Abstract
BackgroundIrinotecan use is limited due to severe toxicity. Preconditioning by fasting (PBF) protects against side effects of irinotecan while preserving its antitumor activity. The mechanisms underlying the effects of PBF still need to be elucidated. Here, we investigated the transcriptional responses of PBF on irinotecan in both tumor and healthy liver tissue.Experimental approachMale 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). Subsequently, both groups received one dose of irinotecan. Twelve hours after administration mice were sacrificed and blood, tumor and liver tissue were harvested. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses.Key resultsThe AL irinotecan group showed worsened organ function and decreased leukocyte numbers. These effects were abated in PBF animals. PBF led to an altered transcriptional response in the liver of irinotecan-treated mice, including decreased cellular injury and increased stress resistance. Hepatic metabolism of irinotecan was also significantly changed due to PBF. The transcriptional response of tumor tissue observed after PBF was hardly affected compared to AL fed animals.ConclusionsTranscriptional changes after PBF to irinotecan treatment showed an improved protective stress response in healthy liver but not in tumor tissue, including changes in irinotecan metabolism. These data help to unravel the mechanisms underlying the effects of fasting on irinotecan and help to improve outcome of chemotherapeutic treatment in cancer patients.
Highlights
Colorectal cancer (CRC) is the second most diagnosed cancer in women and the third most diagnosed in men
Male BALB/c mice with subcutaneous C26 colon carcinoma tumors were divided over a group fed ad libitum (AL) and a group with preconditioning by fasting (PBF) for three days, after which both groups received irinotecan intraperitoneally
Induction of toxicity by irinotecan and possible protective effects of Preconditioning by fasting (PBF) were determined via markers of general (LDH) and liver specific (ALT and aspartate transaminase (AST)) cellular injury, and kidney function
Summary
Colorectal cancer (CRC) is the second most diagnosed cancer in women and the third most diagnosed in men. Levels of the active metabolite of irinotecan, SN-38, were significantly lower in plasma and liver tissue from fasted mice, indicating that dietary preconditioning was able to reduce the systemic toxicity of SN-38 while the phenotypical 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]. Blood samples were analyzed to determine liver, kidney and bone marrow function, tissues were used for transcriptome analyses
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
