Capecitabine in the Treatment of Advanced Gastric Cancer

Jae-Lyun Lee; Yoon-Koo Kang


Future Oncol. 2008;4(2):179-198. 

In This Article

Introduction to the Compound


Capecitabine (5´-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine) is a selective, orally administered fluoropyrimidine carbamate that enables prolonged exposure of tumor tissue to 5-FU. Its aqueous solubility is 26 mg/ml at 20°C, and its molecular formula is C15H22FN3O6, with a molecular weight of 395.35 Da.


After oral administration, capecitabine is first metabolized by carboxyesterase in the liver to 5´-deoxy-5-fluorocytidine (5´-DFCR), which is then converted to 5´-deoxy-5-fluorouridine (5´-DFUR) by cytidine deaminase in the liver and tumor tissue. Finally, 5´-DFUR is converted to 5-FU by the enzyme thymidine phosphorylase (dThdPase), which is found at much higher levels in gastric cancer tissue than in normal tissue, enabling preferential generation of the active drug, 5-FU, at the tumor site (Figure 1).[24] Capecitabine and its intermediate metabolites, 5´-DFCR and 5´-DFUR, are not cytotoxic themselves, but become effective after conversion to 5-FU.

Figure 1.

Metabolic pathway of capecitabine. 5-FU = 5-fluorouracil; DFUR = Deoxy-5-fluorouridine; flDFCR = Deoxy-5-fluorocytidine.

Capecitabine has a wider and more potent spectrum of antitumor activity than other fluoropyrimidines administered at their maximum tolerated doses when tested against xenograft models of human colon, breast, cervical and bladder cancer, as well as gastric cancer.[25,26] In addition, capecitabine-based combinations were more effective than 5-FU combinations in xenograft models. The efficacy of capecitabine has been shown to be additive with that of irinotecan, and supra-additive with either paclitaxel or docetaxel.[26,27] Furthermore, the addition of capecitabine to trastuzumab or bevacizumab showed significantly higher antitumor activity in xenograft models than either agent alone.[28,29] The enzyme dThdPase, a key enzyme that converts 5´-DFUR to 5-FU, is upregulated by several cytotoxic drugs, including taxanes and cisplatin, as well as by x-ray irradiation.[27,30] These findings were subsequently extended to clinical trials incorporating these cytotoxic agents.

As capecitabine ultimately releases 5-FU at the cellular level through the action of dThdPase, and intracellular 5-FU concentration can be counterbalanced by intracellular dihydropyrimidine dehydrogenase (DPD) activity, the role of the dThdPase and DPD as predictive markers for capecitabine activity has been evaluated (Figure 2). In vitro and small clinical studies revealed that dThdPase:DPD ratio has significant correlation with the sensitivity of capecitabine and 5´-DFUR.[31,32] Confirmation of these data in a large clinical study would be of great interest and might serve as tailored therapy based on tumor characteristics.

Figure 2.

Mechanism of action of oral fluoropyrimidines. 5´-DFCR = 5´-deoxy-5-fluorocytidine; 5´-DFUR = 5´-deoxy-5-fluorouridine; DHFU = 5,6-dihydro-5-fluorouracil; DPD = Dihydropyrimidine dehydrogenase; dTDP = 2´-deoxythymidine-5´-diphosphate; dTMP = 2´-deoxythymidine-5´-monophosphate; dTTP = 2´-deoxythymidine-5´-triphosphate; dUMP = 2´-deoxyuridine-5´-monophosphate; FBAL = α-fluoro-β-alanine; FdUDP = 5-fluoro-2´-deoxyuridine-5´-diphosphate; FdUMP = 5-fluoro-2´-deoxyuridine-5´-monophosphate; FdUrd = 5-fluoro-2´-deoxyuridine; FdUTP = 5-fluoro-2´-deoxyuridine-5´-triphosphate; FT = Tegafur; FU = Fluorouracil; FUDP = 5´-fluorouridine-5´-diphosphate; FUMP = 5-fluorouridine-5´-monophosphate; FUPA = α-fluoro-β-ureidopropionic acid; FUrd = 5-fluorouridine; FUTP = 5´-fluorouridine-5´-triphosphate; GI = Gastrointestinal; HFS = Hand-foot syndrome; OPRT = Orotate phosphoribosyl transferase; TS = Thymidylate synthase; UFT = 5-fluorouracil, tegafur and uracil.


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