Leucovorin

Leucovorin is a racemic mixture of diastereoisomers, with the L-isomer (levoleucovorin) being the biologically active moiety. It functions at the molecular level by providing a source of "one-carbon" moieties required for the synthesis of purines and the conversion of deoxyuridylate to thymidylate.

Methotrexate acts as a competitive inhibitor of the enzyme DHFR, which normally reduces folic acid to tetrahydrofolate (THF). By providing a pre-reduced form of folate, leucovorin bypasses the DHFR block, allowing for continued DNA synthesis and cellular repair in normal host cells. It also competes with methotrexate for the same active transport processes into the cell, further reducing the drug's toxic impact. In the treatment of colorectal cancer, leucovorin acts as a biochemical sensitizer. 5-FU is metabolized into fluorodeoxyuridylic acid (FdUMP), which binds to the enzyme thymidylate synthase. Leucovorin is converted into 5,10-methylenetetrahydrofolate, which binds to and stabilizes the FdUMP-thymidylate synthase complex. This "ternary complex" locks the enzyme in an inactive state, leading to a more profound inhibition of DNA synthesis and enhanced tumor cell death. In Cerebral Folate Deficiency (CFD), leucovorin serves as a direct substrate to normalize levels of 5-MTHF in the central nervous system, particularly when folate transport across the blood-brain barrier is impaired by autoantibodies or genetic defects.