Generation of organoids from urinary tract tumor samples was pioneered a few years ago. We generated organoids from two upper tract urothelial carcinomas and from one bladder cancer sample, and confirmed the expression of cytokeratins as urothelial antigens, vimentin as a mesenchymal marker, and fibroblast growth factor receptor 3 by immunohistochemistry. We investigated the dose response curves of two novel components, venetoclax versus S63845, in comparison to the clinical standard cisplatin in organoids in comparison to the corresponding two-dimensional cultures. Normal urothelial cells and tumor lines RT4 and HT1197 served as controls. We report that upper tract urothelial carcinoma cells and bladder cancer cells in two-dimensional cultures yielded clearly different sensitivities towards venetoclax, S63845, and cisplatin. Two-dimensional cultures were more sensitive at low drug concentrations, while organoids yielded higher drug efficacies at higher doses. In some two-dimensional cell viability experiments, colorimetric assays yielded different IC50 toxicity levels when compared to chemiluminescence assays. Organoids exhibited distinct sensitivities towards cisplatin and to a somewhat lesser extent towards venetoclax or S63845, respectively, and significantly different sensitivities towards the three drugs investigated when compared to the corresponding two-dimensional cultures. We conclude that organoids maintained inter-individual sensitivities towards venetoclax, S63845, and cisplatin. The preclinical models and test systems employed may bias the results of cytotoxicity studies.
International journal of molecular sciences. 2022 Jun 04*** epublish ***
Yi Wei, Bastian Amend, Tilman Todenhöfer, Nizar Lipke, Wilhelm K Aicher, Falko Fend, Arnulf Stenzl, Niklas Harland
Center for Medicine Research, Eberhard Karls University, 72072 Tuebingen, Germany., Department of Urology, University Hospital, 72076 Tuebingen, Germany., Institute for Pathology, Eberhard Karls University, 72076 Tuebingen, Germany.