Simple Summary: For patients undergoing multimodal treatment for colorectal liver metastases (CLM), the development of sinusoidal obstruction syndrome (SOS) as a side effect of oxaliplatin-based chemotherapy may endanger the prospects after liver resection. In this study, we aimed to investigate possible protective effects of an additional preoperative inhibition of vascular endothelial growth factor (VEGF) on the occurrence of SOS and its implications on liver function and regeneration after liver resection. After successful establishment of a novel murine model of SOS, we were able to show a reduced incidence of SOS after additive treatment with a VEGF inhibitor. Changes in the VEGF pathway, namely in the expression of VEGF receptor-2 (VEGF-R2), may be responsible for these findings. By preventing the incidence of SOS, the inhibition of VEGF may help to reduce morbidity after liver resection for patients with CLM. Further clinical studies are needed to corroborate our results.
(1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition on the development of SOS in a murine model.
(2) Methods: Male wild-type and CD39-null mice received oxaliplatin, additional anti-VEGF (OxAV), or controls, and were sacrificed or subjected to major partial hepatectomy (MH). Specimen were used for histological analysis of SOS. Liver damage was assessed by plasma transaminases. The VEGF pathway was elucidated by quantitative PCR of liver tissue and protein analysis of plasma.
(3) Results: Mice treated with oxaliplatin developed SOS. Concomitant anti-VEGF facilitated a reduced incidence of SOS, but not in CD39-null mice. SOS was associated with increased plasma VEGF-A and decreased hepatocyte growth factor (HGF). After OxAV treatment, VEGF-R2 was upregulated in wild-type but downregulated in CD39-null mice. Oxaliplatin alone was associated with higher liver damage after MH than in mice with concomitant VEGF-inhibition.
(4) Conclusions: We established a murine model of oxaliplatin-induced SOS and provided novel evidence on the protective effect of VEGF-inhibition against the development of SOS that may be associated with changes in the pathway of VEGF and its receptor VEGF-R2.
colorectal liver metastases
sinusoidal obstruction syndrome
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Inhibition of Vascular Endothelial Growth Factor Protects against the Development of Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Wild-Type but Not in CD39-Null Mice
Charité - Universitätsmedizin Berlin