Toxicity of anticancer drugs in human placental tissue explants and trophoblast cell lines
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IN VITRO SYSTEMS
Toxicity of anticancer drugs in human placental tissue explants and trophoblast cell lines Gaby A. M. Eliesen1 · Hedwig van Hove1 · Maartje H. Meijer1 · Petra H. H. van den Broek1 · Jeanne Pertijs1 · Nel Roeleveld2 · Joris van Drongelen3 · Frans G. M. Russel1 · Rick Greupink1 Received: 20 May 2020 / Accepted: 5 October 2020 © The Author(s) 2020
Abstract The application of anticancer drugs during pregnancy is associated with placenta-related adverse pregnancy outcomes. Therefore, it is important to study placental toxicity of anticancer drugs. The aim of this study was to compare effects on viability and steroidogenesis in placental tissue explants and trophoblast cell lines. Third trimester placental tissue explants were exposed for 72 h (culture day 4–7) to a concentration range of doxorubicin, paclitaxel, cisplatin, carboplatin, crizotinib, gefitinib, imatinib, or sunitinib. JEG-3, undifferentiated BeWo, and syncytialised BeWo cells were exposed for 48 h to the same drugs and concentrations. After exposure, tissue and cell viability were assessed and progesterone and estrone levels were quantified in culture medium. Apart from paclitaxel, all compounds affected both cell and tissue viability at clinically relevant concentrations. Paclitaxel affected explant viability moderately, while it reduced cell viability by 50% or more in all cell lines, at 3–10 nM. Doxorubicin (1 µM) reduced viability in explants to 83 ± 7% of control values, whereas it fully inhibited viability in all cell types. Interference with steroid release in explants was difficult to study due to large variability in measurements, but syncytialised BeWo cells proved suitable for this purpose. We found that 1 µM sunitinib reduced progesterone release to 76 ± 6% of control values, without affecting cell viability. While we observed differences between the models for paclitaxel and doxorubicin, most anticancer drugs affected viability significantly in both placental explants and trophoblast cell lines. Taken together, the placenta should be recognized as a potential target organ for toxicity of anticancer drugs. Keywords Placental toxicity · Cytostatic drugs · Tyrosine kinase inhibitors · Placental tissue explants · Trophoblasts · Pregnancy
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02925-w) contains supplementary material, which is available to authorized users. * Gaby A. M. Eliesen [email protected] 1
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, (Route 137), PO Box 9101, 6500 HB Nijmegen, The Netherlands
2
Department for Health Evidence, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
3
Department of Obstetrics and Gynecology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
Obtaining safety data on the use of drugs during pregnancy is difficult for several reasons. First, pregn
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