Fryar-Tita Elizabeth B, Das Jharna R, Davis J H, Desoto J A, Green Sidney, Southerland William M, Bowen Donnell
Department of Environmental Sciences and Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Anticancer Res. 2007 May-Jun;27(3B):1393-9.
Breast cancer patients are at increased risk of osteoporosis. Contributing factors include age and/or chemotherapy. The selective estrogen modulator, raloxifene (RAL), effective in the prevention of breast cancer and approved for the treatment and prevention of osteoporosis, may prove beneficial in current breast cancer treatment modules. The purpose of this study was to evaluate RAL in combination with 5-fluorouracil (5-FU) and trimetrexate (TMX) to determine the most effective sequence in which to administer these cell cycle specific agents while taking into consideration the cellular mechanism of action. The goal was to maintain cytotoxicity to breast cancer cells and capitalize on the selective estrogen receptor modulatory effects of RAL.
MCF-7 cells were exposed to (i) TMX, 5-FU or RAL alone, or (ii) RAL 24 h prior to 5-FU followed 2 h later by TMX, or (iii) 5-FU 2 h prior to TMX followed 24 h later by RAL. The cell viability was determined using the Quick Cell Proliferation Assay.
The growth rate of MCF- 7 cells exposed to early RAL was 68.25 +/- 4.11% that of the control, however, late RAL exposure produced a growth of 34.75 +/- 4.79% that of the control. Late RAL maintained the cytotoxicity of the regimen. The findings were further supported by cell flow cytometry and Western blot analysis data.
RAL given prior to 5-FU/TMX significantly compromised cytotoxicity to breast cancer cells.
乳腺癌患者患骨质疏松症的风险增加。促成因素包括年龄和/或化疗。选择性雌激素调节剂雷洛昔芬（RAL）对预防乳腺癌有效且已被批准用于治疗和预防骨质疏松症，可能在当前的乳腺癌治疗模式中被证明是有益的。本研究的目的是评估RAL与5-氟尿嘧啶（5-FU）和三甲曲沙（TMX）联合使用时，在考虑细胞作用机制的情况下确定这些细胞周期特异性药物给药的最有效顺序。目标是维持对乳腺癌细胞的细胞毒性，并利用RAL的选择性雌激素受体调节作用。
MCF-7细胞分别暴露于（i）单独的TMX、5-FU或RAL，或（ii）在5-FU前24小时给予RAL，随后2小时给予TMX，或（iii）在TMX前2小时给予5-FU，随后24小时给予RAL。使用快速细胞增殖测定法测定细胞活力。
早期暴露于RAL的MCF-7细胞的生长率为对照组的68.25±4.11%，然而，晚期暴露于RAL后的生长率为对照组的34.75±4.79%。晚期给予RAL维持了该方案的细胞毒性。细胞流式细胞术和蛋白质印迹分析数据进一步支持了这些发现。
在5-FU/TMX之前给予RAL显著降低了对乳腺癌细胞的细胞毒性。
