fluoropyrimidine

Fluoropyrimidine is a class of antimetabolite chemotherapy agents that mimic natural pyrimidines and contain fluorine. The most widely used members are 5-fluorouracil (5-FU) and the oral prodrugs capecitabine and tegafur (often given with uracil in UFT); floxuridine is another example. These drugs are used to treat various solid tumors, particularly colorectal cancer, gastric cancer, pancreatic cancer, and head and neck cancers.

Mechanism of action centers on disruption of pyrimidine metabolism. 5-FU is converted inside cells to active metabolites, the most important being FdUMP, which inhibits thymidylate synthase and reduces the pool of thymidine needed for DNA synthesis. Additional metabolites, FUTP and FdUTP, are incorporated into RNA and DNA, contributing to cytotoxicity. Leucovorin enhances the binding of FdUMP to thymidylate synthase, increasing activity. Capecitabine and tegafur are prodrugs that are converted to 5-FU in tissues, with capecitabine undergoing tumor-selective activation due to higher thymidine phosphorylase activity.

Administration and use: 5-FU is given by bolus injection or continuous infusion, while capecitabine and tegafur are taken orally. They are commonly used in combination regimens for colorectal cancer and other malignancies (e.g., with leucovorin, oxaliplatin, irinotecan, or targeted agents).

Adverse effects and contraindications: Common toxicities include myelosuppression, mucositis, diarrhea, nausea, and hand-foot syndrome (especially with capecitabine). Cardiotoxicity is rare but reported. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at higher risk of severe toxicity; hepatic or renal impairment can alter drug handling.

History: 5-FU was discovered in the 1950s and has since become a foundational chemotherapy agent, with oral prodrugs extending use to outpatient settings.