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

Invest New Drugs. 2019 Oct;37(5):1075-1085. doi: 10.1007/s10637-018-0677-7. Epub 2018 Oct 26.

Abstract

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.

Keywords: Cancer; Drug transporters; Paclitaxel; Placenta; Placental perfusion; Pregnancy; Trophoblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism*
  • Adult
  • Antineoplastic Agents, Phytogenic / blood
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Neoplasm Proteins / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Paclitaxel / blood
  • Paclitaxel / pharmacology*
  • Pregnancy
  • Pregnancy Complications, Neoplastic / drug therapy*
  • Pregnancy Complications, Neoplastic / metabolism
  • Prognosis

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents, Phytogenic
  • Neoplasm Proteins
  • Paclitaxel