Figure 1. . Structures of (A) F10 and (B) 5-fluorouracil and schematic of uptake and important metabolites.

F10 is internalized by active transport into acute lymphocytic leukemia cells (see reference [6]) and converted to FdUMP, which inhibits TS, and FdUTP which is incorporated into DNA under thymineless conditions and poisons Top1 to generate DNA double-strand breaks. 5-FU enters both malignant and nonmalignant cells by passive diffusion and is converted to FUMP (a). FUMP is inefficiently converted to FdUMP (b, c). 5-FU also can be converted to FdUMP (d, e). 5-FU is also catabolized to FBAL, which causes cardio- and neuro-toxicity. The direct conversion of F10 to DNA-directed metabolites enhances DNA damage and contributes to anticancer activity while causes mainly RNA damage that contribute to systemic toxicities.

5-FU: 5-fluorouracil; a: UMPS; b: UMPK; c: RNR; d: TP; e: TK.