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- W2013710945 abstract "Purpose/Objective: Radiation therapy is considered as a standard treatment after surgery for breast cancer in majority of all clinical cases. Adjuvant hormonotherapy with Tamoxifen is widely used in case of estrogeno-dependant post menopausic breast cancer. Experimental studies reported opposite results of the effects of Tamoxifen in combination with ionizing radiation. Recent clinical study confirmed the augmentation of lung fibrosis when these two agents are used in combination. Aromatase inhibitors, such as Letrozol (Femara®), seem to be superior than Tamoxifen in metastatic breast cancer disease with poorer side effects. An ongoing clinical randomised study is being comparing these two drugs in adjuvant setting. In this view, the goal of our study was to evaluate the benefit of the combination of radiation and Letrozol in a pre-clinical model. Materials/Methods: We used human mammary adenocarcinoma cell lines (MCF7–3 (1) and (2)) for all the experiments. MCF7–3 (1) and (2) are transfected cell lines with pHβ-Apr-1-neo vector and with the aromatase expression plasmid, pHβ-neo/aromatase cDNA, respectively. The cells were cultured in DCC and phenol red free medium. All irradiations were performed using a cobalt-60 source with ranging doses from 2 to 6 Gy. All cells were incubated with Letrozol and androstendione (100nM) during one week before the irradiation. To evaluate the effects of letrozol on aromatase activity, we used a radiometric aromatase assay (3H2O release assay). Cytotoxicities of letrozol (0.7μM–7nM) and radiotherapy used alone or in combination were evaluated using clonogenic, M.T.T., and cells numeration assays. In addition, cell cycle analysis using flow cytometry were performed to approach the mechanism of action of our experimental findings. Results: Treatment with Letrozol in MCF7–3 (2) shutted down the measured aromatase activity to the control cells level. Cells numeration assay showed an inhibition of 50 and 75% of the growth of the MCF7–3 (2) when Letrozol is used alone for more than 6 days at 0.7μM and 7nM, respectively. M.T.T. assay confirmed these first results. When radiation therapy was used alone, survival fraction decreased in a dose-dependant manner and survival curves were fitted using a linear-quadratic model. Survival fractions at 2 Gy (SF2) were 0.65 and 0.53 with radiation alone and radiation plus Letrozol, respectively (p=0.001). At 4 Gy, survival fractions were also statistically higher with radiation alone (0.56) than with radiation plus Letrozol (0.09, p=0.0001). Growth of MCF7–3 (2) was decrease by 76% (cells numeration) six days after radiotherapy (2 and 4 Gy) and Letrozol (0.7μM) treatment as compared to radiotherapy alone. This growth reduction of the MCF7–3 (2) cells was higher to 85% after twelve days of the same treatment combination. M.T.T. assay confirmed these results at 2 and 4 Gy in combination with Letrozol (0.7μM). After fifteen days of Letrozol (0.7μM) alone, cell cycle analyses showed a G1 arrest (77%) and a decrease of the S phase (13%) as compared to control cells, 63% and 27%, respectively. In combination treatment, as compared with radiation alone, we observed a decrease of the radio-induced G2 phase arrest (11% vs 15%), cell redistribution in the G1 phase (72% vs 62%), and a decrease of the S cell cycle phase (17% vs 23%). Conclusions: Letrozol is an active cytostatic or cytotoxic agent used alone in breast cancer transfected cell lines. In combination with radiation therapy, Letrozol has been proved to be a powerful radiosensitizer. These radiobiological results are the first pre-clinical findings of radiosensitization of Letrozol and will be further basis for adjuvant therapeutic combination in clinical settings." @default.
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- W2013710945 date "2003-10-01" @default.
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- W2013710945 title "Letrozole (Femara®) sensitises breast cancer cells to gamma irradiation" @default.
- W2013710945 doi "https://doi.org/10.1016/s0360-3016(03)01092-7" @default.
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