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.