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Antimetabolites resemble normal cellular substances and so can subvert normal metabolic pathways in a toxic manner. Three subgroups of antimetabolites are used—folic acid, pyrimidine, and purine analogues.

The prototype folic acid analogue is methotrexate, an inhibitor of dihydrofolate reductase, the enzyme that catalyzes conversion of folic acid to tetrahydrofolate. Tetrahydrofolate deficiency blocks reactions requiring folate coenzymes, disrupting both DNA and RNA synthesis. Methotrexate is an S phase–specific drug that must be actively transported across cell membranes. It can be given PO, IV, IM, or intrathecally. Methotrexate is excreted in the urine, and at high doses may precipitate in renal tubules. Folinic acid can be used to bypass the metabolic blockade produced by folic acid analogues and thus result in rescue of treated cells. Because tumor cells appear less efficient at transport of folinic acid, some degree of selectivity is achieved in the rescue. Resistance to methotrexate may develop due to impaired transport of the drug into cells, production of altered forms, or increased concentrations of dihydrofolate reductase.

Two pyrimidine analogues, 5-fluorouracil and cytarabine, are commonly used. 5-Fluorouracil must be converted to an active 5-fluoro-2′-deoxyuridine-5′-phosphate form to bind the enzyme thymidylate synthetase and block or inhibit DNA and RNA synthesis. This drug is considered S phase–specific. It is used IV but is also available for topical use. Metabolism is via the liver, and the drug readily enters CSF. Occasional CNS reactions have been reported in dogs. Severe irreversible neurotoxicity and sudden death have been described in cats. In people, neurotoxicity is related to deficiency in the enzyme dihydropyrimidine dehydrogenase, but this has not been investigated in veterinary species. Resistance may develop by decreased activation of the drug or acquisition of altered thymidylate synthetase that is not inhibited.

Cytarabine (cytosine arabinoside) is an analogue of 2′-deoxycytidine and must be activated by conversion to a 5′-monophosphate nucleotide. The nucleotide analogue, AraCTP, inhibits DNA synthesis by substitution of arabinose for deoxyribose in the sugar moiety of DNA; cytarabine may also inhibit DNA repair enzymes. This drug is S phase–specific, and its effectiveness in hematopoietic neoplasms is directly proportional to exposure of cells to the drug; continuous infusion or repeated injections are usually required. Inhibition of conversion to AraCTP or increased degradation of AraCTP can account for development of resistance.

Gemcitabine is another nucleoside analogue of cytidine which, unlike cytarabine, has activity against solid tumors. The drug requires active carrier transport into the cytoplasm where it is terminally activated via phosphorylation; consequently, serum levels may not predict intracellular concentrations. By acting as a counterfeit nucleotide, coupled with the ability to inhibit multiple enzymes needed for pyridine biosynthesis and DNA repair, gemcitabine is capable of self-potentiation and synergism with other agents, particularly alkylators. Gemcitabine has also been used as a radiation sensitizer.

Two purine analogues, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are rarely used in veterinary medicine. In people, these drugs are occasionally used for acute leukemias or other autoimmune disorders.

Last full review/revision November 2015 by Lisa G. Barber, DVM; Kristine E. Burgess, DVM, DACVIM (Oncology)

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