Antimetabolite

Antimetabolites are drugs that mimic or antagonize components of cellular metabolism, most notably nucleotides. They interfere with DNA and RNA synthesis, replication, and repair, and are used in cancer chemotherapy and some autoimmune diseases. They are typically most effective against rapidly dividing cells, which rely heavily on de novo nucleotide synthesis and salvage pathways.

Major classes include antifolates (such as methotrexate and pemetrexed) that inhibit dihydrofolate reductase and other enzymes in the folate cycle, depleting thymidine and purine pools; purine analogs (such as 6-mercaptopurine and azathioprine) that mimic purine bases and disrupt purine nucleotide synthesis or are incorporated into nucleic acids; pyrimidine analogs (such as 5-fluorouracil, capecitabine, cytarabine, and gemcitabine) that interfere with pyrimidine metabolism or become incorporated into DNA or RNA; ribonucleotide reductase inhibitors (such as hydroxyurea) that reduce the production of deoxynucleotides.

Therapeutic use encompasses a range of hematologic malignancies (including leukemias and lymphomas) and solid tumors (such as colorectal and breast cancers), as well as immunosuppressive indications in autoimmune diseases and transplantation.

Resistance can arise from reduced drug uptake, increased drug inactivation, amplification or mutation of target enzymes, or altered metabolic pathways. Common toxicities include bone marrow suppression, mucositis, hepatotoxicity, and teratogenic risks; some regimens employ rescue agents or dosing adjustments to mitigate toxicity.

Development of antimetabolites began in the mid-20th century, yielding several cornerstone agents that remain in use in diverse oncologic and immunologic therapies.