Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.
Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis.
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DOI：
10.1158/0008-5472.can-16-0122
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发表时间：
2016-10-01
期刊：
影响因子：
11.2
通讯作者：
Houghton PJ
中科院分区：
文献类型：
--
作者：
Murphy B;Yin H;Maris JM;Kolb EA;Gorlick R;Reynolds CP;Kang MH;Keir ST;Kurmasheva RT;Dvorchik I;Wu J;Billups CA;Boateng N;Smith MA;Lock RB;Houghton PJ
使用人肿瘤异种移植模型评价抗肿瘤剂的传统方法通常使用8-10只小鼠的队列对抗有限的一组肿瘤模型。另一种方法是每个肿瘤系使用更少的动物，允许更多数量的模型捕获癌症类型的更大分子/遗传异质性。我们回顾性分析了67种由儿科临床前测试计划（PPTP）评估的药物，以确定是否从研究的每组中随机选择一只小鼠，预测使用83种异种移植模型的小鼠组的中位反应。使用已确立的缓解标准，将随机选择的小鼠的个体肿瘤缓解与组中位缓解进行比较。共进行了2134次比较。在1604次比较中，单个肿瘤缓解准确预测了组中位缓解（75.16%）。1,000只小鼠随机样本的平均肿瘤反应正确预测率为78.09%。模型具有正确预测的范围（60%-87.5%）。考虑到± 1个缓解类别的错误预测，总体平均正确的单个小鼠预测率为95.28%，并预测了67项药物研究中66项的组数据的总体客观缓解率。对于分子靶向药物，鉴定了偶尔例外的应答者模型，并在具有相同基因型的其他模型中证实了该药物的活性。假设目标是大的治疗效果，这种替代实验设计具有与传统方法相似的预测价值，允许使用更大数量的模型，更充分地涵盖疾病类型的异质性。
Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8–10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program (PPTP) to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared to the group median response using established response criteria. A total of 2134 comparisons were made. The single tumor response accurately predicted the group median response in 1604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%–87.5%). Allowing for mis-prediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types.