HPB
.jpg "Alexandra Gangi, MD photo")
Alexandra Gangi, MD
Assistant Professor, Director of Gastrointestinal Tumor Program
Cedars Sinai Medical Center
Los Angeles, California, United States
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Sinusoidal obstruction syndrome (SOS) occurs in patients with colorectal liver metastases treated with chemotherapy. Prevention and treatment of SOS will minimize complications following liver directed therapy; however, effective strategies have yet to be identified. S-adenosylmethionine (SAMe) is a major precursor for glutathione (GSH), a key cellular antioxidant. Hepatic SAMe deficiency is associated with oxidative stress, genomic instability, and mitochondrial dysfunction. We hypothesize that the use of SAMe will prevent or attenuate liver injury associated with administration of systemic therapy.
Methods: C57BL/6 mice (n=6 per group) were treated with vehicle, FOLFOX, or FOLFOX + SAMe weekly (intraperitoneal oxaliplatin 6 mg/kg followed 2 h later by 5-FU 50 mg/kg and folinic acid 90 mg/kg ± SAMe 100mg/kg/day by oral gavage) for 5 weeks. PAI-1 deficient mice (n=8 per group) were treated with vehicle or FOLFOX for 5 weeks. Mice were euthanized 1 week post final treatment. Immunohistochemical (IHC) analysis of murine liver for presence of SOS was assessed by blinded pathologists. Blood and liver tissue were evaluated for elevation of inflammatory and liver injury markers.
Results:
: In this murine model, known markers associated with SOS were increased following FOLFOX administration including: PAI-1 (encoded by Serpine1), TNFα, MMP9, CXCl1, and vWF, with a 6-fold increase in Serpine1 mRNA levels. SAMe administration blocked induction of all five markers induced by FOLFOX administration and protected against FOLFOX-induced liver injury biochemically and histologically (Figure 1). Further, PAI-1 induction was present only in hepatocytes and sinusoidal endothelial cells with SAMe treatment inhibiting the induction. Lastly, FOLFOX treatment in PAI-1 deficient mice failed to induce either SOS or liver injury.
Conclusions: Conclusions: SAMe administration offers a protective role in FOLFOX induced SOS. Lack of PAI-1 appears to protect from FOLFOX-induced SOS. Further studies investigating the cell type of origin of PAI-1 associated with FOLFOX induced liver injury is warranted.