluorouridine triphosphate) are formed. There are two possible mechanisms of cell damage under the action of active metabolites of 5-fluorouracil. First, 5-fluoro-2′-deoxyuridine monophosphate and folate cofactor N5-10 methylenetetrahydrofolate covalently bind with thymidylate synthetase to form a single complex, which leads to suppression of the formation of thymidylate, a precursor of thymidine triphosphate required for DNA synthesis. Second, in the process of RNA synthesis, nuclear transcriptional enzymes may mistakenly include 5-fluoruridine triphosphate instead of uridine triphosphate, which leads to disruption of RNA processing and protein synthesis.
Fluorouracil is administered intravenously, because it is poorly absorbed from the gastrointestinal tract. It has high toxicity, manifested by myelosuppression, ulcerative lesions of the mucous membranes of the digestive tract (including ulcerative stomatitis, enteritis, etc.). In terms of the spectrum of antitumor action, fluorouracil differs from analogs of folic acid (methotrexate) and purines (mercaptopurine, etc.) and is most active in the treatment of colorectal cancer, malignant tumors of the breast, stomach, pancreas, etc.
Tegafur (prodrug), a fluoride derivative of pyrimidine, which is hydrolyzed in the body to form fluorouracil, has similar properties to fluorouracil. Compared to fluorouracil, tegafur is a less toxic compound.
A new modification of fluorouracil is another fluoropyrimidine derivative – capecitabine, which, unlike fluorouracil, is used as an oral cytostatic agent. In the body, under the influence of thymidine phosphorylase, capecitabine is converted to 5-fluorouracil (5-FU). Sequential enzymatic biotransformation of capecitabine to 5-FU creates higher concentrations in tumor tissues than in surrounding healthy tissues.
The mechanism of the antitumor action of tegafur and capecitabine, therefore, is due to the formation of fluorouracil and its subsequent biotransformation.
After activation in tissues, cytarabine forms cytarabine α 5′-triphosphate, which competitively inhibits DNA polymerase (an enzyme that catalyzes the reaction of DNA synthesis from precursors – deoxyribonucleoside α 5′-triphosphates), which leads to inhibition of DNA synthesis. In addition, cytarabine insignificantly affects RNA synthesis (it can be incorporated into DNA and RNA). Cytarabine has anti-leukemic activity. Especially active against myeloblasts, lymphoblasts, lymphocytes, to a lesser extent – granulocytes, erythrocytes and platelets.
Hydroxycarbamide was synthesized in 1869, but its antitumor activity in clinical studies was only proven in the 1980s. The cytotoxic effect of hydroxycarbamide is due to inhibition of the enzyme ribonucleotide reductase, as a result, DNA synthesis is disrupted in the absence of an effect on the synthesis of RNA and protein.
Gemcitabine and raltitrexide belong to new structural analogs of antimetabolites obtained by directed chemical synthesis.
Gemcitabine is a nucleoside (deoxycytidine) analogue. Has a phase specificity of action: it stops the vital activity of cells in the S-phase and blocks the tumor progression of cells in the G1 / S-phase. Gemcitabine undergoes intracellular metabolism by nucleoside kinases to form active di- and triphosphate nucleosides. The cytotoxic effect is due to the combined effect of these active metabolites. Diphosphate nucleosides inhibit ribonucleotide reductase, which catalyzes the formation of deoxynucleoside triphosphates required for DNA synthesis. Triphosphate nucleosides actively compete with deoxycytidine triphosphate for incorporation into nucleic acid molecules. After the incorporation of intracellular metabolites of gemcitabine into the DNA chain, one more additional nucleotide is added to its growing strands, which leads to a complete inhibition of further DNA synthesis and makes DNA repair impossible. Gemcitabine is effective in pancreatic cancer, non-small cell lung cancer, bladder cancer, etc.
Raltitrexide specifically inhibits thymidylate synthetase, a key enzyme in the synthesis of thymidine triphosphate (required for DNA synthesis), causing DNA fragmentation and cell death. It is used for colon cancer.
In general, antimetabolites have a pronounced antitumor effect and are effective in a number of malignant neoplasms. Some of them have immunosuppressive properties (methotrexate, cytarabine, etc.). Currently, the cellular mechanisms of action of known antimetabolites are being clarified and a directed search for new compounds of this group is underway.
Below is a list of antimetabolites:

  • Azacitidine
  • Capecitabine
  • Cladribinum
  • Cytarabin
  • Decitabine
  • Fludarabin
  • Fluorouracil
  • Gemcitabine
  • Hydroxycarbamide
  • Mercaptopurine
  • Methotrexate
  • Nelarabin
  • Pemetrexedum
  • Raltitrexid
  • Tegafur + Uracil
  • Tegafurum
  • Tioguanine