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

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Summary

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.

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Acknowledgements

The authors wish to thank Ms. Helen Shriver for her help in the manuscript preparation. The authors also wish to thank Mrs. Christelle Simasotchi (PremUp Foundation – Université Paris Descartes) for her contribution in the study.

Funding

This work was supported by INSERM (Institut National de la Santé et de la Recherche Médicale).

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Authors and Affiliations

  1. INSERM, UMR-S1139, Paris, France

    Paul Berveiller, Séverine A. Degrelle, Vassilis Tsatsaris, Danièle Evain-Brion, Thierry Fournier & Sophie Gil

  2. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Paul Berveiller, Séverine A. Degrelle, Vassilis Tsatsaris, Danièle Evain-Brion, Thierry Fournier & Sophie Gil

  3. Department of Gynecology and Obstetrics, Centre Hospitalier Intercommunal de Poissy Saint Germain, 10, rue du champ Gaillard, F78300, Poissy, France

    Paul Berveiller

  4. Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France

    Olivier Mir

  5. Department of Obstetrics, Port-Royal Maternity, Cochin Teaching Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France

    Vassilis Tsatsaris

  6. PremUp Foundation, Paris, France

    Vassilis Tsatsaris, Danièle Evain-Brion, Thierry Fournier & Sophie Gil

  7. Department of Obstetrics and Gynecology, Tenon Teaching Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France

    Lise Selleret

  8. Department of Hormonal Biology, Cochin Teaching Hospital, Assistance Publique – Hôpitaux de Paris, Paris, France

    Jean Guibourdenche

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  1. Paul Berveiller
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Correspondence to Paul Berveiller.

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Conflict of interest

Dr. Berveiller declares that he has no conflict of interest.

Dr. Mir has acted as consultant for Astra-Zeeneca, Amgen, Bayer Healthcare, Blueprint Medicines, Bristol-Myers Squibb, Eli-Lilly, Incyte, Ipsen, Lundbeck, Novartis, Pfizer, PharmaMar, Roche, Servier and Vifor Pharma.

Dr. Degrelle declares that she has no conflict of interest.

Pr. Tsatsaris declares that he has no conflict of interest.

Dr. Selleret declares that she has no conflict of interest.

Pr. Guibourdenche declares that he has no conflict of interest.

Dr. Evain-Brion declares that she has no conflict of interest.

Dr. Fournier declares that he has no conflict of interest.

Pr. Gil declares that she has no conflict of interest.

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All procedures performed in studies involving our patients were in accordance with the ethical standards of the Local Ethic Committee (CPP, Paris Cochin, N°18–05, France) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in our study.

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Berveiller, P., Mir, O., Degrelle, S.A. et al. Chemotherapy in pregnancy: exploratory study of the effects of paclitaxel on the expression of placental drug transporters. Invest New Drugs 37, 1075–1085 (2019). https://doi.org/10.1007/s10637-018-0677-7

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