Despite an improvement of prognosis in breast and colon cancer, the outcome of the metastatic disease is still severe. Microevolution of cancer cells often leads to drug resistance and tumor-recurrence. To target the driving forces of the tumor microevolution, we focused on synergistic drug combinations of selected compounds. The aim is to prevent the tumor from evolving in order to stabilize disease remission. To identify synergisms in a high number of compounds, we propose here a three-step concept that is cost efficient, independent of high-throughput machines and reliable in its predictions. We created dose response curves using MTT- and SRB-assays with 14 different compounds in MCF-7, HT-29 and MDA-MB-231 cells. In order to efficiently screen for synergies, we developed a screening tool in which 14 drugs were combined (91 combinations) in MCF-7 and HT-29 using EC25 or less. The most promising combinations were verified by the method of Chou and Talalay. All 14 compounds exhibit antitumor effects on each of the three cell lines. The screening tool resulted in 19 potential synergisms detected in HT-29 (20.9%) and 27 in MCF-7 (29.7%). Seven of the top combinations were further verified over the whole dose response curve, and for five combinations a significant synergy could be confirmed. The combination Nutlin-3 (inhibition of MDM2) and PX-478 (inhibition of HIF-1α) could be confirmed for all three cell lines. The same accounts for the combination of Dichloroacetate (PDH activation) and NHI-2 (LDH-A inhibition). Our screening method proved to be an efficient tool that is reliable in its projections. The presented three-step concept proved to be cost- and time-efficient with respect to the resulting data. The newly found combinations show promising results in MCF-7, HT-29 and MDA-MB231 cancer cells.

中文翻译：

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人类乳腺癌和结肠癌细胞系中基因组和代谢稳定抗肿瘤疗法（GMSAT）的协同作用：一种筛选协同作用的新方法。

尽管乳腺癌和结肠癌的预后有所改善，但转移性疾病的结果仍然很严重。癌细胞的微进化常常导致耐药性和肿瘤复发。为了瞄准肿瘤微进化的驱动力，我们专注于选定化合物的协同药物组合。目的是防止肿瘤发展，以稳定疾病缓解。为了识别大量化合物的协同作用，我们在此提出了一个三步概念，该概念具有成本效益、独立于高通量机器且预测可靠。我们使用 MTT 和 SRB 测定法在 MCF-7、HT-29 和 MDA-MB-231 细胞中对 14 种不同的化合物创建了剂量反应曲线。为了有效筛选协同作用，我们开发了一种筛选工具，其中使用 EC25 或更低将 14 种药物（91 种组合）组合在 MCF-7 和 HT-29 中。最有希望的组合通过 Chou 和 Talalay 的方法进行了验证。所有 14 种化合物均对三种细胞系均表现出抗肿瘤作用。该筛选工具在 HT-29 中检测到了 19 种潜在协同作用（20.9%），在 MCF-7 中检测到了 27 种潜在协同作用（29.7%）。其中七个组合在整个剂量反应曲线上得到了进一步验证，并且对于五个组合可以确认显着的协同作用。Nutlin-3（抑制 MDM2）和 PX-478（抑制 HIF-1α）的组合可以在所有三种细胞系中得到证实。二氯乙酸盐（PDH 激活）和 NHI-2（LDH-A 抑制）的组合也是如此。事实证明，我们的筛选方法是一种有效的工具，其预测也是可靠的。事实证明，所提出的三步概念对于所得数据而言具有成本效益和时间效率。新发现的组合在 MCF-7、HT-29 和 MDA-MB231 癌细胞中显示出有希望的结果。