Changes of gene expression of thymidine phosphorylase, thymidylate synthase, dihydropyrimidine dehydrogenase after the administration of 5′-deoxy-5-fluorouridine, paclitaxel and its combination in human gastric cancer xenografts

Background: Although a variety of combination chemotherapies has been tested in gastric carcinoma, the most effective chemotherapeutic regimen and the precise mechanisms underlying anticancer agent combination have not yet been sufficiently elucidated. Materials and Methods: Experimental chemotherapy was performed using human gastric carcinoma xenografts, MKN-45 and TMK-1, to examine the anticancer effects and gene expressions of the enzymes involved in 5-fluorouracil metabolism, thymidine phosphorylase (dThdPase), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD). Nude mice were treated with 5 '-deoxy-5-fluorouridine (5 '-dFUrd), or paclitaxel alone or in combination. The in vivo antitumor effects on gene expressions of the enzymes were examined using the quantitative real-time RT-PCR method. Results: The combined use of 5 '-dFUrd and paclitaxel showed additive to synergistic antitumor effects on both gastric cancer xenografts. There were significant differences of the gene expressions of dThdPase, TS, and DPD between the xenografts. The expression of dThdPase mRNA was consistently up-regulated by the administration of paclitaxel, while no constant direction of TS mRNA and DPD mRNA change was found in the xenografts. Conclusion: A synergistic antitumor effect of the combined administration of 5 '-dFUrd and paclitaxel was found in gastric cancer xenografts and up-regulation of dThdPase mRNA may be an important underlying mechanism especially in tumors with high gene expression of this enzyme.