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. (Cancer Sci 2011; 102: 2038-2042 T he malignant grade of estrogen receptor (ER)-positive breast cancer is generally low, thus patients with this cancer have a better prognosis than those with ER-negative breast cancer. However, ER-positive breast cancers have low sensitivity to chemotherapy and the survival benefit of chemotherapy is limited.(1-3) Estrogen receptors play a crucial role in the development and progression of breast cancers and modulate many genes including of chemoresistant factors. The low sensitivity to chemotherapy may be caused by ER itself or by ER modulation of the levels of factors that cause resistance to chemotherapy. (4)(5)(6)(7)(8)(9)(10)(11) Tamoxifen has significant efficacy for ER-positive breast cancer. However, the mechanism is not completely understood. Tamoxifen is metabolized and the metabolites (4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen) have different affinities for ER and exert a variety of agonist and antagonist properties.(1,12-14) Fulvestrant, a selective ER inhibitor, is an active hormone drug for advanced breast cancer, and a randomized phase II comparative study of a fulvestrant high-dose regimen for advanced hormone receptor-pos...

Combinatorial Therapy Using Dovitinib and ICI182.780 (Fulvestrant) Blocks Tumoral Activity of Endometrial Cancer Cells

“…Our results provide the first evidence that dovitinib treatment sensitizes FGFR2 mutant cells to pure steroidal selective ER modulators such as ICI182.780. In breast cancer, some authors have reported in vitro and in vivo assays using combinational therapy using ICI182.780 with chemotherapeutic agents such as Doxorubicin (46); Paclitaxel (47), Vinorelbine (48), and Doxotaxel (49), although the results are quite promising, the number of studies is limited and combinational treatment using modern hormone therapy with chemotherapeutic agents has not been examined toughly; specially in endometrial carcinoma treatment. However, several experimental approaches using anticancer kinase inhibitors in tumor cells have revealed numerous feedback loops and have shown that blocking one signaling pathway can block tumor growth partially, but they are not sufficient to cause a complete tumor regression, thereby allowing resistant cells to emerge (50).…”

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

“…MCF-7 cells (1.1x10 4 ) were seeded in a 6-well plate. After cell adherence and rapid growth, cells were treated with TPI at different concentrations for 24 h, after which cold PBS was used to stop each treatment.…”

“…Currently, breast cancer is classified into five major groups on the basis of molecular profiling. Doxorubicin, gemcitabine, and taxanes are major clinical chemotherapeutic agents (4,5) Side-effects and drug resistance are common problems in patients taking long-term medication (6).…”

Current medical treatment of estrogen receptor-positive breast cancer

“…It is useful especially in patients with advancer BC and as second-line therapy in TAM-resistant tumors [36] . Fulvestrant sensitizes ER-negative BC to chemotherapy, showing a synergistic action with various cytotoxic agents, such as docetaxel [39,40] . In the treatment of patients with metastatic ER+ BC, the combination of fulvestrant plus an AI (anastrozole) was superior to anastrozole alone, and fulvestrant as single-drug therapy represents a reasonable alternative to AIs [41,42] .…”