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Introduction
The oral fluoropyrimidine capecitabine (Xeloda®) is sequentially activated by three enzymes (Fig. 1), carboxylesterase, cytidine deaminase (CD) and thymidine phosphorylase (TP), and generates 5-FU selectively within tumor tissues (1–4). 5′-Deoxy-5-fluorouridine (5′-DFUR, doxifluridine, Furtulon®) is an anticancer drug mainly used for patients with breast, colorectal and gastric cancers in Japan and the rest of East Asia, and is an intermediate of the capecitabine activation pathway, which is generated from 5′-DFUR by CD in the liver and in tumors (Fig. 1). 5-FU that has been delivered to the tumor tissues is inactivated by an enzyme, dihydropyrimidine dehydrogenase (DPD), which is expressed in the tumor tissues. We previously demonstrated that the sensitivity of human tumor xenografts to capecitabine and 5′-DFUR correlated significantly with the expression ratio of TP to DPD in tumor tissues (5). On the other hand, thymidylate synthase (TS) and other pyrimidine nucleoside-metabolizing enzymes are also reported as predictive factors for 5-FU sensitivity (6–8). In the present study, therefore, we investigated the relationship between the expression levels of 12 enzymes associated with pyrimidine nucleoside metabolisms (including TP, DPD, and TS) in tumor tissues and the sensitivity of the tumors to capecitabine and 5′-DFUR as compared with that to 5-FU in xenograft models.
Analyzing the factors that predict sensitivity to anticancer drugs is important and useful not only for selecting potential responders but also for developing new combinations. By selecting patients who will potentially respond to the therapy, it is possible to avoid the unnecessary treatment of patients who would not respond, thus sparing them the possible adverse effects. Furthermore, predictive factors render scientific rationales for new combination therapies, by which the sensitivity factor could be upregulated or the resistance factor be downregulated. In the present study, it was revealed that, of the pyrimidine nucleoside-metabolizing enzymes, only TP and DPD predicted a response to capecitabine and 5′-DFUR. Therefore, quantifying the expression levels of TP and DPD in tumor tissues makes it possible to select responders to capecitabine and 5′-DFUR. Moreover, investigating how combination partners regulate their expression during therapy would optimize combination therapies. Furthermore, capecitabine and 5′-DFUR may also be effective in 5-FU failure patients, even though these agents are 5-FU derivatives.
Materials and methods
Xenograft models
We used 80 xenograft models...