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 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.
Obstet Gynecol. 2013 Oct;122(4):737-744. doi: 10.1097/AOG.0b013e3182a1ba56.
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.
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.
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.
Combining gefitinib with methotrexate potently inhibits placental cell growth in vitro and in mouse models. The combination may have potential in treating ectopic pregnancies.
胎盘是所有组织中表皮生长因子（EGF）受体表达最高的组织，该受体是一种促进细胞存活和生长的细胞信号通路。因此，EGF 受体抑制可能有潜力治疗异位妊娠。我们进行了临床前研究，以检查吉非替尼（一种口服 EGF 受体抑制剂）与甲氨蝶呤联合或不联合使用是否能抑制胎盘细胞生长。
将吉非替尼和甲氨蝶呤添加到胎盘细胞中，检测它们抑制细胞生长、阻断 EGF 受体信号传导和诱导细胞凋亡（程序性细胞死亡）的能力。还将它们施用于两种动物小鼠模型，以检测它们对体内胎盘组织的影响。
EGF 受体在异位妊娠的胎盘组织中高度表达。吉非替尼与甲氨蝶呤联合使用可强力抑制胎盘细胞的生长，包括胎盘细胞系（JEG3、BeWo 细胞）和从早期胎盘分离的细胞。这些药物在阻断 EGF 受体信号和诱导细胞凋亡方面具有相加作用。与单独使用相比，吉非替尼和甲氨蝶呤联合使用可更有效地减少皮下移植到小鼠体内的人胎盘细胞的体积。在皮下移植后第 19 天，平均（±标准误差），移植瘤体积为：吉非替尼治疗组为 821（±68）mm，甲氨蝶呤治疗组为 901（±204）mm，两种药物联合治疗组为 345（±137）mm（与单药治疗相比，两种药物联合治疗均有统计学意义，P<0.01）。与单独使用每种药物相比，联合使用这些药物使妊娠小鼠的胎儿吸收率增加了一倍。
吉非替尼与甲氨蝶呤联合可强力抑制体外和小鼠模型中的胎盘细胞生长。该联合疗法可能有潜力治疗异位妊娠。
