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Effects of Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, on Human Placental Cell Growth

Nilsson, Ulrika W. PhD; Johns, Terrance G. PhD; Wilmann, Tania PhD; Kaitu’u-Lino, Tu’uhevaha PhD; Whitehead, Clare MB, ChB; Dimitriadis, Eva PhD; Menkhorst, Ellen PhD; Saglam, Burcu PhD; Gao, Yane PhD; Greenall, Sameer A. PhD; Horne, Andrew W. PhD; Tong, Stephen PhD

doi: 10.1097/AOG.0b013e3182a1ba56
Original Research

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) mm3 after gefitinib treatment, 901 (±204) mm3 after methotrexate treatment, and 345 (±137) mm3 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.

Adding the epidermal growth factor receptor gefitinib to methotrexate potently inhibits growth of placental cells, both in vitro and in animal models.

Translational 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 2nd 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.

Corresponding author: Stephen Tong, PhD, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, 163 Studley Road, Heidelberg 3084, Victoria, Australia; e-mail: stong@unimelb.edu.au.

Supported by the National Health and Medical Research Council of Australia (NHMRC) Project Grants 606611 (S.T. and T.G.J.), 1008276 (S.T., and T.G.J.), and 550905 (to E.D.); NHMRC Career Development Fellowship #1050765 (S.T.) and NHMRC Training Fellowships #550911 (E.D.); Medical Research Council (MRC) Clinician Scientist Fellowship and MRC Centenary Award #G0802808 (A.W.H.); The Helen MacPherson Trust (S.T.); The Arthur Wilson RANZCOG Fellowship (S.T.) and The Monash University Strategic Grants Scheme (S.T.); and The Victorian Government's Operational Infrastructure Support Program (T.G.J., S.T., and U.W.N.).

Financial Disclosure Drs. Nilsson, Johns, and Tong are joint holders of patents that relate to the use of epidermal growth factor receptor inhibition in treating ectopic pregnancies. The other authors did not report any potential conflicts of interest.

The authors thank Sarah McDonald for technical support and Alistair Williams for help with histopathology.

© 2013 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.