Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice.
Inhibition of epidermal growth factor receptor signalling reduces hypercalcaemia induced by human lung squamous-cell carcinoma in athymic mice.
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DOI：
10.1038/sj.bjc.6603828
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发表时间：
2007-07-16
影响因子：
8.8
通讯作者：
Foley, J.
中科院分区：
文献类型：
--
作者：
Lorch, G.;Gilmore, J. L.;Koltz, P. F.;Gonterman, R. M.;Laughner, R.;Lewis, D. A.;Konger, R. L.;Nadella, K. S.;Toribio, R. E.;Rosol, T. J.;Foley, J.
本研究的目的是评估表皮生长因子受体（EGFR）在甲状旁腺相关蛋白（PTHrP）表达和恶性肿瘤体液高钙血症（HHM）中的作用，使用两种不同的人类鳞状细胞癌（SCC）异种移植模型。一项随机对照研究，在该研究中，RWGT 2和HARA异种移植的裸鼠在发生HHM后接受安慰剂或吉非替尼200 mg kg−1治疗3天。通过测量血浆钙和PTHrP、尿环AMP/肌酐比值和肿瘤体积来评估治疗的有效性。研究终点为78 h。肺SCC细胞系RWGT 2和HARA表达高水平的PTHrP mRNA以及丰富的EGFR蛋白，但很少表达erbB 2或erbB 3。两种细胞系均表达EGFR配体双调蛋白（AREG）的高转录水平，以及转化生长因子-α（TGF-α）和肝素结合表皮生长因子（HB-EGF）mRNA的低水平。用1 μM EGFR酪氨酸激酶抑制剂PD 153035处理并沉淀AREG抗体后，两种细胞系中的甲状旁腺相关蛋白基因表达均降低40-80%。吉非替尼治疗RWGT 2和HARA异种移植的高钙血症小鼠，导致血浆总钙浓度在78小时内显著降低。在RWGT 2和HARA肺SCC细胞系中，自分泌AREG刺激EGFR并增加PTHrP基因表达。在两种HHM的人SCC模型中，通过苯胺基喹唑啉抑制EGFR途径表明EGFR酪氨酸激酶是抗高钙血症治疗的潜在靶点。
The purpose of this study was to evaluate the role of the epidermal growth factor receptor (EGFR) in parathyroid hormone-related protein (PTHrP) expression and humoral hypercalcaemia of malignancy (HHM), using two different human squamous-cell carcinoma (SCC) xenograft models. A randomised controlled study in which nude mice with RWGT2 and HARA xenografts received either placebo or gefitinib 200 mg kg−1 for 3 days after developing HHM. Effectiveness of therapy was evaluated by measuring plasma calcium and PTHrP, urine cyclic AMP/creatinine ratios, and tumour volumes. The study end point was at 78 h. The lung SCC lines, RWGT2 and HARA, expressed high levels of PTHrP mRNA as well as abundant EGFR protein, but very little erbB2 or erbB3. Both lines expressed high transcript levels for the EGFR ligand, amphiregulin (AREG), as well as, substantially lower levels of transforming growth factor-α (TGF-α), and heparin binding-epidermal growth factor (HB-EGF) mRNA. Parathyroid hormone-related protein gene expression in both lines was reduced 40–80% after treatment with 1 μM of EGFR tyrosine kinase inhibitor PD153035 and precipitating antibodies to AREG. Gefitinib treatment of hypercalcaemic mice with RWGT2 and HARA xenografts resulted in a significant reduction of plasma total calcium concentrations by 78 h. Autocrine AREG stimulated the EGFR and increased PTHrP gene expression in the RWGT2 and HARA lung SCC lines. Inhibition of the EGFR pathway in two human SCC models of HHM by an anilinoquinazoline demonstrated that the EGFR tyrosine kinase is a potential target for antihypercalcaemic therapy.
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影响因子：
45.3
作者：
Giaccone, G;Herbst, RS;Johnson, DH
通讯作者：
Johnson, DH
影响因子：
4.1
作者：
HEATH, JK;SOUTHBY, J;GILLESPIE, MT
通讯作者：
GILLESPIE, MT
影响因子：
4.8
作者：
Käkönen, SM;Selander, KS;Guise, TA
通讯作者：
Guise, TA
影响因子：
15.9
作者：
KUKREJA, SC;SHEVRIN, DH;MARTIN, TJ
通讯作者：
MARTIN, TJ
影响因子：
6.2
作者：
Morony, S;Capparelli, C;Dunstan, CR
通讯作者：
Dunstan, CR