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Chemotherapy in pregnancy: exploratory study of the effects of paclitaxel on the expression of placental drug transporters

Authors :
Jean Guibourdenche
Paul Berveiller
Danièle Evain-Brion
Vassilis Tsatsaris
Thierry Fournier
Lise Selleret
Séverine A. Degrelle
Olivier Mir
Sophie Gil
Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139)
Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Université Sorbonne Paris Cité (USPC)
Service de gynécologie et obstétrique [CHI Poissy-Saint Germain]
CHI Poissy-Saint-Germain
Gamètes, implantation, gestation (GIG)
Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Dept Canc Med, Gustave Roussy Canc Campus, F-94805 Villejuif, France
Partenaires INRAE
Maternité Port-Royal [CHU Cochin]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
PremUp Foundation
Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)
Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon]
CHU Tenon [AP-HP]
Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Hôpital Cochin [AP-HP]
Source :
Investigational New Drugs, Investigational New Drugs, Springer Verlag, 2019, 37 (5), pp.1075-1085. ⟨10.1007/s10637-018-0677-7⟩
Publication Year :
2018
Publisher :
Springer Science and Business Media LLC, 2018.

Abstract

International audience; 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.

Details

ISSN :
15730646 and 01676997
Volume :
37
Database :
OpenAIRE
Journal :
Investigational New Drugs
Accession number :
edsair.doi.dedup.....6aa475047d4ad089ac1d40ac37ba459c