Abstract

1. The in vitro antitumor activity (e.g. IC₅₀) of anticancer drugs is important for selecting candidate compounds for in vivo drug efficacy study in the early stage of drug discovery. In this study, we investigated the relationship between in vitro IC₅₀ and in vivo EC₅₀ using six heat shock protein 90 (HSP90) inhibitors.

2. IC₅₀ of each compound was calculated from in vitro cell proliferation assays using the NCI-N87 cancer cell line. Each compound was administered to NCI-N87 xenograft mice, and EC₅₀ and the maximum tumour-killing rate constant were calculated from pharmacokinetics/pharmacodynamics analyses using plasma concentrations and tumour volumes.

3. IC₅₀ obtained in vitro was poorly correlated with EC₅₀ obtained in vivo, while a good correlation (r = 0.856) was observed between them when corrected with the unbound fraction ratio.

4. The results of this study using of HSP90 inhibitors as model compounds suggest importance of the consideration of an unbound fraction to evaluate the relationship between IC₅₀ and EC₅₀. These results will contribute to improvement in the prediction accuracy of in vivo drug efficacy from in vitro activity and the efficiency of drug discovery research.

摘要

1. 的体外抗肿瘤活性（例如IC ₅₀抗癌药的）是用于选择候选化合物为重要的体内药物发现的早期阶段药物功效研究。在这项研究中，我们使用六种热休克蛋白 90 (HSP90) 抑制剂研究了体外IC ₅₀和体内EC ₅₀之间的关系。

2. 使用 NCI-N87 癌细胞系，从体外细胞增殖试验中计算出每种化合物的IC ₅₀。将每种化合物施用于 NCI-N87 异种移植小鼠，并使用血浆浓度和肿瘤体积从药代动力学/药效学分析计算EC ₅₀和最大肿瘤杀伤率常数。

3. 体外获得的IC ₅₀与体内获得的EC ₅₀相关性较差，而 当用未结合的分数比率校正时，它们之间观察到良好的相关性（r = 0.856）。

4. 该研究使用HSP90抑制剂作为模型化合物的结果表明考虑未结合部分以评估IC ₅₀和EC ₅₀之间的关系的重要性。这些结果将有助于提高从体外活性预测体内药效的准确性和药物发现研究的效率。