title: Antitumor activity of chemoendocrine therapy in premenopausal and postmenopausal             models with human breast cancer xenografts.
abstract: 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.
authors.affiliation: Product Research Department, Kamakura Research Laboratories,                     Chugai Pharmaceutical Co., Ltd., Kamakura 247-8530, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Kataoka
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Moriya
authors.forename: Noriaki
authors.initials: N
authors.lastname: Sawada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yasuno
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kondoh
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: Kazushige
authors.initials: K
authors.lastname: Mori
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000069287:Capecitabine; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017930:Genes, Reporter; D006801:Humans; D000077289:Letrozole; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000008:administration & dosage; D017698:Postmenopause; D017697:Premenopause; D013629:Tamoxifen / Q000008:administration & dosage; D013939:Thymidine Phosphorylase / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D003841:Deoxycytidine; D000069287:Capecitabine; D000077289:Letrozole; D001141:Aromatase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil