of the ternary TS-FdUMP-CH2-THF complex induces TS expression due to the inhibition of a negative feedback mechanism whereby TS binds to its own mRNA and inhibits the translation process. The ternary complex is not able to bind to this mRNA, leading to increased expression of TS and constituting a possible resistance mechanism. Finally, TS inhibition leads to an increase in intracellular dUMP pools, which eventually compete with 5-FdUMP for binding with TS.

4.3. 5-FU prodrugs

5-FU requires intravenous administration, and a number of oral prodrugs have been designed to circumvent this limitation. One of them is ftorafur (tegafur), which is completely absorbed in the gastrointestinal tract and metabolized to 5-FU through two major pathways. The first of them involves microsomal hydroxyl-ation of the C-5' position of the tetrahydrofuran moiety by cytochrome P450, followed by spontaneous decomposition to 5-FU and succinic aldehyde. An hydrolytic pathway due to cytosolic hydrolases (pyrimidine nucleoside phos-phorylase) is also possible, giving 5-FU and 2-tetrahydrofuryl phosphate (Fig. 2.19). Ftorafur was introduced in the clinic in 1967 and showed a significant antitumor response. However, due to severe digestive and cardiac toxicities, it was soon replaced by its combinations with several other enzyme inhibitors, especially UFT and S-1 (see Sections 4.4.1 and 4.4.3).

The levels of the hydrolytic enzyme thymidine phosphorylase (TP) are significantly higher in several solid tumors, such as colorectal, breast, and kidney cancers, compared with normal tissues. This led to assay doxifluridine

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