title: Combination treatment with fulvestrant and various cytotoxic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) has a synergistic effect in estrogen receptor-positive breast cancer.
abstract: Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo.
authors.affiliation: Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Ikeda
authors.forename: Naruto
authors.initials: N
authors.lastname: Taira
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nogami
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Shien
authors.forename: Masanori
authors.initials: M
authors.lastname: Okada
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Shien
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Doihara
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Miyoshi
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000473:pathology*; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000077267:Fulvestrant; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009376:Neoplasms, Hormone-Dependent / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011897:Random Allocation; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D043823:Taxoids / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000077235:Vinorelbine; D023041:Xenograft Model Antitumor Assays
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009363:Neoplasm Proteins; D043823:Taxoids; D013629:Tamoxifen; D000077143:Docetaxel; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D014747:Vinblastine; D004317:Doxorubicin; D017239:Paclitaxel; D000077235:Vinorelbine; D005472:Fluorouracil