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Abstract
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 O2−) 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.
Highlights
Ablative therapies, surgical resection or liver transplantation are the first-line treatment for patients affected with Hepatocellular carcinoma (HCC).[8]
We have evaluated possible variations in oxidative stress induced by treatment: we have assessed the O2À levels in peripheral blood mononuclear cells (PBMC) and the nitric oxide (NO), superoxide dismutase (SOD) and CAT serum levels
To evaluate the intracellular levels of reactive oxygen species (ROS), PBMC of 23 resistant and 20 responsive patients enrolled in the So.long-acting release (LAR) study were incubated with dihydroethidine followed by FACS analysis of the oxidative product, ethidium, which emits red fluorescence
Summary
Surgical resection or liver transplantation are the first-line treatment for patients affected with HCC.[8]. Advanced tumor stage and poor liver function preclude the majority of patients from these surgical interventions. In addition to this obstacle, transplantation is indicated only for early small HCC, and its application is limited by the availability of liver grafts.[9] there is an urgent need to develop an effective systemic therapy for patients with advanced HCC.[10]. Many advances in the knowledge of the molecular mechanisms that govern tumor development and progression have been made.[11] More recently, single agent sorafenib (Bayer 43-9006; Nexavar, Bayer AG Inc., Leverkusen, Germany), a putative multi-targeted kinase inhibitor, has shown to prolong the overall survival (OS) of patients with advanced HCC in the pivotal phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Oriental study.[9] Currently, sorafenib is the only approved targeted therapy for patients with advanced HCC.
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