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Estrogen Down-Regulator Fulvestrant Potentiates Antitumor Activity Of in vivo 33 : 1439-1445 (2019) doi:10.21873/invivo.11622 Estrogen Down-regulator Fulvestrant Potentiates Antitumor Activity of Fluoropyrimidine in Estrogen-responsive MCF-7 Human Breast Cancer Cells MAMORU NUKATSUKA 1, HITOSHI SAITO 2, SHINZABURO NOGUCHI 3 and TEIJI TAKECHI 1 1Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan; 2Pharmacology Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan; 3Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka, Japan Abstract. Background: Endocrine therapy is clinically where it remains the fifth-leading cause of cancer-related administered in hormone-responsive breast cancer. death (3). Endocrine therapy is a well-established first-line Combinations of fluoropyrimidine S-1 and an aromatase treatment for estrogen receptor (ER)- α- positive, metastatic inhibitor or anti-estrogen are considered beneficial in Japan. breast cancer (4). Current endocrine therapy treatment Herein we assessed new combinations of S-1 and fulvestrant. options for menopausal patients with hormone-responsive Patients and Methods: Cytotoxicity of fulvestrant and breast cancer include selective ER α modulators ( e.g. 5-fluorouracil (5-FU) was assessed in hormone-responsive tamoxifen), aromatase inhibitors ( e.g. anastrozole, letrozole, (MCF-7) and non-responsive (MDA-MB-231) breast cancer and exemestane), and, in addition, selective ER α down- cell cultures. Fulvestrant and S-1 were evaluated for regulators ( e.g. fulvestrant). An evaluation of several clinical antitumor activity in mice and their effects on estrogen trials of combination therapies testing fulvestrant with receptor (ER)- α and progesterone receptor (PgR) levels in cyclin-dependent kinase 4 and 6 inhibitors [PALOMA-3 (5), MCF-7 xenografts using immunohistochemical methods. MONALEESA-3 (6), and MONARCH2 (7)] or Results: Fulvestrant inhibited growth of MCF-7, but not of phosphoinositide 3-kinase inhibitors [FERG1 (8), BELLE-2 MDA-MB-231 xenografts. Combinations of 5-FU and (9), BELLE-3 (10)] indicated that combination with the fulvestrant were superior to monotherapy in vitro. In vivo cyclin-dependent kinase 4 and 6 inhibitor palbociclib was antitumor activity of S-1/fulvestrant combination therapy associated with a significantly extended progression-free was significantly (p<0.05) enhanced compared to that of survival as compared with that of fulvestrant monotherapy. both monotherapies. Fulvestrant partially down-regulated According to the guideline from the European Society for expression of ER α and PgR, but in combination with S-1, it Medical Oncology, antagonistic interactions are predicted to almost completely blocked their expression. Conclusion: occur using concomitant combination therapy of endocrine Chemo-endocrine combination therapy using S-1 and therapy and chemotherapy, and, therefore, simultaneous fulvestrant is beneficial in estrogen-responsive breast cancer. chemo-endocrine therapy is not recommended (11). However, in contrast to other chemotherapeutic agents, Breast cancer is the most common cancer in women around clinical trials in Japan showed that only tegafur (a masked 5-FU the world, including in the United States (1, 2) and Japan, derivative)/uracil (UFT), an oral fluoropyrimidine, used in combination with tamoxifen, improved overall survival, compared to surgery alone (12, 13). Furthermore, there was no significant difference in relapse-free survival between those This article is freely accessible online. treated with UFT therapy and cyclophosphamide/methotrexate/ 5-fluorouracil (5-FU) therapy (14, 15). We attempted to Correspondence to: Mamoru Nukatsuka Ph.D., 224-2, Ebisuno confirm the conclusions of this clinical trial. In vitro studies on Hiraishi, Kawauchi-Cho Tokushima-Shi, Tokushima 771-0194, ER-positive human breast cancer cell lines KPL-1 and ML-20 Japan. Tel: +81 886655337, Fax: +81 886655296, e-mail: showed that 4-OH-tamoxifen exerted synergistic inhibitory [email protected] effects with 5-FU but not with doxorubicin or paclitaxel (16). Kew Words: Breast cancer, endocrine therapy, chemotherapy, Furthermore, in vitro growth inhibition by 5-FU was assessed progesterone receptor, estrogen receptor, S-1, fulvestrant, chemo- in the presence and absence of 17 β- estradiol (E 2). Growth of endocrine combination therapy. KPL-1 and ML-20 cells was inhibited in E 2-depleted fetal 1439 in vivo 33 : 1439-1445 (2019) bovine serum (FBS), which mimics the status after treatment the serum level in mice achieved by administering the E 2 pellet with an aromatase inhibitor (17). based on our previous experiment (data not shown). Fulvestrant and Oral fluoropyrimidine S-1 contains tegafur in combination 5-FU were dissolved in DMSO and diluted with culture medium on day 1. The final DMSO concentration was less than 0.5%. Cell with gimeracil (a potent inhibitor of 5-FU degradation) and growth rates were determined colorimetrically on day 6 by crystal potassium oxonate at a molar ratio of 1: 0.4: 1; the violet staining according to the method reported by Saotome et al. combination has lower gastrointestinal toxicity by blocking (27). The concentration inhibiting cell growth by 50% (IC 50 ) was 5-FU activation in the gastrointestinal tract (18, 19). S-1 is calculated by regression analysis. considered beneficial and is approved as a clinical therapy Interactions between 5-FU and fulvestrant against MCF-7 cells for gastric (20), breast (21) and other solid tumor types in were analyzed using the isobologram method (28). The dose–response over 40 countries. S-1 potentiates the antitumor activity of curves for treatment with 5-FU and fulvestrant alone were used to derive three isoeffect curves (Mode I, IIa, and IIb), which were anastrozole in vitro as observed using an aromatase- analyzed in relation to the IC 50 values. The areas enclosed by the transfected, ER-positive human breast cancer cell line, and three isoeffect curves shown in Figure 2 indicate the envelope. The in vivo (22). In addition to aromatase inhibitors, the specific data points located within the envelope represent additive effects, and ER down-regulator fulvestrant (23) is approved for data points below the envelope represent supra-additive effects. menopausal patients with hormone-responsive breast cancer (24-26). However, studies on combination therapies In vivo antitumor activity. Five-week-old female BALB/cAJcl nu/nu consisting of fulvestrant and other chemotherapeutics are mice were purchased from CLEA Japan Inc. (Tokyo, Japan) and limited. In this study, we aimed to evaluate a new chemo- housed under specific pathogen-free conditions; food and water were provided ad libitum . After the animals had been in quarantine endocrine therapy using S-1 in combination with fulvestrant. for 5 days, SE-121 pellet (0.025 mg E 2/pellet) was implanted into the left flank subcutaneously. Because high E 2 doses were found to Patients and Methods be associated with high mortality in mice due to renal toxicity in a preliminary experiment, one pellet containing 0.025 mg E 2 per Chemicals. Tegafur, gimeracil, and potassium oxonate were animal was identified as the optimal amount (data not shown). obtained from Taiho Pharmaceutical Co., Ltd. (Tokyo, Japan). One week after the procedure, MCF-7 cells suspended in saline Fulvestrant was purchased from Funakoshi Co., Ltd. (Tokyo, Japan). were injected in the right axillary subcutaneously at a dose of 4×10 6 E2, Dulbecco’s modified Eagle’s medium/Ham’s F-12 (1:1) and FBS cells per mouse. To evaluate the antitumor activity, the mice were were purchased from Sigma–Aldrich Japan (Tokyo, Japan). SE-121 randomized according to tumor volume once the mean tumor 3 pellet, which contained 0.025 mg E 2/pellet for a 60-day release volume reached approximately 38-46 mm (day 0). Each group period, was obtained from Innovative Research of America consisted of seven mice. One group of mice with no tumor- and SE- (Sarasota, FL, USA). Hydroxypropyl methylcellulose was purchased 121-pellet-free was used as negative control (n=7). from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). 5-FU, peanut S-1 was prepared by mixing tegafur, gimeracil, and potassium oil, dimethyl sulfoxide (DMSO), and crystal violet were purchased oxonate at a molar ratio of 1:0.4:1 in 0.5% hydroxypropyl from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan). methylcellulose. S-1 was administered orally at the reported All other reagents were commercially available products of the effective dose (10 mg/kg, at 10 ml/kg) (18) once daily for 18 highest grade. consecutive days. Fulvestrant was dissolved in peanut oil and administered into the left femor subcutaneously on day 1 at a dose Antibodies. Rabbit monoclonal antibodies to human ER α ( ab16660, of 5 mg in 50 μl per animal. Clone SP1 ) and human progesterone receptor (PgR) (ab16661, The tumor diameters were measured twice a week until day 18, Clone SP2) were purchased from Abnova Japan KK (Tokyo, Japan). the last day of administration, and the tumor volume was estimated Horseradish peroxidase-conjugated goat anti-rabbit IgG Fab using the formula 0.5× length × width 2. fragment HistostarTM (Rb) for mouse tissue analysis was purchased All the animal studies were performed according to the from Medical & Biological Laboratories Co., Ltd. (Nagoya, Japan) guidelines of and approved by the Institutional Animal Care and and used for immunohistochemical (IHC) staining. Use Committee at Taiho Pharmaceutical Co., Ltd. (Approval Number: 17PB06). In vitro cell culture and growth inhibition testing. ER-positive human breast cancer cell line MCF-7, originally obtained from the IHC staining of ER α and PgR. To perform the IHC staining on American Tissue Culture Collection (ATCC, Rockville, MD, USA), mouse tissue, tumors were excised on day 19, the day after the last was kindly provided by the Osaka University Graduate School of S-1 administration, fixed in 10% phosphate-buffered formaldehyde Medicine (Osaka, Japan) and ER-negative human breast cancer cell (pH 7.4) for 1 day followed by the preparation of paraffin- line MDA-MB-231 was purchased from the ATCC.
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