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Effects of gefitinib, an epidermal growth factor receptor inhibitor, on human placental cell growth
Ulrika W Nilsson1, Terrance G Johns, Tania Wilmann
1Translational Obstetrics Group, University of Melbourne, Mercy Hospital for Women, Heidelberg, the Ritchie Centre and the Centre for Cancer Research, Monash Institute of Medical Research, Monash University, and the Embryo Implantation Group, Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia; the 2 Affiliated Hospital, Xian Jiatong University School of Medicine, Xian Jiatong, China; and the MRC Centre for Reproductive Health, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
Objective:
Placenta has the highest expression of epidermal growth factor (EGF) receptor of all tissues, a cell signaling pathway promoting survival and growth. Therefore, EGF receptor inhibition could potentially treat ectopic pregnancy. We undertook preclinical studies to examine whether gefitinib (orally available EGF receptor inhibitor) with or without methotrexate inhibits placental cell growth.
Methods:
Gefitinib and methotrexate were added to placental cells and their ability inhibit cell growth, block EGF receptor signaling, and induce apoptosis (programmed cell death) was examined. They were also administered to two animal mouse models to examine their effects on placental tissue in vivo.
Results:
Epidermal growth factor receptor was highly expressed in placental tissue from ectopic pregnancies. Combining gefitinib with methotrexate potently inhibited growth of placental cells, including placental cell lines (JEG3, BeWo cells) and cells isolated from first-trimester placenta. These drugs were additive in blocking EGF receptor signaling and inducing apoptosis. Gefitinib and methotrexate administered together were more potent in decreasing the volume of human placental cells xenografted subcutaneously onto mice compared with either alone. By day 19 after xenografting, mean (± standard error of the mean), xenograft volumes were: 821 (± 68) mm after gefitinib treatment, 901 (± 204) mm after methotrexate treatment, and 345 (±137) mm after both drugs were given (P<.01 for both comparisons of single therapy compared with combination therapy). Combining these agents doubled rates of fetal resorption in pregnant mice compared with each drug alone.
Conclusion:
Combining gefitinib with methotrexate potently inhibits placental cell growth in vitro and in mouse models. The combination may have potential in treating ectopic pregnancies.
Insights
Combining gefitinib and methotrexate effectively inhibits placental cell growth and may treat ectopic pregnancies. This combination therapy shows promise for treating abnormal pregnancies by targeting placental growth signaling pathways.
Area of Science:
- Reproductive Biology
- Pharmacology
- Oncology
Background:
- The epidermal growth factor (EGF) receptor is highly expressed in placental tissue, regulating cell survival and growth.
- EGF receptor inhibition presents a potential therapeutic strategy for managing ectopic pregnancies.
Purpose of the Study:
- To investigate the efficacy of gefitinib, an EGF receptor inhibitor, alone and in combination with methotrexate, in inhibiting placental cell growth.
- To evaluate the effects of gefitinib and methotrexate on EGF receptor signaling and apoptosis in placental cells and in vivo models.
Main Methods:
- Placental cells and cell lines (JEG3, BeWo) were treated with gefitinib and methotrexate in vitro.
- In vivo studies involved administering these drugs to mouse models with xenografted human placental cells and pregnant mice.
- Assays measured cell growth inhibition, EGF receptor signaling blockade, apoptosis induction, xenograft volume, and fetal resorption rates.
Main Results:
- Combined gefitinib and methotrexate potently inhibited placental cell growth in vitro and in xenograft models.
- The combination therapy demonstrated additive effects in blocking EGF receptor signaling and inducing apoptosis.
- In vivo, the combination significantly reduced placental cell xenograft volumes and doubled fetal resorption rates in pregnant mice compared to single-agent treatments.
Conclusions:
- Combination therapy with gefitinib and methotrexate effectively inhibits placental cell proliferation and growth in preclinical models.
- This combination therapy holds significant potential as a novel treatment approach for ectopic pregnancies.
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