Franny Jongbloed

52 CHAPTER 3 ABSTRACT Irinotecan use is limited due to severe toxicity. Fasting protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of fasting still need to be elucidated. Here, we investigated the transcriptional responses to fasting and irinotecan in both tumor and healthy liver tissue. Male BALB/c mice were subcutaneously injected with C26 colon carcinoma cells. Twelve days after tumor inoculation, two groups were fasted for three days and two groups were allowed food ad libitum (AL). Within each diet group, one group received irinotecan intraperitoneally, the other vehicle. Twelve hours after injection mice were sacrificed, and blood, tumor and liver tissue were harvested. Blood samples were analyzed for side effects, tissues were used for microarray analyses. The AL irinotecan group had worsened organ function and leukocyte numbers. These effects were abated in fasted animals. A dampened transcriptional response to irinotecan was observed in liver of fasted compared to AL fed mice, including a decreased inflammatory and increased stress resistance response. Tumor tissue did not show a homogeneous response amongst groups. The transcriptional response after fasting as seen in liver was absent in tumor tissue. Fasting reduces toxicity of irinotecan by inducing a protective stress response in healthy liver but not in tumor tissue. These data further help to unravel the mechanisms involved in the effects of fasting on chemotherapeutic side effects and preservation of antitumor activity, and pave the way to improve outcome of chemotherapeutic treatment in cancer patients.