Yanagida Shota, Kanda Yasunari
Division of Pharmacology, National Institute of Health Sciences.
Graduate School of Biomedical and Health Sciences (Pharmaceutical Sciences), Hiroshima University.
Yakugaku Zasshi. 2024;144(3):265-271. doi: 10.1248/yakushi.23-00164-3.
Recent advances in cancer therapy have significantly improved the survival rate of patients with cancer. In contrast, anti-cancer drug-induced adverse effects, especially cardiotoxicity, have come to affect patients' prognosis and quality of life. Therefore, there is a growing need to understand the anti-cancer drug-induced cardiotoxicity. Human induced pluripotent stem (iPS) cell-derived cardiomyocytes (hiPSC-CMs) have been used to assess drug-induced cardiotoxicity by improving the predictability of clinical cardiotoxicity and the principles of the 3Rs (replacement, reduction and refinement). To predict the anti-cancer drug-induced cardiotoxicity, we developed a novel method to assess drug-induced proarrhythmia risk using hiPSC-CMs by participating in the international validation. In addition, we established the chronic contractility toxicity assessment by image-based motion analysis. The compound BMS-986094, which was withdrawn from clinical trials, inhibited contractility velocity and relaxation velocity in hiPSC-CMs. Currently, we are trying to investigate the predictability of the contractility assay by comparing the hiPSC-CM data with adverse events reports from real-world database. In this review, we would like to introduce the novel imaging-based contractility method using hiPSC-CMs and future perspectives in anti-cancer drug-induced cardiotoxicity.
癌症治疗的最新进展显著提高了癌症患者的生存率。相比之下,抗癌药物引起的不良反应,尤其是心脏毒性,已开始影响患者的预后和生活质量。因此,越来越需要了解抗癌药物引起的心脏毒性。人类诱导多能干细胞(iPS)衍生的心肌细胞(hiPSC-CMs)已被用于通过提高临床心脏毒性的可预测性和3R原则(替代、减少和优化)来评估药物引起的心脏毒性。为了预测抗癌药物引起的心脏毒性,我们通过参与国际验证,开发了一种使用hiPSC-CMs评估药物引起的心律失常风险的新方法。此外,我们通过基于图像的运动分析建立了慢性收缩性毒性评估。从临床试验中撤回的化合物BMS-986094抑制了hiPSC-CMs的收缩速度和舒张速度。目前,我们正试图通过将hiPSC-CM数据与来自真实世界数据库的不良事件报告进行比较,来研究收缩性测定的可预测性。在这篇综述中,我们想介绍使用hiPSC-CMs的基于成像的新型收缩性方法以及抗癌药物引起的心脏毒性的未来前景。