Combination of Oral Fluoropyrimidine and Docetaxel: Reappraisal of Synergistic Effect Against Gastric Carcinoma Xenografts

Abstract

Background: The synergistic antitumor effect of a combination of docetaxel and capecitabine is reported to be attributable to docetaxel-mediated up-regulation of thymidine phosphorylase (dThdPase). Materials and Methods: Intravenous docetaxel (15 mg/kg) was given to nude mice bearing xenografts of the gastric cancer cell lines MKN45 and MKN28. Mice were sacrificed on days 7, 10 and 22 and tumor samples were taken to measure the activities of thymidylate synthase, dihydropyrimidine dehydrogenase, dThdPase and orotate phosphoribosyltransferase. The efficacy of capecitabine or S-1, alone and in combination with docetaxel, was then evaluated in vivo. Docetaxel was administered intravenously on days 8 and 22 at 15 mg/kg, while capecitabine (269 mg/kg) or S-1 (7.5 mg/kg) were administered orally 5 times a week for 4 weeks. Results: Tumor regression was observed only for a combination of capecitabine and docetaxel against MKN28, while additive growth inhibition was obtained by the combination of docetaxel and both S-1 and capecitabine on MKN45 tumor xenografts. Induction of dThdPase activity was observed only for MKN45. The activity of no other enzyme was significantly affected following administration of docetaxel. Conclusion: The combination of oral fluoropyrimidine and docetaxel showed augmented antitumor activity, but this may be attributed to mechanisms other than changes in 5-fluorouracil-metabolizing enzymes.