Similarly, sunitinib, a multitarget receptor tyrosine kinase inhibitor, was reported to induce increases in VEGF levels and other

proangiogenic STA-9090 factors in mice.37 Sorafenib treatment did have an effect on liver mass restoration in the animals receiving the drug postoperatively, independent of drug administration prior to surgery or starting the day after the operation. Liver regeneration was impaired in these mice, albeit mildly and only at a late timepoint. Similar observations were noted in a study looking at the effects of anti-VEGF therapy after partial hepatectomy.38 For the earlier timepoints studied, the difference in liver mass recuperation was not significant, suggesting that inhibition of the RAS/MAPK/ERK pathway and the VEGFR kinase is not critical to initiate liver regeneration, but plays a role in sustaining the process. A possible explanation for the late appearance of the antiangiogenic effect is that, chronologically,

replication of endothelial cells follows replication of hepatocytes.39 On the other hand, an earlier effect concerning hepatocyte proliferation was observed, as assessed by BrdU incorporation. The proliferation assay showed significantly reduced DNA synthesis at early timepoints (24 and 72 hours), pointing to an inhibitory effect on parenchyma restitution. Considering 上海皓元 clinical settings, these findings may be of importance for patients receiving sorafenib while being treated with a local ablative therapy such as BAY 57-1293 research buy transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). It also may be of relevance for patients who

are subjected to portal vein ligation to induce a compensatory hypertrophy in view of a hemihepatectomy. An important finding of our work is that sorafenib stopped the day before surgery had no impact on liver regeneration in this preclinical study. It did not impair hepatocyte proliferation nor ERK phosphorylation; only the hepatic VEGF levels were increased at baseline, returning to control values as early as 1 day postoperatively. The compound sorafenib is a competitive inhibitor, implying reversibility of its actions, and has a half-life of 25-48 hours40, 41 in man. These findings suggest that patients receiving sorafenib while waiting for liver transplantation may receive a small-for-size liver, without having a negative effect of prior sorafenib treatment on liver size adaptation. Further, considering an indication for sorafenib as a neoadjuvant treatment, our data suggest that drug administration may be continued until the day preceding surgery without compromising liver mass recuperation.