Metrics other than potency reveal systematic variation in responses to cancer drugs.
Metrics other than potency reveal systematic variation in responses to cancer drugs.
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DOI：
10.1038/nchembio.1337
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发表时间：
2013-11
影响因子：
14.8
通讯作者：
Sorger, Peter K.
中科院分区：
文献类型：
--
作者：
Fallahi-Sichani, Mohammad;Honarnejad, Saman;Heiser, Laura M.;Gray, Joe W.;Sorger, Peter K.
对抗癌药物的细胞反应的大规模分析通常集中在效力（IC 50）的变化上，假设这是有效/无效药物或敏感/耐药细胞之间最重要的差异。我们采用了多参数方法，包括分析剂量-反应曲线（HS）的斜率、曲线下面积（AUC）和最大效应（Emax）。我们发现这些参数中的一些随细胞系而系统地变化，而另一些则随药物类别而变化。对于细胞周期抑制剂，Emax通常但不总是与细胞增殖率相关。对于靶向Akt/PI 3 K/mTOR通路的药物，剂量-反应曲线异常浅。经典药理学对这种现象没有现成的解释，但单细胞分析表明，它与靶点抑制程度的显著和可遗传的细胞间变异性相关。我们得出结论，在药物反应的比较分析中应考虑效价以外的参数，特别是在接近和高于IC 50的临床相关浓度下。
Large-scale analysis of cellular response to anti-cancer drugs typically focuses on variation in potency (IC50) assuming that it is the most important difference between effective/ineffective drugs or sensitive/resistant cells. We took a multi-parametric approach involving analysis of the slope of the dose-response curve (HS), the area under the curve (AUC) and the maximum effect (Emax). We found that some of these parameters vary systematically with cell line and others with drug class. For cell-cycle inhibitors, Emax often but not always correlated with cell proliferation rate. For drugs targeting the Akt/PI3K/mTOR pathway dose-response curves were unusually shallow. Classical pharmacology has no ready explanation for this phenomenon but single-cell analysis showed that it correlated with significant and heritable cell-to-cell variability in the extent of target inhibition. We conclude that parameters other than potency should be considered in the comparative analysis of drug response, particularly at clinically relevant concentrations near and above IC50.
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影响因子：
11.2
作者：
Bazzaro, M;Lee, MK;Roden, RBS
通讯作者：
Roden, RBS
影响因子：
3.3
作者：
Mitchison TJ
通讯作者：
Mitchison TJ
影响因子：
64.8
作者：
Garnett, Mathew J.;Edelman, Elena J.;Heidorn, Sonja J.;Greenman, Chris D.;Dastur, Anahita;Lau, King Wai;Greninger, Patricia;Thompson, I. Richard;Luo, Xi;Soares, Jorge;Liu, Qingsong;Iorio, Francesco;Surdez, Didier;Chen, Li;Milano, Randy J.;Bignell, Graham R.;Tam, Ah T.;Davies, Helen;Stevenson, Jesse A.;Barthorpe, Syd;Lutz, Stephen R.;Kogera, Fiona;Lawrence, Karl;McLaren-Douglas, Anne;Mitropoulos, Xeni;Mironenko, Tatiana;Thi, Helen;Richardson, Laura;Zhou, Wenjun;Jewitt, Frances;Zhang, Tinghu;O'Brien, Patrick;Boisvert, Jessica L.;Price, Stacey;Hur, Wooyoung;Yang, Wanjuan;Deng, Xianming;Butler, Adam;Choi, Hwan Geun;Chang, JaeWon;Baselga, Jose;Stamenkovic, Ivan;Engelman, Jeffrey A.;Sharma, Sreenath V.;Delattre, Olivier;Saez-Rodriguez, Julio;Gray, Nathanael S.;Settleman, Jeffrey;Futreal, P. Andrew;Haber, Daniel A.;Stratton, Michael R.;Ramaswamy, Sridhar;McDermott, Ultan;Benes, Cyril H.
通讯作者：
Benes, Cyril H.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1073/pnas.1018360108
发表时间：
2011-05-03
影响因子：
11.1
作者：
Sampah, Maame Efua S.;Shen, Lin;Siliciano, Robert F.
通讯作者：
Siliciano, Robert F.