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Objective:To investigate effects of capecitabine metronomic chemotherapy combined with exemestane on the proliferation of breast cancer MCF-7 cells and PI3-K/AKT signaling pathway.Methods:MCF-7 cells cultured in vitro were divided into the control group (adding DMEM without drugs), 30 μmol/L exemestane group, capecitabine metronomic chemotherapy combined drugs group [30 μmol/L exemestane combined with different concentrations (50, 33, 17 μmol/L) of capecitabine]. CCK-8 assay was used to detect the cell proliferation inhibition rate, the half-maximal inhibitory concentration ( IC50) was calculated, and the changes of cell cycle and apoptosis rate of MCF-7 in different drug groups were assessed by using flow cytometry. The related-protein expression of PI3K-AKT signaling pathway of MCF-7 cells was detected by using Western blot. Results:The IC50 of capecitabine and exemestane on MCF-7 cells for 72 h was 101.2 μmol/L and 60.6 μmol/L, respectively. The proliferation inhibition rate of MCF-7 cells in 30 μmol/L exemestane for 24 h and 48 h combined with 50, 33 and 17 μmol/L capecitabine group was higher than that in 30 μmol/L exemestane group (all P<0.01). The apoptosis rates were (18.1±2.6)%, (34.6±3.0)%, (27.6±1.3)%, (23.1±1.6)%, respectively in 30 μmol/L exemestane group, 30 μmol/L exemestane + 50 μmol/L capecitabine group, 30 μmol/L exemestane + 33 μmol/L capecitabine group, 30 μmol/L exemestane + 17 μmol/L capecitabine group, and the difference was statistically significant ( F = 23.652, P<0.01). Compared with the control group, the proportion of MCF-7 cells in phase G 2 of 30 μmol/L exemestane group was increased [(16.7±2.6)% vs. (10.6±2.2)%], while that in phase G 1 was decreased [(53.3±4.0)% vs. (56.3±3.2)%]. The proportion of MCF-7 cells in phase S of 30 μmol/L exemestane + 50 μmol/L capecitabine group was increased [(39.0±3.6)% vs. (33.1±2.0)%]. MCF-7 cells of 30 μmol/L of exemestane + 33 μmol/L capecitabine group were more blocked in phase S [(51.7±4.1)%], and cells in phase G 2 were nearly disappeared [(1.2±0.5)%]; the cell proportion MCF-7 cells in phase G 2 of 30 μmol/L exemestane plus 17 μmol/L capecitabine group was increased [(26.2±3.1)%]. Western blot analysis showed that low dose capecitabine metronomic chemotherapy promoted exemestane to inhibit the expression of PI3K, motivated AKT serine phosphorylated at protein 473 [the increased expression of p-AKT (473)], promoted S6 protein expression at downstream of signaling pathway and increased its phosphorylation level (the increased expression of p-S6), thereby activating apoptosis signal. Conclusion:Capecitabine metronomic chemotherapy combined with exemestane can synergistically inhibit the proliferation of breast cancer MCF-7 cells and activate apoptosis mechanisms of MCF-7 cells through affecting PI3K-AKT signaling pathway.
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Background and purpose:Radiotherapy and endocrine therapy are both important parts of adjuvant therapy for breast cancer, yet few studies have been conducted focusing on the interaction between radiation and endocrine therapy. Up to now, no conclusion has been drawn on the timing sequence of adjuvant radiation and endocrine therapy, which is indeed crucial in clinical practice. This study intended primarily to investigate the effect of concurrent or sequential exemestane combined with radiation on radiosensitivity of MCF-7 cells and its possible mechanism,and further to provide rationale for optimal clinical treatment modality.Methods:MCF-7 cells were arranged into three trial groups: the radiation group, exemestane sequenced with radiation group and exemestane followed radiation group. Radiosensitivity was evaluated by clonogenic assay, cell proliferation was measured by MTT assay, the ability to induce cell apoptosis was evaluated by DAPI staining assay, the changes of Bcl-2 and Bax were detected by Western blot.Results:Sensitive enhancement ratios (SER) were 1.51 and 1.37 in the exemestane sequenced with radiation group and exemestane followed radiation group, respectively. Compared with the radiation group, the percentage of cellular proliferation inhibition and apoptosis increased obviously in the exemestane sequenced with radiation group and exemestane followed radiation group. Exemestane combined with radiation made the Bax protein increase obviously and the Bcl-2 protein lowered significantly.Conclusion:Exemestane can enhance the radiosensitivity of MCF-7 cells, whose mechanism might be relevant to the promotion of cellular apoptosis. However,the treatment sequence does not affect the outcome.
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Objective To investigate the combined effect of exemestane and low-dose methotrexate on exemestane-resistant MCF-7 human breast cancer cells( MCF-7/EXE). Methods Antiproliferative effects of exemestane and low-dose of methotrexate, alone and in combination on growth of MCF-7/EXE cells were assessed by using the MTT assay. Synergistic interaction between the two drugs was evaluated in vitro by using the combination index ( CI) method. The cell cycle distribution was analyzed by flow cytometry in a half inhibitory concentration of exemestane and low-dose of methotrexate . The changes of apoptosis on MCF-7/EXE cells exposed to two drugs alone or in com-bination were observed by fluorescence microscope. The expression of Bcl-2,AKT,P-AKT and cyclooxygenase-2 was investigated by Western blot. Results MTT assays indicated that the combination treatment apparently decreased the viability of MCF-7/EXE cells compared to single drug treatment (CI<0. 9). In addition, the combination of exemestane and low-dose methotrexate exhibited a synergistic inhibition of cell proliferation, arrested the cell cycle in the S phase significantly and produced a stronger inhibitory effects on P-AKT, Bcl-2 and cyclooxygenase-2 ex-pression than control or individual drug treatment. Conclusion The combination of the two inhibitors significantly increases the response as compared to single agent treatment, suggesting that combination treatment which can re-verse the resistance of exemestane could be a more effective approach to breast cancer.
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PURPOSE: Exemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported. METHODS: Data on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months). RESULTS: The median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs. CONCLUSION: Exemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment.
Subject(s)
Female , Humans , Androstadienes , Aromatase , Aromatase Inhibitors , Breast , Breast Neoplasms , Disease Progression , Disease-Free Survival , Medical Records , Multivariate Analysis , Neoplasm Metastasis , ErbB Receptors , Receptor, ErbB-2 , Retrospective StudiesABSTRACT
Objective To observe the efficacy and side effects of exemestane in postmenopausal breast cancer patients with bone metastasis.Methods One hundred and ten postmenopausal breast cancer patients with bone metastasis were treated with exemestane 25 mg.Results In the evaluable data from 110 patients,the complete remission(CR)was encountered in 7 cases,partial remission(PR)in 28 cases,with a total response rate of 31.8％ ;Thirty nine patients had stabled diseases for more than 24 weeks.It produced a clinical benefit (CR + PR + SD)over 24 weeks in 74 cases(67.3％).Diseases progressed in 12 of the cases(10.9％).The patients with positive ER and PR status had a higher chance to be benefited from the treatment than those with negative receptor status.The clinical efficacy was not correlated with treatment history,pathological subtypes and bone,liver,lung and lymph node metastasis(x2 =0.045,0.078,0.200,P ＞ 0.05).No severe adverse effects were observed.Conclusion Exemestane is effective to treat bone metastasis of breast cancer with minor adverse reactions and good tolerability.
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Background and purpose:Tamoxifen is the main endocrine therapy of premenopausal breast cancer with positive hormone receptors but numerous patients have developed advanced refractory breast cancer due to drug resistance.Our study investigated the role of combining oophorectomy and exemestane in the treatment of advanced refractory breast cancer.Methods:Oophorectomy was carried out in all patients.Exemestane was administered orally (25 mg/d) one week after the operation.The median time of progression (TTP),the median survival time as well as the survival rate were calculated using the Kaplan-Meier methods.Results:Seventeen patients ranging between the ages of 26 and 44 years (median:36 years) were treated resulting in an overall response rate of 64.70%,TTP was 8 months and the median survival time was 31 months.The survival rates for 1 year,3 years and 5 years were 88.24%,64.71%,29.41%,respectively.No grade Ⅲ and Ⅳ side effects appeared.Conclusion:Oophorectomy when combined with exemestane showed antitumor activity for advanced refractory premenopausal breast cancer through positive hormone receptor and it is also well-tolerated.
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Objective To determine the investigation progression on exemestane in the treatment of breast cancer. Methods The literatures of recent years on the studies of exemestane were reviewed. Results Exemestane is an effective steroidal aromatase inactivator with superior tolerability, safety and efficacy in the adjuvant, neo-adjuvant and metastatic therapy of breast cancer. Conclusion With the progression of clinical trial with exmestane, exemestane will be regarded as an important drug in comprehensive therapy of breast cancer.
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0.05),while those of the cells treated with 6?10-5,6?10-6,6?10-7 mol/L of exemestane were significantly different from that of controls(P