Summary
5-Fluorouracil (5-FU) and Leucovorin (folinic acid) have a well-established synergistic interaction commonly used in cancer chemotherapy. Leucovorin enhances the antitumor efficacy of 5-FU by stabilizing the inhibitory complex with thymidylate synthase, but this combination also increases the risk of severe toxicities including myelosuppression and gastrointestinal effects.
Introduction
5-Fluorouracil (5-FU) is a fluoropyrimidine antimetabolite chemotherapy agent primarily used to treat colorectal, breast, gastric, and pancreatic cancers. It works by inhibiting thymidylate synthase and incorporating into RNA and DNA, disrupting cellular processes. Leucovorin (folinic acid) is a reduced folate derivative that serves as a cofactor in one-carbon transfer reactions and is commonly used as a rescue agent for methotrexate toxicity or as a modulator to enhance the efficacy of fluoropyrimidine chemotherapy.
Mechanism of Interaction
The interaction between 5-Fluorouracil and Leucovorin involves biochemical modulation that enhances therapeutic efficacy. 5-FU is converted intracellularly to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which forms a ternary complex with thymidylate synthase and the folate cofactor 5,10-methylenetetrahydrofolate. Leucovorin increases intracellular folate pools, providing more cofactor availability and stabilizing the FdUMP-thymidylate synthase complex. This results in more potent and prolonged inhibition of thymidylate synthase, leading to enhanced cytotoxicity and improved antitumor activity.
Risks and Symptoms
The combination of 5-Fluorouracil and Leucovorin significantly increases the risk of severe toxicities compared to 5-FU alone. Primary concerns include severe myelosuppression with neutropenia, thrombocytopenia, and anemia, which can lead to life-threatening infections and bleeding. Gastrointestinal toxicities are markedly enhanced, including severe diarrhea, mucositis, stomatitis, and nausea/vomiting. Dermatologic reactions such as hand-foot syndrome may be more pronounced. The enhanced efficacy comes with a narrow therapeutic window, requiring careful patient selection and monitoring. Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are at particularly high risk for severe, potentially fatal toxicities.
