Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines.
Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines.
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在阿霉素 - 巴列赛序列中添加5-氟尿嘧啶会增加乳腺癌细胞系中caspase依赖性凋亡。
DOI：
10.1186/bcr1274
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发表时间：
2005
影响因子：
7.4
通讯作者：
Amadori, D
中科院分区：
文献类型：
--
作者：
Zoli, W;Ulivi, P;Tesei, A;Fabbri, F;Rosetti, M;Maltoni, R;Giunchi, DC;Ricotti, L;Brigliadori, G;Vannini, I;Amadori, D
该研究的目的是评估阿霉素 (Dox)、紫杉醇 (Pacl) 和 5-氟尿嘧啶 (5-FU) 组合的活性，以确定最有效的治疗方案，并研究在人类乳腺癌细胞中的作用机制。该研究在 MCF-7 和 BRC-230 细胞系上进行。通过磺胺罗丹明 B 测定评估细胞毒活性，并通过中值效应原理评估药物相互作用的类型。通过流式细胞仪评估细胞周期扰动和细胞凋亡，并通过蛋白质印迹评估细胞凋亡相关标志物（p53、bcl-2、bax、p21）、半胱天冬酶和胸苷酸合酶（TS）表达。 5-FU 作为单一药物使用，在两种细胞系中均表现出较低的细胞毒活性。 Dox→Pacl 序列产生协同杀细胞作用，并增强了两种细胞系随后暴露于 5-FU 的功效。具体来说，Dox→Pac1 序列将细胞阻断在 G2-M 期，而添加 5-FU 则迫使细胞完成细胞周期或杀死它们。此外，Dox→Pacl 预处理使两种细胞系的基础 TS 表达显着降低，可能有利于 5-FU 活性的增加。序列 Dox→Pacl→48-h 清洗→5-FU 产生协同且高度依赖于时间表的相互作用（组合指数 < 1），导致在两个实验模型中诱导细胞凋亡，无论激素、p53、bcl-2 或 bax 状态如何。通过 caspase-9 激活和抗凋亡诱导因子过度表达诱导 MCF-7 细胞凋亡。在 BRC-230 细胞系中，细胞凋亡过程仅由半胱天冬酶依赖性机制触发。特别是，在三种药物治疗结束时，caspase-8 激活触发了下游刽子手 caspase-3，并在较小程度上触发了 caspase-7。在我们的实验模型中，不同的生物分子谱代表了人类乳腺癌的不同生物学特性，Dox→Pacl→48小时冲洗→5-FU的方案高度活跃且具有方案依赖性，最近已用于规划I/II期临床方案。
The aim of the study was to evaluate the activity of a combination of doxorubicin (Dox), paclitaxel (Pacl) and 5-fluorouracil (5-FU), to define the most effective schedule, and to investigate the mechanisms of action in human breast cancer cells. The study was performed on MCF-7 and BRC-230 cell lines. The cytotoxic activity was evaluated by sulphorhodamine B assay and the type of drug interaction was assessed by the median effect principle. Cell cycle perturbation and apoptosis were evaluated by flow cytometry, and apoptosis-related marker (p53, bcl-2, bax, p21), caspase and thymidylate synthase (TS) expression were assessed by western blot. 5-FU, used as a single agent, exerted a low cytotoxic activity in both cell lines. The Dox→Pacl sequence produced a synergistic cytocidal effect and enhanced the efficacy of subsequent exposure to 5-FU in both cell lines. Specifically, the Dox→Pacl sequence blocked cells in the G2-M phase, and the addition of 5-FU forced the cells to progress through the cell cycle or killed them. Furthermore, Dox→Pacl pretreatment produced a significant reduction in basal TS expression in both cell lines, probably favoring the increase in 5-FU activity. The sequence Dox→Pacl→48-h washout→5-FU produced a synergistic and highly schedule-dependent interaction (combination index < 1), resulting in an induction of apoptosis in both experimental models regardless of hormonal, p53, bcl-2 or bax status. Apoptosis in MCF-7 cells was induced through caspase-9 activation and anti-apoptosis-inducing factor hyperexpression. In the BRC-230 cell line, the apoptotic process was triggered only by a caspase-dependent mechanism. In particular, at the end of the three-drug treatment, caspase-8 activation triggered downstream executioner caspase-3 and, to a lesser degree, caspase-7. In our experimental models, characterized by different biomolecular profiles representing the different biology of human breast cancers, the schedule Dox→Pacl→48-h washout→5-FU was highly active and schedule-dependent and has recently been used to plan a phase I/II clinical protocol.
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影响因子：
11.2
作者：
Bröker, LE;Huisman, C;Giaccone, G
通讯作者：
Giaccone, G
影响因子：
45.3
作者：
Weiss, RB;Woolf, SH;Norton, L
通讯作者：
Norton, L
影响因子：
45.3
作者：
Holmes, FA;Madden, T;Hortobagyi, GN
通讯作者：
Hortobagyi, GN
影响因子：
8.4
作者：
Peters, GJ;van Triest, B;Pinedo, HM
通讯作者：
Pinedo, HM
影响因子：
8.8
作者：
Zaffaroni, N;Silvestrini, R;Villa, R
通讯作者：
Villa, R