Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays.
Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays.
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DOI：
10.18632/oncotarget.12673
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发表时间：
2017-01-31
期刊：
影响因子：
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通讯作者：
Eastman A
中科院分区：
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作者：
Eastman A
抗癌药物发现和开发的高失败率每年消耗数十亿美元。虽然已经提供了许多解释，但我认为，由于不适当的细胞筛选而产生的错误信息已被完全忽视。大多数细胞培养实验与随后如何向患者施用药物无关。通常，药物开发的重点是生长抑制，而不是细胞杀伤。药物的选择是基于细胞的连续孵育，然后经常给予患者作为一个团。靶标识别和验证通常通过不可避免地模仿连续靶标抑制的基因抑制来进行。体外药物浓度经常远远超过体内浓度。在次优浓度下进行药物协同作用的研究。而对有限数量细胞系的关注可能会歪曲患者群体的潜在疗效。本综述的目的是鼓励更合适的实验设计和数据解释，并改善药物开发领域的细胞为基础的测定。这些原则的应用将大大提高新药成功地转化为患者。
The high failure rate of anticancer drug discovery and development has consumed billions of dollars annually. While many explanations have been provided, I believe that misinformation arising from inappropriate cell-based screens has been completely over-looked. Most cell culture experiments are irrelevant to how drugs are subsequently administered to patients. Usually, drug development focuses on growth inhibition rather than cell killing. Drugs are selected based on continuous incubation of cells, then frequently administered to the patient as a bolus. Target identification and validation is often performed by gene suppression that inevitably mimics continuous target inhibition. Drug concentrations in vitro frequently far exceed in vivo concentrations. Studies of drug synergy are performed at sub-optimal concentrations. And the focus on a limited number of cell lines can misrepresent the potential efficacy in a patient population. The intent of this review is to encourage more appropriate experimental design and data interpretation, and to improve drug development in the area of cell-based assays. Application of these principles should greatly enhance the successful translation of novel drugs to the patient.