The pathogenesis of oxaliplatin induced sinusoidal obstruction syndrome

PhD ThesisOxaliplatin based chemotherapy has demonstrated remarkable efficacy in down staging colorectal liver metastases such that patients initially considered to have inoperable disease are able to undergo a potentially curative resection. In addition the use of neoadjuvant Oxaliplatin based chemotherapy has been shown to improve progression free survival following liver resection. Taken together this means that ever increasing numbers of patients are presenting for liver resection having received multiple cycles of chemotherapy. Whilst this approach has many advantages the use of pre-operative chemotherapy has been associated with the development of sinusoidal obstruction syndrome (SOS) in the liver parenchyma in up to 40% of patients. It is thought that the presence of SOS significantly increase the risks associated with major liver resection. More recent data also suggests that the presence of SOS within the liver may result in poorer disease specific outcomes in the long term and in particular a higher risk of early intra-hepatic recurrence. At present the pathogenesis of SOS in this context is not understood and no treatment exists to either prevent its development or reverse the histological changes in the liver associated with it. The aim of the current study was to develop a reproducible in vivo experimental model of Oxaliplatin induced SOS and to interrogate this to identify the pathophysiological mechanisms which underpin its development. With this knowledge it was hoped that potential therapeutic strategies could be suggested to ameliorate the development of SOS in patients treated with Oxaliplatin based chemotherapy. C57BL/6J mice treated with weekly intraperitoneal injections of Oxaliplatin and 5- FU/Leucovorin for 5 weeks develop histological changes of SOS when maintained on a iv purified, but not chow, diet. This is associated with increased expression of key matrix remodelling genes within the liver parenchyma such as MMP2, MMP9, TIMP1, TGFβ and Procollagen I. The development of these gene expression changes is accelerated in the presence of tumour within the liver perhaps as a consequence of increased production of inflammatory mediators such as CXCL1. The presence of SOS is associated with a dramatic increase in expression of the serine protease family member PAI-1 which is involved in a variety of processes including matrix remodelling, thrombus formation and cellular senescence. Immunohistochemistry revealed endothelial cells in areas of sinusoidal injury stained positive for the cell cycle inhibitor p21CIP1/WAF1 in keeping with senescence in these cells. This process was associated with depletion of hepatic glutathione and decreased expression of the antioxidant transcription factor NRF2 suggesting a role for oxidative stress in the pathogenesis of SOS. To explore this further the experiment was repeated but this time using dietary supplementation with either the thiol donor N-Acetylcysteine (NAC) or the NRF2 activator butyrated hydroxyanisole (BHA) alongside FOLFOX treatment. Whilst supplementation with NAC had no effect on the development of SOS its development was completely prevented by supplementation with BHA suggesting that NRF2 activating antioxidants may be a useful therapeutic strategy in preventing the development of SOS. In conclusion this study has described the first reproducible experimental model of Oxaliplatin induced SOS which accurately reflects the pathogenesis of the disease in humans. Through interrogation of this it has been possible to identify therapeutic strategies which may be of value in preventing the development of SOS in patients with colorectal liver metastases.a Spire surgical research fellowship in year 1 and by a Wellcome Trust clinical research training fellowship (WT090974MA) in years 2&3