Effects of Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, on Human Placental Cell Growth
Effects of Gefitinib, an Epidermal Growth Factor Receptor Inhibitor, on Human Placental Cell Growth
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DOI：
10.1097/aog.0b013e3182a1ba56
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发表时间：
2013-10-01
影响因子：
7.2
通讯作者：
Tong, Stephen
中科院分区：
文献类型：
--
作者：
Nilsson, Ulrika W.;Johns, Terrance G.;Tong, Stephen
目的：胎盘具有所有组织中表皮生长因子（EGF）受体的最高表达，这是一种促进生存和生长的细胞信号通路。因此，EGF受体抑制剂可能治疗异位妊娠。我们进行了临床前研究，以检查是否吉非替尼（口服EGF受体抑制剂）与或不与甲氨蝶呤抑制胎盘细胞growth.METHODS：吉非替尼和甲氨蝶呤加入到胎盘细胞和他们的能力抑制细胞生长，阻断EGF受体信号转导，并诱导细胞凋亡（程序性细胞死亡）进行了检查。他们也被管理到两个动物小鼠模型，以检查其对胎盘组织在vivo.Results的影响：表皮生长因子受体在异位妊娠胎盘组织中的高表达。吉非替尼与甲氨蝶呤组合有效抑制胎盘细胞的生长，包括胎盘细胞系（JEG 3，BeWo细胞）和从早期妊娠胎盘分离的细胞。这些药物在阻断EGF受体信号传导和诱导细胞凋亡方面是相加的。与单独给药相比，吉非替尼和甲氨蝶呤联合给药在减少小鼠皮下异种移植的人胎盘细胞体积方面更有效。异种移植后第19天，平均（+/-平均值的标准误差），异种移植物体积：吉非替尼治疗后为821（+/- 68）mm（3），甲氨蝶呤治疗后为901（+/- 204）mm（3），两种药物治疗后为345（+/- 137）mm（3）（P
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(3) after gefitinib treatment, 901 (+/- 204) mm(3) after methotrexate treatment, and 345 (+/- 137) mm(3) after both drugs were given (P