FU Analogs and Prodrugs

A number of fluoropyrimidines other than 5-FU have been synthesized, most of which act as prodrugs for 5-FU. Capecitabine (Xeloda®) is an orally administered fluoropyrim-idine that is converted to 5-FU by the enzyme thymidine phosphorylase (TP), which is often over-expressed in malignant compared to normal tissues (29). Capecitabine has been shown to be equivalent to 5-FU/LV and was the first oral agent to be approved by the FDA for the treatment of mCRC (30).

Another prodrug, ftorafur (FT/1-tetrahydrofuranyl-5-fluorouracil) is metabolized to 5-FU either by hepatic P-450 microsomal enzymes or ubiquitous cytosolic enzymes (31). The bioavailability is improved by co-administration of uracil in a 4:1 molar ratio ("UFT"), which blocks the degradation of DPD and therefore leads to a more prolonged concentration of 5-FU in tumor tissues (32). Another 5-FU prodrug is S-1, a fourth-generation oral fluoropyrimidine that is a formulation of tegafur (FT) and two modulators: 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo), causing decreased drug incorporation into cellular RNA. FT is a prodrug of cytotoxic fluorouracil (FU), and CDHP prevents its degradation by inactivation of DPD (200 times more potent than uracil), which allows its higher concentrations to enter the anabolic pathways (33). In animal models, Oxo is protective against FT-induced diarrhea, primarily reducing intestinal phosphorylation of FU by inhibiting OPRT (34, 35). Thus, one component of S-1, CDHP, reduces the degradation of cytotoxic FU, thereby prolonging its half-life (36). Oxo, another component, potentially reduces gastrointestinal (GI) toxicity in humans.

A number of studies have investigated S-1 in patients with metastatic gastric cancer and reported response rates ranging from 26-45% (37, 38, 39). One Japanese study reported a 76% RR in patients with gastric cancer treated with S-1 and cisplatin combination chemotherapy (40). Interestingly, the maximum tolerable dose (MTD) of S-1 is higher in Japanese patients compared with Americans. Ajani et al. showed that the dose of S-1 tolerated by Western patients is lower than the dose tolerated by Japanese patients, with a MTD of 50mg/m2/d and 80mg/m2/d, respectively (41).

One possible explanation for the differences in MTD is the significant discrepancy in frequencies of polymorphisms in the TS gene reported in Asians compared with Caucasians (42).

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