Toxicity of anticancer drugs in human placental tissue explants and trophoblast cell lines

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.

Cancer during Pregnancy: A Review of Preclinical and Clinical Transplacental Transfer of Anticancer Agents

“…A recent in vitro study on human cell lines showed that paclitaxel moderately affects explant viability and reduces cell viability by 50% or more in trophoblast cell lines [ 99 ]. The same results were reported with docetaxel, with a maximum 30% decrease in cell viability [ 96 ].…”

“…An in vitro study on human placental tissue explants and trophoblast cell lines exposed to cisplatin or carboplatin concluded that both drugs affect cell and tissue viability at clinically relevant concentrations [ 99 ]. Hence, more data on placental transfer are required.…”

“…An in vitro study on human placental tissue explants and trophoblast cell lines exposed to doxorubicin concluded that it affects both cell and tissue viability at clinically relevant concentrations [ 99 ]. Similarly, a decrease in human cytotrophoblasts viability induced by epirubicin has been demonstrated in vitro [ 96 ].…”

“…A study showed that combining gefitinib with methotrexate potently inhibits placental cell growth in in vitro human cell lines and an in vivo mouse model [ 57 ]. Another in vitro study concluded that gefitinib and crizotinib significantly affect viability of human placental explants, trophoblast cell lines [ 99 ], and BeWo cells [ 94 ].…”

Cancer and Pregnancy: A Comprehensive Review

“…Direct chemotherapy-induced toxic effects caused placental underdevelopment, but other causes, such as malnutrition, stress and immune suppression could not be ruled out [ 70 ]. Another in vitro study examining placental tissue explants of 3rd trimester pregnancies, which were exposed to various cytotoxic drugs at therapeutic plasma concentrations (between 1 µM and 100 µM), such as doxorubicin, paclitaxel, cisplatin, carboplatin, crizotinib, gefitinib, imatinib or sunitinib and all cytotoxic drugs but paclitaxel led to reduced cell and tissue viability within 72 h of exposure [ 72 ]. In vivo animal studies showed impaired umbilical cord blood flow parameters and reduced placenta efficiency when mice were treated with doxorubicin during gestation [ 73 ].…”