Capecitabine is a fluoropyrimidine carbamate prodrug with 70–80% oral bioavailability. As with 5-FU, capecitabine is inactive in its parent form and undergoes extensive metabolism in the liver by the enzyme carboxylesterase to an intermediate, 5′-deoxy-5-fluorocytidine. This metabolite is then converted to 5′-deoxy-5-fluorouridine by the enzyme cytidine deaminase. These two initial steps occur mainly in the liver. The 5′-deoxy5-fluorouridine metabolite is finally hydrolyzed by thymidine phosphorylase to 5-FU directly in the tumor. The expression of thymidine phosphorylase has been shown to be significantly higher in a broad range of solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer (CRC).
Capecitabine is used in the treatment of metastatic breast cancer either as a single agent or in combination with other anti-cancer agents, including docetaxel, paclitaxel, lapatinib, ixabepilone, and trastuzumab. It is also approved for use in the adjuvant therapy of stage III and high-risk stage II colon cancer, and used in the treatment of metastatic CRC as monotherapy or in combination with other active cytotoxic agents, including irinotecan and oxaliplatin. The capecitabine/oxaliplatin (XELOX) regimen is now widely used for the first-line treatment of metastatic CRC as well as in the adjuvant setting for patients with stage III and high-risk stage II colon cancer. The main toxicities of capecitabine include diarrhea and the hand-foot syndrome. While myelosuppression, nausea and vomiting, mucositis, and alopecia are also observed with capecitabine, their incidence is significantly less than that observed with intravenous 5-FU.
TAS-102 is an oral fluoropyrimidine analog approved in 2015 by the U.S. Food and Drug Administration (FDA) for the treatment of progressive, refractory metastatic CRC. As with 5-FU, TAS-102 is inactive in its parent form. It is made up of trifluridine, a fluorinated pyrimidine nucleoside analog, and tipiracil, a thymidine phosphorylase (TP) inhibitor, in a 1/0.5 ratio. Trifluridine is metabolized to the monophosphate form, which inhibits TS, albeit a much weaker TS inhibitor than FdUMP, and also to the triphosphate form, which is directly incorporated into DNA, leading to inhibition of DNA synthesis and function. The role of tipiracil is to inhibit TP, a key enzyme that degrades trifluridine to inactive forms. Thus, tipiracil allows for higher levels of trifluridine, which can then be activated to the active metabolite forms. The advantages of TAS-102 are that it retains clinical activity in 5-FU resistant tumors and it displays similar clinical activity in the setting of wild-type and mutant RAS colorectal cancer. The main dose-limiting toxicity is myelosuppression, with neutropenia more commonly observed than anemia and thrombocytopenia. The other adverse effects commonly observed with this oral fluoropyrimidine are GI toxicity with diarrhea and nausea/vomiting, fatigue, and anorexia.