Rapid Screening of Novel Agents for Combination Therapy in Sarcomas
Rapid Screening of Novel Agents for Combination Therapy in Sarcomas
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DOI：
10.1155/2013/365723
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Reed, Damon R.
中科院分区：
文献类型：
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作者：
Cubitt, Christopher L.;Menth, Jiliana;Reed, Damon R.
对于肉瘤患者，转移性疾病仍然很难治愈，结果仍然不理想。治疗选择并没有很大的改变，尽管在使用靶向药物治疗特定亚型的单一药物方面取得了一些有希望的进展。在这里，我们开发了一个系统来研究靶向和细胞毒性药物在一组肉瘤细胞系中的联合协同作用。研究了药物单独和不同剂量比的联合作用。剂量-反应曲线采用Chou和Talalay（1984）的方法分析协同作用。在A673细胞系小鼠模型中，研究了达沙替尼和曲西利滨的一种有前景的组合，并通过MRI和组织学评估了肿瘤的治疗效果。我们发现组蛋白去乙酰化酶抑制剂与依托泊苷、达沙替尼和Akt抑制剂在细胞系中具有协同作用。索拉非尼和拓扑替康表现出不同的反应。我们系统的药物筛选方法使我们能够筛选大量的肉瘤药物组合。这种方法可以很容易地修改以适应其他细胞系模型，并且验证性分析，例如动物实验，可以为这些罕见恶性肿瘤的临床试验提供出色的临床前数据。
For patients with sarcoma, metastatic disease remains very difficult to cure, and outcomes remain less than optimal. Treatment options have not largely changed, although some promising gains have been made with single agents in specific subtypes with the use of targeted agents. Here, we developed a system to investigate synergy of combinations of targeted and cytotoxic agents in a panel of sarcoma cell lines. Agents were investigated alone and in combination with varying dose ratios. Dose-response curves were analyzed for synergy using methods derived from Chou and Talalay (1984). A promising combination, dasatinib and triciribine, was explored in a murine model using the A673 cell line, and tumors were evaluated by MRI and histology for therapy effect. We found that histone deacetylase inhibitors were synergistic with etoposide, dasatinib, and Akt inhibitors across cell lines. Sorafenib and topotecan demonstrated a mixed response. Our systematic drug screening method allowed us to screen a large number of combinations of sarcoma agents. This method can be easily modified to accommodate other cell line models, and confirmatory assays, such as animal experiments, can provide excellent preclinical data to inform clinical trials for these rare malignancies.