Leyton Julius, Smith Graham, Lees Mark, Perumal Meg, Nguyen Quang-de, Aigbirhio Franklin I, Golovko Oksana, He Quimin, Workman Paul, Aboagye Eric O
Molecular Therapy Group, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom.
Mol Cancer Ther. 2008 Sep;7(9):3112-21. doi: 10.1158/1535-7163.MCT-08-0264.
The mitogenic extracellular kinase 1/2 (MEK1/2) inhibitor, PD0325901, has potent activity in a number of cancer cell types in vitro. In SKMEL-28 human melanoma cells (BRAF mutant), the drug rapidly decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein levels. We investigated if 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography ([18F]FLT-PET) could be used to image changes in cell proliferation following MEK1/2 inhibition in vivo. Mice bearing SKMEL-28 and human colon cancer HCT116 (K-RAS mutant) xenografts were treated daily with PD0325901 at 25 mg/kg and imaged by dynamic [18F]FLT-PET after 1 and 10 days of initiating treatment. The drug decreased tumor [18F]FLT uptake after 1 and 10 days of treatment compared with control animals. The normalized (maximal) [18F]FLT uptake in SKMEL-28 xenografts (at 60 minutes; NUVmax) after 1 day of vehicle or PD0325901 therapy was 1.81 +/- 0.18 versus 1.23 +/- 0.10, respectively (P = 0.03). In this model, NUVmax after 10 days was 2.07 +/- 0.40 versus 1.08 +/- 0.14, respectively (P = 0.03). The corresponding values for HCT116 tumors were 2.30 +/- 0.84 versus 1.88 +/- 0.36 (P = 0.045) after 1 day, and 1.97 +/- 0.13 versus 1.00 +/- 0.03 (P = 0.03) after 10 days. Similar changes were found for other [18F]FLT retention variables. The drug decreased phosphorylated extracellular signal-regulated kinase 1/2, cyclin D1, and thymidine kinase 1 protein. Tumor [18F]FLT-PET variables correlated with proliferation as measured by Ki67 labeling index (r > or = 0.6; P > or = 0.003). In summary, [18F]FLT-PET is a sensitive imaging biomarker for detecting the antiproliferative effect of MEK1/2 inhibition by PD0325901.
促分裂原细胞外激酶1/2（MEK1/2）抑制剂PD0325901在体外对多种癌细胞类型具有强大活性。在SKMEL-28人黑色素瘤细胞（BRAF突变型）中，该药物迅速降低了磷酸化细胞外信号调节激酶1/2、细胞周期蛋白D1和胸苷激酶1的蛋白水平。我们研究了3'-脱氧-3'-[18F]氟胸苷-正电子发射断层扫描（[18F]FLT-PET）是否可用于在体内成像MEK1/2抑制后细胞增殖的变化。携带SKMEL-28和人结肠癌HCT116（K-RAS突变型）异种移植瘤的小鼠每天接受25 mg/kg的PD0325901治疗，并在开始治疗1天和10天后通过动态[18F]FLT-PET成像。与对照动物相比，治疗1天和10天后，该药物降低了肿瘤的[18F]FLT摄取。在接受赋形剂或PD0325901治疗1天后，SKMEL-28异种移植瘤（60分钟时；最大标准化摄取值，NUVmax）的标准化（最大）[18F]FLT摄取分别为1.81±0.18和1.23±0.10（P = 0.03）。在该模型中，10天后的NUVmax分别为2.07±0.40和1.08±0.14（P = 0.03）。HCT116肿瘤1天后的相应值为2.30±0.84和1.88±0.36（P = 0.045），10天后为1.97±0.13和1.00±0.03（P = 0.03）。在其他[18F]FLT保留变量中也发现了类似变化。该药物降低了磷酸化细胞外信号调节激酶1/2、细胞周期蛋白D1和胸苷激酶1蛋白。肿瘤[18F]FLT-PET变量与通过Ki67标记指数测量的增殖相关（r≥0.6；P≥0.003）。总之，[18F]FLT-PET是一种用于检测PD0325901抑制MEK1/2的抗增殖作用的敏感成像生物标志物。
