Investigational New Drugs

, Volume 18, Issue 4, pp 343–354 | Cite as

Capecitabine: Preclinical Pharmacology Studies

  • Hideo Ishitsuka


Capecitabine (N4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine) is a novel fluoropyrimidine carbamate, which was designed to besequentially converted to 5-fluorouracil (5-FU) by three enzymes located inthe liver and in tumors; the final step is the conversion of5′-deoxy-5-fluorouridine (5′-DFUR) to 5-FU by thymidine phosphorylase (dThdPase) in tumors. In human cancer xenograft models, capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma ornormal tissue (muscle). The tumor 5-FU levels were also much higherthan those achieved by intravenous administration of 5-FU at equitoxic doses.Capecitabine and its intermediates are not cytotoxic by themselves,but become effective after their conversion to 5-FU. This tumor selectivedelivery of 5-FU ensured greater efficacy and a more favorable safety profilethan with other fluoropyrimidines. In 24 human cancer xenograft modelsstudied, capecitabine was more effective at a wider dose range andhad a broader spectrum of antitumor activity than 5-FU, UFT or itsintermediate metabolite 5′-DFUR. The susceptibility of the xenografts tocapecitabine correlated with tumor dThdPase levels. Moreover, theconversion of 5′-DFUR to 5-FU by dThdPase in tumor was insufficient in axenograft model refractory to capecitabine. In addition, the efficacy ofcapecitabine was enhanced by dThdPase up-regulators, such astaxanes and cyclophosphamide. The efficacy of capecitabine may, therefore, beoptimized by selecting the most appropriate patient population based on dThdPasestatus and/or by combining it with dThdPase up-regulators. Capecitabinehas additional characteristics not found with 5-FU, such as potentantimetastatic and anticachectic actions in mouse tumor models.With this profile, capecitabine may have substantial potential in cancer treatment.

capecitabine discovery oral fluoropyrimidine pharmacology 


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Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Hideo Ishitsuka
    • 1
  1. 1.Nippon Roche Research Center Kajiwara, KamakuraKanagawaJapan

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