Franny Jongbloed

63 3 PROTECTION OF FASTING ON IRINOTECAN TOXICITY Next, we compared the pathways of liver and tumor tissue of both the AL and fasting groups. The AL groups only had one inhibited pathway in common, involved in neurotransmitter signaling ( i.e. Huntington’s Disease Signaling ). In the fasting groups, three pathways downregulated in the liver appeared to be significantly upregulated in the tumor fasting groups: Colorectal Cancer Metastasis Signaling , Aryl Hydrocarbon Receptor Signaling and Huntington’s Disease Signaling . Of all 72 pathways regulated in tumor tissue of fasted animals, 17/39 (43%) of the pathways in liver tissue of fasting pathways were oppositely regulated. Examining genes specifically of interest in tumor tissue, three genes came forward. Heat shock protein 90 ( Hsp90 ) is prominently expressed in tumor cells and may play a pivotal role in tumor growth 11 . Hsp90 was found to be activated in the tumor AL irinotecan group, whereas the activation in the fasted irinotecan treated tumors was decreased. Two damage response genes either upstream or downstream of P53, Mdm2 and Ccng1 , were also activated in both AL and fasting irinotecan groups. Mdm2 appeared downregulated in the fasting vehicle group, while an activation of Ccng1 in this group could be detected. Irinotecan metabolism related gene expression profiles in liver and tumor tissue We have previously shown that both irinotecan and its active metabolite SN-38 levels are lower in the livers of fasted mice, while plasma levels of irinotecan showed a trend towards higher values compared to AL fed mice 10 . Here, we examined expression of genes involved in the metabolism and transportation of irinotecan (Figures 4, S2).