Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy.
Cell Death Dis. 2011 Apr 28;2(4):e150. doi: 10.1038/cddis.2011.34.
We reported a relevant activity of the combination between sorafenib and octreotide long-acting release (LAR) in advanced hepatocellular carcinoma (HCC) patients. In this work, we have studied if oxidative stress in both serum and peripheral blood mononuclear cells (PBMC) and pERK activation status in PBMC could be predictive of response. In the 20 responsive patients, the decrease of reactive oxygen species levels was already detectable after 10 days (T10) from the beginning of sorafenib administration, and this effect was enhanced by the combined treatment with sorafenib+octreotide LAR (T21). This effect correlated with the modulation of superoxide dismutase (SOD) activity (physiological scavenger of O(2-)) and of serum nitric oxide (NO) levels. Sorafenib alone induced an increase of about 40% of NO levels and of about two-fold of SOD activity in responsive patients, and both effects were significantly potentiated by the combined treatment. We found a gradual reduction of Erk1/2 activity, as evaluated by cytofluorimetric analysis, in 15 responsive patients reaching about 50% maximal decrease at T21. On the other hand, in 17 resistant patients, Erk1/2 activity was about 80% increased at T21. The determination of both the oxidative stress status and pERK activity in PBMC has high value in the prediction of response to sorafenib+octreotide therapy in HCC patients.
我们报道了索拉非尼与奥曲肽长效释放（LAR）联合应用于晚期肝细胞癌（HCC）患者的相关活性。在这项工作中，我们研究了血清和外周血单个核细胞（PBMC）中的氧化应激以及 PBMC 中 pERK 激活状态是否可以预测应答。在 20 例应答患者中，索拉非尼治疗开始后 10 天（T10）即可检测到活性氧（ROS）水平的下降，并且这种作用通过索拉非尼+奥曲肽 LAR 的联合治疗得到增强（T21）。这种作用与超氧化物歧化酶（SOD）活性（O(2-)的生理清除剂）和血清一氧化氮（NO）水平的调节相关。索拉非尼单独诱导应答患者的 NO 水平增加约 40%，SOD 活性增加约两倍，联合治疗显著增强了这两种作用。我们通过细胞荧光分析发现，15 例应答患者的 Erk1/2 活性逐渐降低，在 T21 时达到最大降低约 50%。另一方面，在 17 例耐药患者中，Erk1/2 活性在 T21 时增加约 80%。在 HCC 患者中，PBMC 中氧化应激状态和 pERK 活性的测定对预测索拉非尼+奥曲肽治疗的应答具有重要价值。
