Fluorouracil (5-FU) mechanisms

Fluorouracil is converted in cells to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP), which inhibits thymidylate synthase and leads to “thymineless death” of cells. Incorporation of FdUMP into DNA inhibits DNA synthesis and function while incorporation of 5-fluorouridine-5′-triphosphate (FUTP), another 5-FU metabolite, into RNA interferes with RNA processing and function. Tumor cell resistance mechanisms include decreased activation of 5-FU, increased thymidylate synthase activity, and reduced drug sensitivity of this enzyme.5-Fluorouracil (5-FU), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of thymidine, one of the essential precursors for DNA synthesis.It enters the cell through a carrier-mediated transport system and is converted to the corresponding deoxynucleotide (5-flurodeoxyuridine monophosphate [5-FdUMP];, which competes with deoxyuridine monophosphate for thymidylate synthase.7 5-FdUMP acts as a pseudosubstrate and is trapped with the enzyme and its coenzyme N5,N10-methylene tetrahydrofolic acid (leucovorin), in a ternary complex that cannot proceed to release products. DNA synthesis decreases due to lack of thymidine, leading to imbalanced cell growth and “thymidine-less death” of rapidly dividing cells. [Note: Leucovorin is administered with 5-FU, because the reduced folate coenzyme is required in the thymidylate synthase inhibition. Addition of the coenzyme increases the effectiveness of 5-FU to form a ternary complex and produce an anti pyrimidine effect. For example, the standard regimen for advanced colorectal cancer today is irinotecan plus 5-FU/leucovorin.] 5-FU is also incorporated into RNA, and low levels have been detected in DNA. In the latter case, a glycosylase excises the 5-FU, damaging the DNA. 5-FU produces the anticancer eff ect in the S phase of the cell cycle.