We examined the efficacy of chemoendocrine
therapy using
capecitabine as a chemotherapeutic agent in premenopausal and postmenopausal models with
estrogen receptor (ER)-positive human
breast cancer xenografts.
Tamoxifen and
letrozole were used as endocrine therapeutic agents for premenopausal and postmenopausal models, respectively. The antitumor activity of
capecitabine in combination was significantly superior to either monotherapy treatment in both premenopausal (p<0.01) and postmenopausal (p<0.05) models. No increase in toxicity in terms of
body weight loss was observed during treatment in either of the xenograft models. In the premenopausal model, the level of
thymidine phosphorylase (TP), a key
enzyme generating
5-FU from
capecitabine, was upregulated (p<0.05) in
tumors by
tamoxifen but not by
letrozole treatment in the postmenopausal model. The combination of
5'-deoxy-5-fluorouridine (5'-DFUR; an intermediate of
capecitabine) with
4-hydroxytamoxifen (4-OHT; an active form of
tamoxifen) or
letrozole was also evaluated in vitro by using
estrogen-responsive
element (ERE) reporter gene assays aimed to model premenopausal and postmenopausal
breast cancer. Both combinations decreased the number of
estrogen-responding cells in a concentration-dependent manner and further analysis by isobolograms revealed a synergistic effect of the combination of
5'-DFUR with
4-OHT, and at least an additive effect of the combination of
5'-DFUR with
letrozole. These results suggest that chemoendocrine
therapy using
capecitabine may be a useful treatment modality for patients with
hormone-receptor-positive
breast cancer, regardless of the menopausal status and should be explored in clinical trials.