INSERM, UMR-S1139, Paris, France.
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
Invest New Drugs. 2019 Oct;37(5):1075-1085. doi: 10.1007/s10637-018-0677-7. Epub 2018 Oct 26.
Introduction The use of paclitaxel in pregnant cancer patients is feasible in terms of fetal safety, but little is known about the effects of paclitaxel on the placenta. Using three experimental models, we aimed to assess the effects of paclitaxel on the expression of placental drug transporters. Methods In the in vitro model (human primary trophoblast culture), trophoblasts were isolated from normal term placentas and subsequently exposed to paclitaxel. The transcriptional regulation of 84 genes encoding for drug transporters, and the protein expression of ABCB1/P-gp and ABCG2/BCRP were assessed. In the in vivo model, placental tissues isolated from pregnant cancer patients treated with paclitaxel were analyzed to assess the protein expression of ABCB1/P-gp and ABCG2/BCRP. The same parameters were assessed in extracts from human placental cotyledons perfused ex vivo with paclitaxel. Results In the in vitro model, the expression of twelve drug-transporters genes was found to be significantly down-regulated after exposure to paclitaxel, including ABCC10, SLC28A3, SLC29A2, and ATP7B (involved in the transport of taxanes, antimetabolites, and cisplatin, respectively). The protein expression of ABCB1/P-gp increased by 1.3-fold after paclitaxel administration. Finally, the protein expression of ABCB1/P-gp and ABCG2/BCRP was higher in cotyledons from mothers treated with multiple doses of paclitaxel during pregnancy than in cotyledons perfused with a single dose of paclitaxel. Discussion Paclitaxel modulates the expression of placental drug transporters involved in the disposition of various anticancer agents. Further studies will be needed to assess the impact of repeated or prolonged exposure to paclitaxel on the expression and function of placental drug transporters.
简介 紫杉醇在妊娠癌症患者中的应用在胎儿安全性方面是可行的，但对于紫杉醇对胎盘的影响知之甚少。我们使用三种实验模型，旨在评估紫杉醇对胎盘药物转运体表达的影响。
方法 在体外模型（人原代滋养层培养）中，从正常足月胎盘分离滋养细胞，随后暴露于紫杉醇。评估了 84 个编码药物转运体的基因的转录调节以及 ABCB1/P-糖蛋白和 ABCG2/BCRP 的蛋白表达。在体内模型中，分析了紫杉醇治疗的妊娠癌症患者的胎盘组织，以评估 ABCB1/P-糖蛋白和 ABCG2/BCRP 的蛋白表达。还评估了用紫杉醇离体灌注的人胎盘绒毛小叶提取物中的相同参数。
结果 在体外模型中，暴露于紫杉醇后发现 12 个药物转运体基因的表达明显下调，包括 ABCC10、SLC28A3、SLC29A2 和 ATP7B（分别参与紫杉烷、抗代谢物和顺铂的转运）。紫杉醇给药后 ABCB1/P-糖蛋白的蛋白表达增加了 1.3 倍。最后，在怀孕期间接受多次紫杉醇剂量治疗的母亲的绒毛小叶中，ABCB1/P-糖蛋白和 ABCG2/BCRP 的蛋白表达高于单次紫杉醇灌注的绒毛小叶。
讨论 紫杉醇调节参与各种抗癌药物处置的胎盘药物转运体的表达。需要进一步研究以评估重复或延长暴露于紫杉醇对胎盘药物转运体的表达和功能的影响。
