Schedule dependency of antitumor activity in combination therapy with capecitabine/5'-deoxy-5-fluorouridine and docetaxel in breast cancer models.

Docetaxel and capecitabine are being prescribed for the treatment of breast cancer. In this study, we tried to identify the optimal administration schedule in combination therapy with these anticancer drugs in human cancer xenograft models. Capecitabine was given p.o. daily for 2 weeks (days 1-14), whereas docetaxel was given i.v. on day 1, day 8, or day 15 in a 3-week regimen to the mice bearing MX-1 human breast cancer xenograft. The combination showed better antitumor efficacy than the monotherapy of either agent in either dosing regimen. However, the most potent and synergistic activity was observed when docetaxel was given on day 8. This potent effect appears to be characteristic of the combination of docetaxel with capecitabine or its intermediate metabolite 5'-deoxy-5-fluorouridine (doxifluridine; 5'-dFUrd). Docetaxel given on day 8 showed a potent effect in combination with 5'-dFUrd, but a much weaker effect was observed in combination with 5-fluorouracil or UFT, a fixed combination of tegafur and uracil. Better efficacy was also observed in the MAXF401 human breast cancer xenograft and in the mouse A755 mammary tumor when docetaxel was given at the middle of the capecitabine or 5'-dFUrd treatment rather than other dosing regimens. In contrast, the efficacy in WiDr human colon cancer xenograft was somewhat better when docetaxel was given on day 1. One possible explanation for the synergy is that docetaxel up-regulates tumor levels of thymidine phosphorylase, the enzyme essential for the activation of capecitabine and 5'-dFUrd to 5-fluorouracil. In fact, docetaxel up-regulated the thymidine phosphorylase levels 4.8- and 1.9-fold in the WiDr and MX-1 models, respectively. However, it did not significantly up-regulate in the MAXF401 and A755 models in which a potent combination effect was observed as well. Other mechanisms, particularly those for the synergy with docetaxel given at the middle during capecitabine/5'-dFUrd administration, would also exist. Based on these observations, clinical studies on the day 8 combination regimen with docetaxel and capecitabine/5'-dFUrd are warranted.