Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.
Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.
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DOI：
10.1001/archoto.2009.17
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发表时间：
2009-04
影响因子：
--
通讯作者：
Clayman, Gary L.
中科院分区：
文献类型：
--
作者：
Henderson, Ying C.;Ahn, Soon-Hyun;Clayman, Gary L.
甲状腺乳头状癌（PTC）是最常见的甲状腺恶性肿瘤，通常具有突变，RET/PTC重排或BRAF突变。这两种突变都可以激活丝裂原活化蛋白激酶激酶/细胞外信号相关激酶信号转导途径，从而激活调节细胞增殖、分化和凋亡的转录因子。检测CI-1040（PD 184352）（一种特异性MEK 1/2抑制剂）对携带RET/PTC 1重排或BRAF突变的PTC细胞的影响。在体外和体内评价CI-1040对PTC细胞的作用。使用细胞增殖测定、细胞周期分析和免疫印迹法在体外评价CI-1040对PTC细胞的影响。在原位小鼠模型中评价CI-1040的体内抗肿瘤作用。对于具有BRAF突变的PTC细胞，抑制50%细胞生长所需的CI-1040浓度为0.052μM，对于具有RET/PTC 1重排的PTC细胞为1.1μM。口服CI-1040 3周后（300 mg/kg/d）对具有PTC细胞原位肿瘤植入物的小鼠，与未处理的小鼠相比，携带RET/PTC 1重排的植入物（n=5）的平均肿瘤体积减少47.5（从701.9到368.5 mm 3），BRAF突变的种植体（n=8）的平均体积减少了31.3%（从297.3到204.2 mm 3）。CI-1040在体外和体内抑制PTC细胞生长。由于RET/PTC重排是甲状腺癌所特有的，并且高百分比的PTC具有任一突变，因此这些发现支持CI-1040用于PTC患者的临床评价。
Papillary thyroid carcinoma (PTC), the most common type of thyroid malignancy, usually possesses mutations, either RET/PTC rearrangement or BRAF mutation. Both mutations can activate the mitogen-activated protein kinase kinase/extracellular signal–related kinase signaling transduction pathway, which results in activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. To test the effects of CI-1040 (PD184352), a specific MEK1/2 inhibitor, on PTC cells carrying either an RET/PTC1 rearrangement or a BRAF mutation. The effects of CI-1040 on PTC cells were evaluated in vitro and in vivo. The effects of CI-1040 on PTC cells were evaluated in vitro using a cell proliferation assay, cell cycle analysis, and immunoblotting. The antitumor effects of CI-1040 in vivo were evaluated in an orthotopic mouse model. The concentrations of CI-1040 needed to inhibit 50% cell growth were 0.052μM for PTC cells with a BRAF mutation and 1.1μM for PTC cells with the RET/PTC1 rearrangement. After 3 weeks of oral administration of CI-1040 (300 mg/kg/d) to mice with orthotopic tumor implants of PTC cells, the mean tumor volume of implants bearing the RET/PTC1 rearrangement (n=5) was reduced 47.5% compared with untreated mice (from 701.9 to 368.5 mm3), and the mean volume of implants with a BRAF mutation (n=8) was reduced 31.3% (from 297.3 to 204.2 mm3). CI-1040 inhibits PTC cell growth in vitro and in vivo. Because RET/PTC rearrangements are unique to thyroid carcinomas and a high percentage of PTCs possess either mutation, these findings support the clinical evaluation of CI-1040 for patients with PTC.
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作者：
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