5-Fluorouracil Plus Thymidine or Leucovorin by Continuous I.V. Infusion in the Treatment of Advanced Colorectal Carcinoma

5-Fluorouracil (FUra) has been the drug of choice in the treatment of colorectal cancers (1,2), and it is widely utilized in a variety of other malignancies (3). FUra exerts its antiproliferative effect following metabolic activation to various nucleotides (Chart 1). 5-Fluorouridine triphosphate (FUTP), due to its resemblance with uridine triphosphate (UTP), is incorporated into RNA (4–7); the consequence of this incorporation is the production of fraudulent mRNA, rRNA and tRNA which can ultimately cause cell death. The other proposed mechanism for FUra cytotoxicity is the inhibition of thymidylate synthetase (dTMP-S) by 5-fluorodeoxyuridine monophosphate (FdUMP) (8–11), leading to decreased thymidine triphosphate (dTTP) pools and to inhibition of DNA synthesis. The biochemical mechanism by which FdUMP binds to the dTMP-S involves a cofactor, N5,10methylene tetrahydrofolic acid (N5,10CH₂FH₄). Santi et al. have calculated that the dissociation constant (Kd) of the ternary complex FdUMP-dTMP-SN5,10CH₂FH₄, is of the order of 5×10-11M. In absence of the reduced folate cofactor, FdUMP binding to dTMP-S is relatively weak, with a Kd of about 10-5M (9). An additional proposed mechanism of cytotoxicity of FUra is its incorporation into DNA (12–15). To date, little is known about the biological significance of this finding.