Franny Jongbloed

53 3 PROTECTION OF FASTING ON IRINOTECAN TOXICITY INTRODUCTION Colorectal cancer (CRC) is the second most diagnosed cancer in women and the third most diagnosed in men. Estimated new colorectal cancer cases account for 1.4 million cases and 693,900 deaths worldwide occurring in 2012 1 . At initial presentation, 15-20% of patients already has liver metastases and another 45% is diagnosed with liver metastases in the follow-up after resection of the primary tumor 2 . Irinotecan is a pro-drug of the topoisomerase-I inhibitor SN-38, and is applied in first and second line chemotherapy treatment for colorectal carcinoma 3,4 . Irinotecan can induce severe and unpredictable side effects including myelosuppression, diarrhea, and in some cases even death as a complication of side effects 5 . Dietary restriction (DR) is a method to trigger highly conserved survival mechanisms that enhance the resistance of organisms against stressors and diseases 6 . We recently showed that 3-day fasting prior to a toxic dose of irinotecan significantly prevented the occurrence of side effects in Apc -mutant mice 7 . Furthermore, tumor size and proliferation were reduced equally in ad libitum (AL) fed and fasted animals. Levels of the active metabolite of irinotecan, SN-38, were significantly lower in plasma and liver tissue from fasted mice, indicating that dietary precondition was able to reduce the systemic toxicity of SN-38 while the phenotypic effect on tumor tissue remained unaltered 7,8 . These data support the concept of differential stress resistance (DSS), which states that tumor cells are unable to elicit a protective response since they remain driven towards growth due to mutations in onco- and tumor suppressor genes 8,9 . However, the molecular mechanisms that govern these processes remain largely unknown. Insight into these mechanisms could facilitate translational research into the clinic since it may reveal alternative approaches to DR such as specialized forms of DR or DR mimetics which may induce similar effects without the disadvantages of fasting, including additional body weight loss in cancer patients. Therefore, in this study we investigated the transcriptional responses to fasting and irinotecan exposure in tumor and in healthy liver tissue. RESULTS Fasting induces a chemoprotective phenotype in the liver Male BALB/c mice with subcutaneously injected C26 colon carcinoma tumors were divided in two groups of six mice each. One group was housed under AL food conditions, while the other group was fasted for three days prior to irinotecan administration. After