Franny Jongbloed

13 1 GENERAL INTRODUCTION & AIMS AND OUTLINE OF THIS THESIS compared to ad libitum fed mice, while pro-inflammatory markers, including interleukin-6, were significantly reduced after induction of renal IRI 1 . These beneficial effects were reproduced in models of hepatic, cardiac, and cerebral IRI, showing that the effects of DR are not organ specific and might be applicable in multiple settings of acute stress 24-26 . It did not take long before other research fields tried to exploit the beneficial effects of short-term DR, and started to apply it on different models of acute stress. One of these is chemotherapy , one of the treatments against cancer. Irinotecan, a chemotherapeutic agent used in the treatment of colorectal carcinoma, is known to induce severe and unpredictable side effects including myelosuppression, diarrhea, and in some cases even death as a complication of side effects, thereby severely reducing the applicability of the drug 27 . Recently, it was shown that 3-day fasting prior to the administration of a high dose of irinotecan significantly prevented the occurrence of side effects in mice 28 . Furthermore, tumor growth was reduced equally in ad libitum fed and fasted animals, indicating that the antitumor effect of the drug was unimpaired by the dietary preconditioning 29 . The mechanisms underlying the beneficial effects of DR on chemotherapy have not yet been unraveled either, and further studies were more than warranted in order to understand the molecular mechanisms by which DR exerts its beneficial effects. Discovering these mechanisms may lead to regimens that are easier to apply in a clinical setting as well as the development of a dietary mimetic. Despite the impressive body of evidence on the positive effects of DR, a high level of skepticism was present among clinicians about the clinical translation of DR to surgical patients 30 . Not only would it be difficult for patients to voluntarily restrict themselves in their calorie intake, restricting food intake prior to surgery goes against the generally held beliefs that patients should be well fed before surgery to prevent malnutrition 3 . Even more so, since mice and men cannot be compared one to one, the ideal diet composition and duration needed for inducing similar effects in humans is not yet known 31 . In a pilot study in living kidney donors, Van Ginhoven et al. showed as one of the first that three days of 30% DR followed by 24 hours of fasting prior to kidney donation was feasible and safe, and that kidney donors were highly motivated and open to participate in such a study 32 . Unfortunately, the diet had only marginal beneficial effects on surgical outcome. Although serum insulin levels were significantly reduced by the diet compared to the control group, it was uncertain whether this was the result of the 4-day dietary intervention or the 24 hours of fasting only 33 . Therefore, no clear set of objective markers for compliance to the diet was present up-to-date.