We read with interest the observations of Lentschener et al., who have attempted unsuccessfully to replicate our murine model of FOLFOX-induced sinusoidal obstruction syndrome (SOS) (Robinson et al, 2013a, 2013b). While the drug treatment regimen and experimental conditions used in these experiments were broadly similar to those used by us, we do note some key important differences.
During our initial attempts to develop a model of FOLFOX-induced SOS, we similarly found that animals maintained on standard chow diets did not develop the histological features of SOS – a finding described in our original description of this model (Robinson et al, 2013a). We observed that switching to a purified diet (D01060501, Research Diets Inc, New Brunswick, NJ, USA) but maintaining an otherwise identical experimental protocol did lead to the development of histological features of SOS. We have previously hypothesised (although not proven) that this may be attributable to the presence of phytoestrogens in standard animal diets, which have a protective effect on the development of liver injury (Ascencio et al, 2004; McCarty et al, 2009). While the diet utilised by Lentschener et al. does contain reduced phytoestrogens as compared with standard chow diets (Global Rodent diet-2016, Harlan Laboratories, Madison, NJ, USA), these are still present. Of course it may be that other constituents in the diet are having a role, but we have not explored this.
It would be also interesting to know which substrain of C57BL/6 mouse was utilised by Lentschener et al. In our experiments, we utilised the C57BL/6J substrain that differs from the C57BL/6N substrain by the deletion of exons 7–11 of the nicotinamide nucleotide transhydrogenase (Nnt) gene that has key roles in the mitochondrial response to oxidative stress (Mekada et al, 2009; Simon et al, 2013). As we have previously reported, oxidative stress appears to have a key role in the development of SOS, and therefore the choice of C57BL/6 substrain may be particularly important in this context, although we haven’t specifically explored this.
The final observation to make is that all drugs in our description of the model were obtained from Sigma-Aldrich (Dorset, UK), whereas those used by Lentschener et al, were from different sources. Whether these different preparations have the same pharmacological characteristics in vivo is not known.
While we do believe that FOLFOX-induced SOS can be modelled in mice, we acknowledge that the work of Lentschener et al, does highlight how subtle differences in the experimental protocol can have a significant impact on the reproducibility of this model.
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The authors declare no conflict of interest.
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Robinson, S., Mann, D., Manas, D. et al. Response to 'Comment on 'The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome'’. Br J Cancer 115, e8 (2016). https://doi.org/10.1038/bjc.2016.268
Journal of Clinical and Experimental Hepatology (2019)